INSULIN THERAPY Dr. S.M.Sadikot. Hon.

Endocrinologist, Jaslok Hospital and Research Centre, Mumbai 400026 11th January 1922 is a red letter day in the history of diabetes. Culminating a summer of hard work, epoch making experiments, many failures and finally, what could be "success", Frederick Banting and Charles Best were convinced that they had isolated insulin. Now it had to be proved that what they had isolated would work in humans. Leonard Thomson, was a 14 year old boy with insulin dependent diabetes. On 11th January 1922, the first injection of insulin, as prepared by the two doctors, was given to Leonard. Subsequently, other patients too were injected with insulin by Banting and Best. It would be worth while to quote the results in their own words. Writing in the Canadian Medical Association Journal, Banting summarised his findings as follows: "Following the production of what appears to be a concentrated internal secretion of the pancreas and the demonstration of its physiological activity in animals, and under careful control, its relatively low toxicity, we are presenting a preliminary report on the pharmacological activity of this extract in human diabetes mellitus. Clinical observation at this juncture would appear to justify the following conclusions: (1) Blood sugar can be markedly reduced even to normal values. (2) Glycosuria can be abolished. (3) The ace- tone bodies can be made to disappear from the urine. (4) The respiratory quotient shows evidence of increased utilisation of carbohydrates. (5) A definite improvement is observed in the general condition of these patients and in addition the patient themselves report a subjective sense of well-being and increased vigor for a period following the administration of these preparations". Euphoria accompanied the availability of insulin. It was hoped that we would be able to prevent the acute and also the chronic long-term complications of diabetes. To a certain extent, the hopes have proved true. There is no doubt that insulin therapy has allowed a number of people with diabetes to live a much longer and better life than it would otherwise have been possible. In 1982, a banquet was held in New York attended largely by insulin dependent diabetics. The Chief Guest, one of the first individuals who had received insulin from the hands of Banting himself put matters in the right perspective, " If today, this hall resounds to the vibrant voices of living beings, and not to the ghoulish wailings of our ghosts, it is entirely due to the great courage and spirit of two radicals who had the confidence, some would call it obstinacy, to believe in themselves, even in the face of adversity. If the world does make progress, it is due to such free thinkers, rather than those who would rather follow the straight, safe and well trodden path." At the same time, we must accept that the initial euphoria that "diabetes had been defeated" was, and is, misplaced. Whilst it has been possible to prevent, or adequately manage acute complications of diabetes like ketoacidosis, we have failed to prevent or treat some of the long term complications of diabetes. Whilst it would be nave to feel that the longterm complications of diabetes are so simple that they would have a single etiology, there is enough evidence to show that good control of diabetes can prevent, to a large extent, and definitely alleviate most of these dreaded complications affecting the eye, kidneys, nerves etc. Then why is that in spite of having insulin in our therapeutic armamentarium, we are unable to offer optimal control and thereby prevent these very complications? Could it be that we have been unable to optimise the use of insulin thus far? The most important stumbling block to the optimal use of insulin seems to be the inablity to define and understand the precise role that insulin therapy should play in our management of diabetes. Very often, patients who should preferably be on insulin are treated with massive doses of oral agents without effective control of the blood glucose levels, whilst many obese Type 2 patients, who have a fair amount of endogenous insulin, and should be managed with diet and exercise are administered excessive doses of insulin in an attempt to bring about control. I think that it is this "abuse" of insulin with all its attendant problems that prevents us from offering our diabetics the best possible "use" of insulin therapy and as a consequence, optimal management of their diabetes. So which patients should receive insulin therapy? Patients Who Should Receive Insulin Therapy 1 ) It is obvious that insulin therapy is mandatory for all Type 1 patients;

2) Any diabetic with significant chronic complications like coronary artery disease, cerebrovascular disease, peripheral artery disease, neuropathy, retinopathy, nephropathy etc. should receive insulin; 3) Any diabetic with an acute problem like severe infections, injuries etc., should be given insulin; 4) All diabetics with tuberculosis should always be given insulin; 5) Most diabetics undergoing surgery may need to be stabilised on insulin; 6) Pregnant diabetics, if not tightly controlled with diet and exercise should be given insulin to ensure tight control; 7) Any patient, even if well controlled on oral agents, who shows even the slightest evidence that may contraindicate the use of oral agents. For example, a liver disorder should entail stopping of the tablet and the patient should be shifted over to insulin; 8) All underweight patients and those with malnutrition related diabetes should be given a high calorie diabetic diet and covered with insulin; 9) Patients with INSULIN-REQUIRING diabetes, even though they are not prone to ketosis, should be identified and their management supplemented with insulin to get the best possible control; I really feel that once a decision is made that a person would do better with insulin therapy, it becomes essential for the doctor to be able to convince the patient that insulin injections are the best for the patient. No compromise should be entertained about administering it. It is true that many of our patients have a great aversion to taking insulin and overcoming this resistance is quite a difficult problem. Unfortunately, many doctors give in to this resistance. Although, they may offer many excuses for this, I am quite skeptical of most of these. I feel that the real reason is that they are afraid of losing the patient to some other doctor who will give the patient oral tablets. I think that this attitude is indefensible. If the patient needs insulin, then there is no compromise in so far as the doctor is concerned. Having treated quite a few patients with diabetes, a substantial number of whom are on insulin, I feel that the major contributing factor to the initial patient resistance is the totally false and anecdotal concepts that they have about the problems and dangers associated with insulin therapy. Simple explainations to clear these misconceptions, accompanied with a certain amount of firmness and occasionally a threat about the potential loss of eye, limb and/or life, is often sufficient to overcome the initial patient resistance, Later, once patients are well stabilised on insulin, they feel so much better that they often opt to continue the insulin therapy. A few patients benefit by being hospitalised,. especially in a diabetic unit. Seeing other patients receive, or take their own, injections of insulin, somehow seems to make the concept of taking insulin injections much more acceptable. In these diabetic units, they also see patients with foot problems which may have needed amputation, patients with vision loss etc., and this too helps in their resolve to take insulin. I have known many "adamant" patients accept insulin injections after a short period of hospitalisation. At the same time, it is essential to add a word of caution. It is widely felt that high insulin levels in the blood may be an important factor in causing associated problems such as obesity, hypertension, lipid disorders and atherosclerosis (Syndrome X). Thus, one should guard against a misplaced enthusiasm to use insulin in all Type 2 patients unless they fall into one of the categories listed above. As we have discussed in the section dealing with oral agents, the hyperglycemia in many Type 2 patients is mainly due to peripheral resistance to the action of insulin. In such patients the optimal treatment would be to use drugs insulin " sensitisers" such as glitazones and/or metformin. Even in those who also have a decreased secretion of insulin from their beta cells, it may be worth while to see if the use of small doses of insulin "secretagogues" would optimize the control. It is only when a rational use of oral agents fails to provide the desired levels of control that one would add insulin to the therapy under normal circumstances. There should be NO misplaced enthusiasm to use insulin in all diabetic patients. Of course, the pendulum should not completely swing the other way. Those who need insulin MUST be given it! After deciding that a patient will need to take insulin, the next step is to decide which insulin one will use.

Such a great plethora of insulins are available for clinical use that there is often some confusion about which insulin to use. In this context, it is interesting to note that even 10 years back more than 43 different varieties of insulin were available in the U.S.A. and that these were made by just 3 companies! But the picture much more clear, if one realizes that when choosing the insulin, there are two major areas. The first, which in my opinion is relatively minor, is the species of insulin one will use. The more crucial area is the "time of activity" characteristics of the insulin. Species of Insulin It is really unfortunate that there has been so much controversy generated regarding the species of insulin to be used. I think that this is a relatively minor matter, and the time, money and effort spent in generating this controversy could easily have been put to better use. The insulins available for routine clinical use are the beef, porcine and human insulins. Basically this means that the beef or Bovine insulins are got from beef pancreas, the porcine insulin is got from pig pancreas whilst the "human" insulin is manufactured through genetic engineering. Today, all insulins available are of the pure variety and the contamination is not an issue. Beef insulins differ from human insulin in three amino acids, whilst porcine insulin differs from human insulin in only one amino acid. Thus, porcine amino acids are less immunogenic than beef insulins. At the same time, it must be mentioned that this does not significantly affect the efficacy of the bovine or porcine insulins in most patients. Human insulins are replacing the other insulins in most developed countries, but its cost is the inhibiting factor to its widespread acceptability in most developing countries. I personally feel that the decision about the species of insulin to be used should be a matter best left to the patients and their doctors. At the same time, many experts feel that that there are certain circumstances where it may be better to use the "human" variety of insulins. Patients who should preferably use human insulins are: a) All patients who are on beef or porcine insulins and manifest resistance due to the presence of antibodies; b) Patients requiring intermittent therapy, i.e. patients with gestational diabetes, those undergoing major surgery, patients with acute infections, etc., who otherwise may be controlled on diet, with or with out OHA's, should use human insulins. c) Patients who require very large doses of beef or porcine insulins (>80 units/day), may benefit with change over to human insulins.

Time-Activity Characteristics This is an area of major importance and a thorough understanding of the time of activity character of the insulin which is to be used is essential for the correct initiation and more importantly, of the adjustment of the insulin doses. What does one mean by time-activity characteristics. In simple terms it implies knowledge about when, after being injected, a particular insulin would start showing its action, the time when peak activity would be seen and also the time when the activity of the insulin would cease. In India, presently, the following insulins are available:

Rapid acting

This is seen in "special" types of insulin which are called insulin analogs. Human insulin has been further modified to alter the time of its activity. Presently only Lyspro is available in India, although insulin aspart should soon be available for clinical use. Short acting;

Short-acting (regular) insulin usually reaches the blood within 30 minutes after injection. It peaks 2 to 4 hours later and stays in the blood for about 4 to 8 hours. Intermediate acting;

Intermediate-acting (NPH and lente) insulins reach the blood 2 to 6 hours after injection. They peak 4 to 14 hours later and stay in the blood for about 14 to 20 hours. Intermediate-acting insulins include lente and NPH. Insulin preparations with a predetermined proportion of NPH mixed with regular, such as 70% NPH to 30% regular, or a 50/50 mix are called intermediate acting for purposes of classification, although their activity characteristics would be different from either only NPH/Lente or only Regular insulins.

Long acting;

Long-acting (ultralente) insulin takes 6 to 14 hours to start working. It has no peak or a very small peak 10 to 16 hours after injection. It stays in the blood between 20 and 24 hours. This can be seen at a glance in the following chart This can be seen at a glance in the following chart Insulin Lyspro Insulin- aspart Regular NPH Lente Ultralente Insulin Glargine Begins Working 15-20 minutes 15-20 minutes 30-60 minutes 2-4 hours 3-4 hours 4-6 hours 2-3 hours Peaks At 30-90 min 40-50 min 80-120 min 6-10 hours 6-12 hours 10-16 hours almost no peak Ends Working 3-4 hours 3-4 hours 4-6 hours 14-16 hours 16-18 hours 18-20 hours 18-26 hours Lows Occur At 2 to 4 hr 2 to 4 hr 3 to 7 hr 6 to 12 hr 7 to 14 hr 12 to 24 hr 4 to 24 hr

However, each person responds to insulin in his or her own way. That is why onset, peak time, and duration are given as ranges. Fortunately, the picture becomes much more clear, if it is realised that from a practical and clinical viewpoint, insulins can be divided into two main groups, depending on their time course of action. These are the "shortacting (SAI)" and the "intermediate acting (IAI)" insulins. Within these two main groups, the insulins may differ in their source of origin and other details, but for all practical purposes, they are similar in their mode and duration of action. The rapid acting insulin analogues are very useful for use in special circumstances and whilst they can be used in place of the SAI's, this has not yet become standard practice. Longer acting insulins like Ultralente are very rarely used in India.

Traditionally, one starts with a dose of an intermediate acting insulin (IAI) given before breakfast; I am often asked whether there is any formula whereby one could calculate the dose that should be given. Let me make it quite clear at the outset that there is no such magic formula! When I was an undergraduate in medical college, I was taught that one should start with a dose of intermediate acting insulin which was one tenth the level of the fasting blood glucose. In other words, if the FBG was 250 mg%, then one should give 25 units of the IAI. This just does not work and frankly could lead to quite serious problems for reasons which I shall discuss below. So, how much insulin should be given? I usually start with a small dose of IAI, unless there are adequate reasons for lowering the blood glucose levels very rapidly. In practice, this words out to an initial dose of an IAI of about 8-12 units. There are many valid reasons for starting with this small dose. There is no method by which we can judge the sensitivity of the patient to insulin. Although it has been said that the thin patients are more sensitive to insulin than normal weight or overweight patients, this is just a generalisation. There is a great amount of difference in the sensitivity to insulin. Even patients with the same weight and similar blood glucose levels would tend to differ in the response that they show to a certain dose of insulin. As we are dealing with patients and not generalities, it would be prudent to start with a small initial dose, judge the response in the patient and adjust the dose accordingly. This will allow the patients to escape from the hazards of hypoglycemia especially if the patient turns out to be very sensitive to insulin injections and a large dose of insulin has been given. In fact, one of the commonest emergencies many of us are called to treat are patients who have gone into severe hypoglycemia when they have been given large doses of insulin due to the fact that the fasting blood glucose levels were very high ! I have discussed how patients may differ in their individual characteristic with regards to the time course of action of the insulin. There may be "early", normal or "late" activators. It is not possible to forecast how a patient would react. A high initial dose may cause the patient to have hypoglycemic reactions at odd hours, which would be quite problematic. A small initial dose would not only protect the patient from these vagaries, but also allow us to judge the type of activator that the patient is. To sum up, I would once again like to emphasise that the dose of insulin is determined empirically and that it is always better to start with a small dose and adjust according to the response, unless there are relevant reasons for the rapid lowering of the raised blood glucose levels. After I start the patient on 8-12 units of IAI, given before breakfast at about 8 a.m., I ask the patient to do home blood glucose monitoring. In the absence of home blood glucose monitoring, I ask the patient to estimate his blood glucose levels every 3-4 days and adjust the doses according to these reports. Many patients do not like testing their blood every 3-4 days. It is worthwhile to explain to them that this is required only till the blood glucose levels are normalised. This small explaination makes the patient much more willing to accept intensive testing of blood in the initial stages until his blood glucose have stabilised to acceptable levels. Of course, IDDM patients, pregnant women etc., may have to continue to keep a close and frequent check in order to maintain good control. Before we discuss the adjustments in the treatment, it would be worthwhile to be very clear in our minds about the aims of the treatment. We would like the patient to have "acceptable" blood glucose levels throughout the 24 hours of the day. This means that the fasting blood glucose levels, the premeal and the postmeal blood glucose levels as also the levels in the interim period should all be stabilised at these acceptable values. It goes without saying that this should not be accompanied by frequent and/or severe episodes of hypoglycemia. Once, this aim of the treatment is clear, the adjustments in the doses of insulin will be much easier to understand. I review the patient every week until the patient is stabilized on the insulin therapy if I am seeing the patient in the clinic situation. I do not feel that any person with diabetes, unless he has some complication, should be admitted into hospital just for controlling his diabetes. Even if a patient is admitted, I do not think that the insulin doses should be changed more frequently than every 2 days.

Let us now discuss the various types of response that we would tend to see to the initial dose and our management of these responses. SCENARIO 1 A few of the patients would show during the followup that their fasting and postmeal blood glucose levels are within normal, acceptable limits. This means that the patient is controlled and the dose of insulin should be continued. I try and decrease the dose by about 2 units and see whether the control is still acceptable. If this is so, then I continue to gradually decrease the dose of the IAI (about 2 units at a time) until I find that the blood glucose values are higher than acceptable. The dose is then increased by about 2 units and the patient called back after 15 days to see about his control. If he continues to remain in control, then he is called for a routine followup after 6-8 weeks. I would like to make it clear that this scenario is rarely seen. SCENARIO 2 The more usual response is that both, the fasting and the post lunch blood glucose levels continue to remain high and that the urine, if tested, shows glucosuria throughout the day. In such cases, the dose of the IAI is gradually increased (again by about 2-4 units at a time) and the patient examined every week. This would be repeated until either, the patient shows adequate control with the fasting and the post meal blood glucose levels within acceptable limits and no glucosuria throughout most of the day, or one of the following scenarios would occur. SCENARIO 3 Whilst, the fasting blood values would be within acceptable limits, the post lunch blood glucose values would be higher than normal. This is often accompanied by high post breakfast blood glucose values, whilst the evening or the pre-dinner values are acceptable. This is quite commonly seen. The action of the IAI normally, starts after 3-4 hours, peaks about 8-12 hours and lasts for 18-24 hours. Therefore, if the injection of the IAI is taken before breakfast, say around 8-8.30 a.m., then the peak activity would occur in the evening or around the pre-dinner time. This peak activity could cause the blood glucose values at this time to be acceptable. As the activity of the IAI is supposed to start after 3-4 hours and then gradually increase, it may not show sufficient activity to cover the post breakfast and the post lunch levels which would occur within 1-2 hours and 5-6 hours after the injection when the activity of the IAI would just be gradually starting. If we were to increase the dose of the IAI, so that it would show stronger activity after 5-6 hours and may help in correcting the raised post lunch blood glucose levels, but then it is quite possible that at the time of its peak activity, the action of the IAI would be strong enough to cause hypoglycemia which would be manifest in the evening or just before dinner. "Late" activators could go into hypoglycemia later in the night, possibly in sleep. Therefore, it may not be possible to increase the dose of the IAI in order to control the post lunch blood glucose values, without exposing the patient to hypoglycemia later. The answer to this problem is to add a small amount of short acting insulin (SAI) along with the dose of the IAI, in the morning injection. The rational for this is that the SAI would help in controlling the post lunch values! At first sight, this may appear doubtful. The action of SAI starts within about 30 minutes of the injection, peaks around 1-2 hours and lasts for 4-6 hours. How could the addition of SAI under these circumstances, given before breakfast help to control the post lunch values? Clinically, this works! It could help through various mechanisms. It could act on the glucose levels in the post breakfast period and lower them so that the pre-lunch blood glucose values would be lower than before. This would lead to a lowering of the post lunch blood glucose values. As an example, let us suppose that with the prescribed diet, the rise in the level of the blood glucose after lunch would be in the vicinity of 80mg%. If with only IAI, the pre-lunch blood glucose values would be 150%, then the values seen after lunch would be 230mg%. But, if the addition of SAI causes the pre-lunch blood glucose levels to be about 100mg% (this would be possible due to the fact that the early activity of the SAI would tend to lower the blood glucose values seen after breakfast and also before lunch), then the addition on the lunch increase of 80mg% would cause the post lunch blood glucose levels to be about 180mg%. This would be a definite improvement over 230mg%!

More importantly, when the patient takes SAI regularly for a while, the time characteristics of its activity change somewhat. It has been shown that activity of the SAI starts slightly later, peaks later and also lasts longer. Therefore, activity of the SAI would still be present to a significant extent after lunch, even if the injection is taken before breakfast. It should be remembered that in India, breakfast is usually taken at about 8-8.30 a.m., whilst lunch is at about 1 p.m. Therefore, even with a time action lasting 6 hours some of the effect of the pre-breakfast SAI would be seen in the post lunch period, With the prolongation of the time of activity of the SAI with prolonged use, this effect would be all the more significant! Before adding the short acting insulin (SAI) to the morning injection of the intermediate acting insulin (IAI), I check the blood glucose levels of' the patient in the evening and also just before dinner, i.e. between 4-8 p.m. If these levels are seen to be in the "well-controlled" range; then I slightly decrease the dose of the IAI whilst adding the SAI. This precaution is necessary to protect the patient from the hazards of hypoglycemia occurring at these times. If this is not done, the decrease in the afternoon blood glucose levels, and consequently the evening blood glucose levels, brought about by the SAI, added to the low in the blood glucose levels brought about by the peak activity of the morning IAI would make the patient prone to episodes of hypoglycemia. Often, this judicious use of an SAI along with the IAI brings about adequate control in a number of patients, with acceptable fasting and post prandial blood glucose levels and the absence of glucosuria (in a patient with a normal renal threshold for glucose). SCENARIO 4 A situation which is less frequently seen than the one described above, is one where the morning, post lunch, and even the evening and pre-inner blood glucose levels are within acceptable limits. But, the fasting blood glucose levels are consistently above normal and acceptable values. We have seen that the action of the IAI lasts for around 24 hours and therefore an increase in the dose of the IAI could help, in theory, to control the raised fasting glucose levels. But, this would in clinical practice, lead to unwanted hypoglycemia during the day, as we have seen that in this case, except for the fasting values, the blood glucose levels are well controlled during the day. Therefore, if one is sure that one is not dealing with the Somogyi phenomenon or the Dawn phenomenon, then the treatment strategy would be to add a small dose of IAI to be taken by the patient before dinner, or at bedtime. This is basically putting the patient on a type of Multiple Dose Regimen (MDR). This strategy would help in normalising the raised fasting levels. The peak activity of the IAI is normally seen after 8-12 hours. As dinner is usually taken around 8-8.30 p.m. the peak activity of this would be seen the next morning in time to help in normalising the fasting levels. Early activators who show a peak activity after 6-8 hours would be able to take the injection around bedtime such that the peak activity would occur in the early morning hours (and help normalise the raised fasting blood glucose levels) rather than in the middle of the night. When adding an evening dose of IAI, I decrease the morning dose of the IAI injection. This would protect the patient from hypoglycemia. We have seen that the morning dose of the insulin is sufficient to control the blood glucose throughout the day, but the waning of its overnight activity allows the blood glucose to rise to high fasting level. We have also seen that adding more insulin would further depress the blood glucose levels and therefore, we cannot increase the morning dose of insulin. But, when the evening dose of insulin is given, it must not be forgotten that some of its activity will be present for 24 hours and would add to the insulin effect even during the day. As the blood glucose levels are already well controlled, this further insulin effect would tend to bring the blood glucose down further and possible depress them to hypoglycemic levels! Therefore, even though the dose of the morning injection is reduced the additive activity of both the morning and evening insulin injections would bring about adequate control during the day and the night. SCENARIO 5 This scenario is quite the same as that seen in scenario 4. Here, the addition of the evening dose of IAI helps in normalising the fasting blood glucose levels, But, in this case, the post dinner blood glucose levels tend to be higher than acceptable. The

treatment strategy here is to add a small dose of SAI to be taken before dinner. This would help in keeping the post dinner blood glucose levels down, whilst the two injections of IAI (taken at morning and evening) would, both, keep the blood glucose levels in the well-controlled range throughout the rest of the 24 hour period. Although, I have divided the response of the patient into these 5 distinct scenarios and have discussed the treatment strategies for each, it should be clear that one would rarely see such clearly demarcated responses. What we see in practice is often a permutation and combination of the scenarios that we have discussed. Obviously, the treatment strategies would also need to be adjusted to meet these variations, But from the basic principles of dose adjustment seen in the 5 scenarios and an understanding of the time course of activity of the two groups of insulin, it should be quite easy to evolve a specific strategy to combat most of the various responses that patients would tend to show to the initial dose of the intermediate acting insulin. It is fortunate that the vast majority of the patients that we see in clinical practice have a significant amount of endogenous insulin secretion and are therefore much more easier to manage with these conventional methods of giving insulin. One modification, or "short-cut" of this conventional method which I have found to be quite useful in clinical practice is to start with a small mixture of the short acting and the intermediate acting insulin given before breakfast. The response to this is judged after 3-4 days. Depending on this, the dose is adjusted and the patient retested after a few days. When a stage is reached that the patient is receiving about 25-30 units of insulin in the morning injection, I do not increase the dose any further, I examine the patient for the presence of any conditions which may be hampering the blood glucose control. Some of the common conditions which reduce the insulin action include, infections, obesity, insulin receptor and post-receptor defects, ketosis, destruction of insulin at the site of injection, true immune mediated resistance, hormonal conditions associated with excess of cortisol, Growth hormone and thyrotoxicosis, associated use of drugs which increase glucose intolerance. If present, this is obviously treated. In the absence of any such associated condition, I add a small dose of an insulin sensitiser such as a glitazone or metformin. If the postprandial blood glucose levels are in the very high range, acarbose would be an helpful addition. I usually would not add a sulfonylurea to the insulin, as these, especially the older ones, basically try and increase the endogenous insulin secretion. This is not too important once we are injecting insulin! It is often seen that the addition of this small dose of oral agent tends to bring about quite an acceptable control! I am often asked why I stop increasing the dose after about 25-30 units and add an oral agent in a patient with Type 2 diabetes. This is absolutely empirical and based on the fact that the amount of insulin secreted by a normal person during the day is about 35-40 units. I also feel that when a dose of insulin taken as on injection reaches these levels, further increases rarely help, but the patient may benefit from splitting the dose into two smaller injections taken before breakfast and before dinner. Many patients would be extremely reluctant to take the second shot of insulin and in quite a few of these, the addition of small dose of an oral agent to the morning injection of insulin does bring about control. It goes without saying that IDDM patients and pregnant women who need insulin are not given the oral agents but they may need to split the injection or even go in for MDR.

Multiple Dose Regimens (MDRs) Multiple dose regimens are not very commonly required for the routine management of most Type 2 patients, but may be important in special cases. Most Type 2 patinets who require insulin for optimal management do well with judicious use of combination therapy (insulin with OHA). Regimens 1)Twice daily mixture of short, acting and intermediate acting insulins; one given before breakfast and the other before dinner. Once the daily dose at a single injection reaches around 30 units, it would be preferable to divide the insulin requirements into twice daily injections. This is the most commonly used MDR regimen. 2) The same as above, but with the addition of a short acting insulin injection given before lunch.

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3) Injections of short acting insulin given before breakfast and before lunch and a mixture of short acting and intermediate acting insulin given before dinner. SOME PRACTICAL ASPECTS IN INSULIN THERAPY STORAGE One of the commonest problem that patients seem to have is about the storage of insulin that they are using. Many of them are under the impression that a refrigerator is essential for storing the insulin vial and since, many do not have a "fridge", they worry that the insulin will spoil and not be effective. It should be made clear that refrigeration is not needed for storing the insulin vial that is in current use. Regular (plain) insulins are stable at room temperatures of about 750F for many months. This is true also of the longer acting insulins. In fact, the newer insulins that are being increasingly used these days are even more stable than the older insulins. This is due to the fact that the newer insulins have a neutral pH whilst the older ones have a slightly acidic pH. Occasionally, when the longer acting insulins are kept at room temperatures consistently above 100 F, they tend to form clumps, whilst this does not cause a significant loss of potency, it may be difficult to withdraw the insulin through the needle and the vial may have to be discarded. With the wide availability of insulin all over, the need to store large quantities of insulin by patients is no longer necessary. I usually advise the patients that they only keep one extra vial for use in an emergency like the currently used vial breaking accidently. If for any reason vials of insulin have to be stocked for many months they may be stored at 40 F in refrigerator, especially in those places where the room temperature would be high for many months in a year. The vials should NEVER be kept in the deep freeze or the freezer section of the refrigerator. In fact, any insulin vial that has been kept in this freezer section should be thrown away. This point is, unfortunately, not too well known and many patients do tend to stock the insulin vials in the deep freeze or the freezer section under the mis- taken notion that this would ensure that the insulin would keep better. In fact, I have noticed many chemists keep their stock of insulin in the deep freeze and only remove the number of vials which they feel they would sell during the day, and then store these in the non-freezer section of the refrigerator. If refrigeration facilities are unavailable, then the currently used vial can be stored at room temperature away from heat and direct sunlight. If vials have to be stored for longer periods, a simple method is or the unopened vials to be stored in the earthen pots which contain drinking water and are found in most homes where a refrigerator is not present. The very fact that insulin can be kept at room temperature without loss of potency for many months, makes it easy to carry along when travelling. There is no need to carry the insulin packed with ice in a thermos or carry along any other cooling apparatus like thermocole, etc. The insulin vial and the acces- sories can be carried in the travelling bag. I usually suggest to the patient that he carry the vial that is currently being used in the bag that he will take with him personally rather than keeping it in the bag that would be put in the baggage compartment of the train or be checked in at the airport. This is due to fact that I am not convinced that the patient and his baggage would arrive at the same place and at the same time! I also advise patients that they should always carry extra insulin vials and syringes etc., to face emergencies like a stay of longer duration than expected, breakages, loss and other similar problems, especially if they are travelling to places where replacements may not be easily available. STERILISATION More and more patients are now using disposable syringes and needles. When these are used, the problems of sterilisation do not arise. They are used once and then thrown away. New syringes and needles are used for the next injection. An added advantage is that due to the use of the new needles, these are always very sharp and thus easier and less painful during an injection. But the major drawback against the use of these disposable materials is the cost and many of the patients do find the cost prohibitive in the long run. In order to circumvent this, it is now accepted that the "disposable" syringe and needle can be reused by the same person. After the injection is taken, the syringe and the needle is carefully placed back in the plastic cover in which they have been sold. They are taken out again, used and then replaced. How many times can the syringe and needle be reused. I usually tell the patient to use them till the patient feels that the needle has become blunt and needs more pressure to go in. This usually works out to 5-6 injections before

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bringing out a new syringe. Many patients still use glass syringes and reusable needles. They know that the best way to sterilise them is to boil the syringes and the needles everytime before use. Unfortunately, many of the patients find this time consuming and inconvenient. Whilst, I would prefer that the patients do boil the materials everytime before use, a compromise that does work is for the patients to boil the syringes and needles and then place them in alcohol. This should, preferably, be isoproplyl alcohol but in its absence, 70% alcohol should do as well. The syringe and the needle should be put back in the alcohol after use. When they are reused without re-boiling, it is essential that all traces of alcohol be removed before filling in the insulin again. This can be done by pushing the plunger in and out several times and exposing the material to the air so that all the alcohol may be removed or would evaporate. Unless this is carefully done, the remaining alcohol may interfere with the insulin that is drawn into the syringes. Some authorities feel that if the syringes and the needles are stored thus in alcohol, it may be sufficient to boil all the syringes and needles once a week. I feel that if the materials cannot be boiled every time before use, and thus are stored in alcohol, they should be boiled at least every 2-3 days. At the same time, this method of storing the syringes and the needles in alcohol makes it convenient to use during travelling when it may not be possible to boil them before use. INJECTING INSULIN PREPARING THE INSULIN INJECTION Follow these steps when preparing a single type of insulin for an injection. 1. Roll the bottle (vial) gently between your hands. This will warm the insulin if you have been keeping the bottle in the refrigerator. Roll a bottle of cloudy insulin until the white powder has dissolved.

2. Wipe the rubber lid of the insulin bottle with an alcohol wipe or a cotton ball dipped in alcohol. If you are using a bottle for the first time, remove the protective cover over the rubber lid. 3. Remove the plastic cap covering the needle on your insulin syringe (without touching the needle). 4. Pull the plunger of the syringe back and draw air into the syringe equal to the number of units of insulin to be given.

Illustration of step 4. 5. Insert the needle of the syringe into the rubber lid of the insulin bottle. Push the plunger of the syringe to force the air into the bottle. This equalizes the pressure in the bottle when you remove the dose of insulin. Leave the needle in the bottle.

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Illustration of step 5.

6. Turn the bottle and syringe upside down and hold them in one hand. Position the tip of the needle so that it is below the surface of insulin in the bottle. Pull back the plunger to fill the syringe with slightly more than the correct number of units of insulin to be given.

Illustration of step 6.

7. Tap the outside (barrel) of the syringe so that trapped air bubbles move into the needle area. Push the air bubbles back into the bottle. Make sure you now have the correct number of units of insulin in your syringe.

Illustration of step 7.

8. Remove the needle from the bottle. Now you are ready to give the injection.

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Follow these steps when preparing two types of insulins to be given in the same injection: 1. Roll the insulin bottles (vials) gently between your hands. This will warm the insulin if you have been keeping the bottle in the refrigerator. Roll the cloudy insulin bottle until all the white powder has dissolved. 2. Wipe the rubber lid of both insulin bottle with an alcohol wipe or a cotton ball dipped in alcohol. If you are using a bottle for the first time, remove the protective cover over the rubber lid. 3. Remove the plastic cap covering the needle on your insulin syringe (without touching the needle). 4. Pull the plunger back on your insulin syringe and draw air into the syringe equal to the number of units of cloudy insulin to be given.

Illustration of step 4.

5. Push the needle of the syringe into the rubber lid of the cloudy insulin bottle. Push the plunger of the syringe to force the air into the bottle. This equalizes the pressure in the bottle when you later remove the dose of insulin. Remove the needle from the bottle.

Illustration of step 5.

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6. Pull the plunger of the syringe back and draw air into the syringe equal to the number of units of clear insulin to be given. 7. Push the needle of the syringe into the rubber lid of the clear insulin bottle. Push the plunger to force the air into the bottle. Leave the needle in place. 8. Turn the bottle and syringe upside down and hold them in one hand. Position the tip of the needle so that it is below the surface of insulin in the bottle. Pull back the plunger to fill the syringe with slightly more than the correct number of units of clear insulin to be given.

Illustration of step 8.

9. Tap the outside (barrel) of the syringe so that trapped air bubbles move into the needle area. Push the air bubbles back into the bottle. Make sure that you have the correct number of units of insulin in your syringe. Remove the needle from the clear insulin bottle.

Illustration of step 9.

10. Insert the needle into the rubber lid of the cloudy insulin bottle. Do not push the plunger because this would force clear insulin into your cloudy insulin bottle. If clear insulin is mixed in the bottle of cloudy, it will alter the action of your other doses from that bottle. 11. Turn the bottle and syringe upside down and hold them in one hand. Position the tip of the needle so that it is below the surface of insulin in the bottle. Slowly pull back the plunger of the syringe to fill the syringe with the correct number of units of cloudy insulin to be given. This will prevent air bubbles entering the syringe. Remove the needle from the bottle.

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Illustration of step 11.

12. You should now have the total number of units for the clear and cloudy insulin in your syringe. For example, if 10 units of clear and 15 units of cloudy are needed, you should have 25 units in your syringe. Now you are ready to give the injection. GIVING THE INJECTION Injection sites include the abdomen, outer upper arms, the thighs, buttocks, or hip areas. Do not inject insulin near bony places or joints. Do not give injections closer than 1 inch apart. Insulin absorption can vary from site to site. The best absorption site is the abdomen. Try and rotate the injection site

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Your doctor will help you learn to inject insulin. This is an illustration of giving an insulin injection in your thigh.

The Timing of the Injection The interval between the injection and the following meal should be at least 30 minutes, although there is an excellent study which has shown that the optimal period is 45 minutes. This is an extremely important point as most of the patients are under the misapprehension that unless they eat at once they will collapse with hypoglycemia. This is the reason we often see the comical scene of indoor patients who sit with the food tray in front of them, an arm bare to take the injection and then start to eat as soon as the nurse has given the injection! Why should there be such a time gap? Under normal physiological circumstances, one sees that the insulin levels in the body RISE even before the food is absorbed. In other words, the body does not wait for the food to get absorbed, the blood glucose to rise, and then start responding with insulin. It ANTICIPATES the rise of the nutrients and is ready to act on them. The time interval allows some of the injected insulin to get absorbed and thus the insulin levels in the body would be already raised to meet the postprandial demands. THE ABSORPTION OF INJECTED INSULIN (BIOA VAILABILITY) Insulin therapy does not end with the act of injection itself. If the injected insulin is to be effective, it must get absorbed from the subcutaneous site, enter the bloodstream and thus reach the insulin receptors where it would exert its activity. Unfortunately, not much attention is paid to this aspect inspite of the fact that it plays a crucial intermediate role in our quest for optimal insulin therapy. In clinical practice, one often comes across patients who show an odd or unexpected reaction to the insulin. This response may take several forms. Some patients show little, if any, response to insulin in spite of the fact that the insulin is potent, injected correctly and at doses where one would expect to find at least some response. There are patients who show erratic timing of the activity of insulin. As an example, a patient may show peak activity to an injection of the intermediate acting insulin after 8-12 hours, as is normally expected. But often he shows activity which is in keeping with those who are "early" activators and at other times, the time of peak activity would classify him as a "late" activator! Now a person does not change his characteristic activity pattern suddenly or often. There are patients who in spite of a correct dosage of insulin continue to show a high 2-3 hour post prandial blood glucose levels and then go into hypoglycemia at a later period, say after 5-7 hours! One also comes across patients who are well controlled on a certain dose of insulin and are fairly stable. The patient may suddenly go into hypoglycemia even though the routine daily dose of insulin has been injected. Patients with Type 1 diabetes may even relapse into ketosis. Faced with such patients, our first reaction is to put the blame squarely on the patient. One feels that the patient has not followed his diet regime or has made a mistake in the injection, either in the dosage or techniques. I do not deny that this may be true in quite a few patients, but I feel that when one is confronted with a patient who often manifests such bizarre responses, one should consider that the response could be due to factors that may affect the absorption of insulin from the

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site of injection, thereby varying the amount of insulin that enters the bloodstream and consequently, show a varying response. Since, we want the patient to show a predictable and consistent response, it is imperative that we understand the reason for this varying absorption rates. The basic time lag between the injection of insulin and the appearance of that insulin in the blood stream is that the commercial insulins which are available are hexameric. This means that six molecules of insulin are "joined" together. These have to disperse into monomeric ( single molecule of insulin) or dimeric ( two molecules of insulin) in the extravascular region before the insulin can be absorbed into the blood stream. The differences in the rate of absorption is due to the differing milieu in which the hexameric molecule has to disperse. All the factors which we used to make use of to alter the rate of absorption basically acted through changing the rate of dispersion of the hexameric insulin. Now with the availability of insulin analogues which are in the monomeric or dimeric state and therefore almost instantly absorbed into the blood stream after being injected, the manipulations which we used to do in the past are no longer necessary and now it even seems laughable about some of the things we used to recommend to the patient! The best solution for a patient showing erratic absorption is to change them over to the insulin analogues. COMPLICATIONS OF INSULIN THERAPY Hypoglycemia Many would not consider this as a complication of insulin therapy, thinking of this as more of an excessive side effect of the therapy. Hypoglycemia is discussed in a seperate section. Edema Insulin does cause salt and water retention. Thus, patients may complain of edema, rapid weight gain and a feeling of bloating. The edema is usually mild and usually disappears after a few weeks. Occassionally, it may be more severe and may require the use of a diuretic. In patients with cardiac problems, hypertension and renal problems, this salt and water retention may create additional problems and some modification may be required in their treatment of these conditions. Allergy Allergic reactions to insulin have now become very rare now that the "pure" varieties of the insulin are available and due to the increasing use of human insulins. All the same, they do occur and the treating doctor should be aware of this. Unfortunately, when we think of allergic reactions, we usually refer to the full blown systemic reaction. Allergic reactions to insulin may be local or systemic. One should be aware that a patient may exhibit a local reaction even with the first injection although it is more common to be manifest after a few injections have been taken. The local reaction may be "immediate" (manifesting within 15 minutes to two hours of the injection) of "delayed" (seen within 6-24 hours of the injection). Some patients may exhibit both the immediate and the delayed reactions. The allergic lesions may be characterised by local pruritus, erythema, and indurated areas which may be from 1-5 cms. in diameter. The lesions may gradually increase in intensity for up to a day and then gradually subside within a few days. Some patients show a true systemic form of insulin allergy. In some patients, severe systemic reactions are preceeded for a few days during which the severity of the localised reactions seems to increase significantly. Such an occurence should be taken as a warning that a severe systemic reaction is in the offing and adequate steps should be taken to avoid this. Fortunately, such severe reactions occur very rarely (about 0.1% of patients receiving the newer insulins). When one is faced with a mild form of localised insulin allergy, one should, first make sure that the insulin is being injected subcutaneously and not intradermally, and is at room temeperature. The patient may be allergic to the alcohol used to disinfect the skin. More importantly, some patients are allergic to the to the protamine contained in the longer acting insulins, although this is quite rare, and such a patient may tolerate the lente insulins better than the NPH insulins. In case the patient is shown to be allergic to protamine, it should be very clearly mentioned in his case records, especially if the patient is to undergo any cardiovascular surgery as a large amount of protamine is often used post operatively. If in spite of this, the patient still continues to show an allergic reaction, the next step would be to shift the patient over to

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the rDNA derived human insulins. As with the case of localised allergy, it is more prudent to prevent the systemic allergy from occuring rather than in trying to manage it once this has occurred! Interrupted insulin therapy, especially with the animal insulins should be avoided and such patients should be preferably treated with rDNA derived human insulins. But if a patient taking animal insulins does show systemic reactions, then again it would be better to shift to the rDNA derived human insulins. This may help in the occasional patient. The reason why we see such a rare positive response, is that systemic insulin allergy is due to the presence of antibodies and these are known to be directed against the insulin molecule itself rather than against any impurity contained in the insulin. Therefore, once the antibodies have been formed and the allergic reaction is manifest, a simple change over to the human insulin may not be effective. As I have shown before, the beef and the porcine insulin molecule differs from the human insulin molecule by three and one amino acid respectively. Whilst this discrepancy may have initiated the antibody formation, once the antibodies are formed, they would be directed even against the other parts of the insulin molecule! Thus, removing the source of the antibody formation would not stop the allergic reaction but may help in decreasing further progression. When faced with a seemingly intractable problem of insulin allergy in a patient with diabetes in whom insulin therapy is mandatory, the only option left before us is to desensitise the patient. This is best left in expert hands. Insulin Resistance True insulin resistance is usually defined as a situation in which the patient receives more than 200 units of insulin per day for two or more consecutive days in order to try and achieve a control of the blood glucose levels. In my opinion, this definition is quite arbitrary, and as the amount of insulin secreted by the pancreas in a normal person is about 35-40 units per day, it is logical to assume the presence of some degree of insulin resistance when OPTIMALLY administered insulin doses exceed a total of around 50-60 units daily, especially in a "compliant" patient. I have purposely tried to highlight the point about optimal administration of the insulin, I have seen numerous patients who were receiving around 100-120 units of insulin in a once a day dose and showed a poor control. When many of them are shifted over to a twice a day regimen (both times being given a mix of the short and intermediate acting insulins) they show an excellent control with the daily total insulin administration of around 40-50 units! Surely these patients are not really resistant although one could say that they manifest "iatrogenic" resistance! In any case, whenever we talk about insulin resistance, we need to be quite clear in our minds as to what exactly we are referring to. From a purely theoretical viewpoint, true insulin resistance is a condition where there is an immunological barrier to insulin action. This is due to the presence of specific antibodies that interfere with the action of insulin so that massive doses are required before any therapeutic response is seen. At the same time, there are many other causes and conditions, which for varied reasons, manifest an antagonism to insulin action such that more than normal doses of insulin are needed for a response. These conditions cannot be considered to be causes of "true" insulin resistance as there is no immunological barrier to insulin action involved. These cause "relative" insulin resistance and from a purely clinical view, they constitute the vast majority of cases where we find the insulin requirements to be much larger than normal. I would therefore classify insulin resistance into: True insulin resistance, caused by immunological mechanisms and relative insulin resistance caused by a variety of factors which manifest as increased insulin requirements, but which do not have an immunological basis. As my approach is more clinical, and as cases of relative insulin resistance are so much more common and important, I would like discuss a few of the more common and important factors first. I feel that it is imperative to reiterate that the increased insulin requirements are in spite of optimally administered doses in a compliant patient. Infection It is quite well know that in the presence of any infection, diabetic control deteriorates and the insulin doses may have to be increased quite a bit. Con- versely, when faced with a clinical situation wherein the control deteriorates without an obvious cause, or where it is difficult to control the blood glucose levels in spite of optimal management, and relatively large doses are required, it is imperative that a thorough search be made for the presence of any obvious or occult infection. In my experience, the most common infection in our country would be active tuberculous infections. The association of diabetes with tuberculosis is frequent enough to justify routine ruling out of tuberculosis not only when faced with a case with "difficult" control but in all cases! The other common problem is caused by urinary tract infection which may not cause symptoms or signs that would bring it into clinical diagnostic consideration. Thus, a routine urine

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examination is also mandatory to rule out a urinary tract infection. Obesity Type 2 patients who are overweight and especially those with a raised waist to hip ratio often manifest resistance to the action of insulin. It is well documented that in most of these patients, the pancreas secretes more than average insulin. Yet they show a poor control and the situation may not become better even with the injection of additional doses of insulin. In such patients the problem seems to lie with the peripheral insulin receptor and the best management for such patients would be to try to optimise the weight of the patient with diet, exercise and the possible use of a small amount of sensitisers such as metformin and/or the glitazones. Thyrotoxicosis Another relatively common cause of relative insulin resistance is the presence of an increase in the activity of those hormones that have an antagonistic effect to that of insulin. These are hormones like glucagon, growth hormone, cortisol and thyroid hormones. From a clinical viewpoint, the commonest condition that causes an increase in insulin requirements in so far as these hormones are concerned is thyrotoxicosis. This conditions is not as rare as one may imagine especially in the young. I have seen patients whose weight loss has been attributed to the diabetes itself and whose diarrhea has been thought of as due to amebiasis or even autonomic neuropathy! When the thyrotoxicosis is controlled, one sees a good diabetic control with small doses of insulin. Bioavailability I have already discussed the factors associated with the bioavailability of insulin from the site of the injection. It is obvious that if the injected insulin is not properly absorbed from the site of injection, it would not reach the receptors in sufficient amounts to be effective, thus creating a relative insulin resistance. Besides this, in the rare patient, the increased insulin requirement may be due to an increased amount of degradation of insulin at the site of injection. Finally let us come to the problem of true insulin resistance. This is due to an immune based mechanism. All patients who receive insulin therapy, especially with the older conventional insulin, do show a presence of antibodies, but the titers of these antibodies are in such a low range that this seldom causes any clinical problem. These titers are usually in the range of 10 units per liter of serum. In patients showing a true insulin resistance, these titers may range from 100 to as high as 50,000 units per liter of serum. Beef insulin differs from human insulin in three amino acids and the porcine insulin differs from human insulin in one amino acid. Thus, beef insulin would have a greater tendency to give rise to the antibodies as compared to porcine insulin. But once again I would like to make it clear that in most instances these antibodies do not reach a significant level. Higher antibody levels can also be seen in people who receive intermittent therapy especially with the older insulins. The reason why the antibody titers assume a clinical significance in only a relatively few patients is not quite clear but may be due to differences in immune responsiveness of individual patients. Although true insulin resistance can be managed in specialized centers it is a complex matter and the best way to avoid this problem is to use the newer insulins which are now available, and also by avoiding needless intermittent insulin therapy. Lipodystrophy and scar formation Whilst injecting insulin, one should invariably rotate the site of the injection so that no area of the body about 3 cms. in diameter, should receive the injection more than once every three to four weeks. One of the complications of not following this rule, is that when the insulin is repeatedly injected into the same area, the skin and subcutaneous tissue may become thickened and scarred with the formation of insulin lumps. As injections in this scarred area are relatively painless, the patient keeps injecting the insulin into this area. This exposes the patient to bizzare reactions as the absorption of insulin from such a site is delayed and wholly unpredictable. Insulin lipodystrophy comprises both, lipoatrophy as well as lipohypertrophy. The insulin induced lipoatrophy is basically a loss of subcutaneous fat at the site of the insulin injections. Insulin induced lipoatrophy may not seem to very important from a purely clinical viewpoint but it may give rise to considerable cosmetic disfigurement and many of the younger patients would rather discontinue the insulin therapy than accept these unsightly blemishes.

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It has been shown that rotating the site of the injection, using a slightly longer needle so that the injection goes deep into the subcutaneous tissue, or even in- tramuscularly, are some of the simple manoevers to avoid lipoatrophy, as is the routine use of the newer and purer insulins. In fact, if the newer insulins are injected into the site of lipoatrophic areas, these will fill out again! This is due to the new deposition of fat in the lipoatrophic areas and may take about 3-4 weeks. The areas which have thus filled out should get injections of insulin every three to four weeks or else it is possible that these areas may lose some of the fat again. Of course, now that only the pure monocomponent insulins are available for use, one will see less and less of lipoatrophy. Lipohypertrophy is much more rare than lipoatrophy. It basically means that the subcutaneous fat cell at the site of the insulin injection undergo hypertrophy and is presumably a manifestation of the lipogenic action of insulin. One factor that predisposes to lipohypertrophy is the repeated injection of insulin at the same site. Once slight hypertrophy develops, the patient may continue to inject his insulin at the same site as this is less painful than other normal areas. Since lipohypertrophy is related to the inherent lipogenic action of insulin, it can occur even with the newer insulins. The best management of established lipohypertrophy would be to avoid using that site for the injection for a long time in order to allow the increased fat to resolve by itself.

DIABETIC NEPHROPATHY Dr. S.M.Sadikot. Hon. Endocrinologist, Jaslok Hospital and Research Centre, Mumbai 400026 Renal dysfunction is fairly common in people with diabetes. Approximately 25% to 40% of patients with Type 1 diabetes ultimately develop diabetic nephropathy (DN), whilst the corresponding figures for Type 2 diabetes are in 5% to 15% although some studies show that the figure may go as high as 40% even in this category of patients. Diabetic nephropathy (DN) progresses through about five predictable stages. Progression through these five stages is rather predictable because the onset of DM 1 can be identified, and most patients are free from age-related medical problems. The time line for Type 2 patients is not too clear as the onset can be quite insiduos and some patients progress through the stages very rapidly. The five stages are: Stage 1 (very early diabetes) Increased demand upon the kidneys is indicated by an above-normal glomerular filtration rate (GFR). Stage 2 (developing diabetes) The GFR remains elevated or has returned to normal, but glomerular damage has progressed to significant microalbuminuria (small but above-normal level of the protein albumin in the urine). Patients in stage 2 excrete more than 30 mg of albumin in the urine over a 24-hour period. Significant microalbuminuria will progress to endstage renal disease (ESRD). Therefore, all diabetes patients should be screened for microalbuminuria on a routine basis. Stage 3 (overt, or dipstick-positive diabetes) Glomerular damage has progressed to clinical albuminuria. The urine is "dipstick positive," containing more than 300 mg of albumin in a 24-hour period. Hypertension (high blood pressure) typically develops during stage 3. Stage 4 (late-stage diabetes) Glomerular damage continues, with increasing amounts of protein albumin in the urine. The kidney's filtering ability has begun to decline steadily, and the levels of blood urea and serum creatinine have begun to increase. The glomerular filtration rate (GFR) decreases about 10% annually. Almost all patients have hypertension at stage 4. Stage 5 (end-stage renal disease, ESRD) GFR has fallen to approximately 10 milliliters per minute (<10 mL/min) and renal replacement therapy (i.e., hemodialysis, peritoneal dialysis, kidney transplantation) is needed. Why is renal dysfunction so common in patients with diabetes? Poor glycemic control, hypertension, dyslipidemias are the major predisposing factors to renal dysfunction in a person with diabetes. Genetics also play an important role: Patients who have one or two deletions of the angiotensin-converting enzyme (ACE) gene, a defect in the sodium proton pump, or a family history of hypertension are at increased risk for progression to diabetic nephropathy. However in such patients renal

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dysfunction does not occur until diabetes develops; the worse and more prolonged the hyperglycemia, the greater the risk of diabetic nephropathy. Whilst some people feel that renal dysfunction is a part and parcel of the diabetic scene and will invariably occur with time, it is also widely accepted that we can do quite a bit to delay the onset. In spite of this, if renal dysfunction does occur, early diagnosis and certain specific treatments can, if not reverse, at least slow down the rate of progression of the renal dysfunction so that it reaches its end stage at a very late age. So how are we to avoid or the least delay the onset and rate of progression of renal dysfunction? Diagnosis Early diagnosis of the onset of complications is a crucial factor. However, early in the diabetic nephropathy, there are no clinical signs or symptoms of renal disease. Glomerular changes can be identified only by renal biopsy which is impractical to carry out in every patient! From a clinical viewpoint, every patient with diabetes who presents for the first time and regularly thereafter should be tested for the presence of microalbuminuria. Aggressive intervention can delay and possibly stop progression through the stages of diabetic nephropathy (DN). Unfortunately, many patients often seek medical attention only after having progressed to stage 3 or 4. I do not agree with those who feel that screening for microalbuminuria is not as useful in type 2 diabetes because it is not as clearly predictive of progression to overt nephropathy as in Type 1 diabetes. As we have discussed before, due to the insiduos onset of Type 2 DM, one may not be able to see a distinct prediction of progression to end stage renal disease, but treating the raised albumin levels is definitely helpful. Moreover, the presence of microalbuminuria is associated with an increased risk of developing cardiovascular disease and retinopathy. Even normally, a person excretes about 5 micrograms of albumin per minute in his urine. With incipient diabetic nephropathy, the amount of albumin that the patient excretes in the urine increases and this should alert us to the possibility of diabetic kidney disease. Incipient nephropathy is the stage of microalbuminuria; Microalbuminuria is defined as albumin excretion rate: a) between 30-300mg per 24 hours, or b) an albumin excretion rate exceeding 20ug/minute and less than 200ug/minute. Albumin excretion can be estimated through the following methods: 1) 24 hour urine collection. 2) Timed collection, say over a period of four hours. 3) Spot urinary sample

The results are analysed as follows:

24 hour collection mg / 24 hours Normal Microalbuminuria Clinical Albuminuria <30 30-300 >300 Timed collection ug / min <20 20-200 >200 Spot collection ug/mg Creatinine <30 30-300 >300

Although dipsticks are available to detect microalbumin levels, they are costly. It may be worthwhile to do a spot or timed collection of urine and then see the albumin to creatinine ratio to judge the level of renal involvement. In the absence of methods to routinely look for the presence of microalbuminuria, the use of dipsticks to look for albumin in the urine must suffice to warn of the presence of diabetic nephropathy, and it is essential that this test routinely and

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frequently be carried out in all patients. Unfortunately, our routine method of detecting the presence of albumin in the urine is not very sensitive and by the time albumin can be detected even by the use of the "dipstick", the amount of albumin excreted is around 150 micrograms per minute, which is too late to diagnose microalbumin excretion levels.. It should be clear that there are numerous causes for the presence of albumin in the urine and diabetic nephropathy is only one of these. Therefore, if albumin is found in the urine of a diabetic, it should not be taken to mean that the patient has nephropathy. I usually ask my patients to repeat the test after a few days and only if this positive, then I investigate to rule out the other more common causes of albuminuria. The most frequent cause of albuminuria is any infection in the urinary tract although any generalised infection in the body can cause albuminuria. Hypertension, cardiac failure and indeed drugs used in the management of these two conditions are also known to lead to albuminuria. Even in a diabetic, one should always keep in mind that the renal involvement may be due to a non-diabetic cause. Even otherwise, a very poorly controlled diabetic may show an increased excretion of albumin in the urine without signifying diabetic nephropathy. This usually corrects itself after adequate control. Many people show a positive test after exercise and importantly, although this is not well known, drinking a large amount of water may increase the albumin excretion. Many a patient when he has to go for a test where he will need to give a urine sample, drinks a large amount of water so as to be able to give the sample without any problem, without realising that this act in itself may increase the amount of albumin in the urine. It should be mentioned that this is usually seen if something like two or three big glasses of water are rapidly drunk. It should also be remembered that many young people normally excrete albumin in the upright position. In other words there are numerous causes of an increase in the urinary albumin excretion and all these have to be ruled out before one accepts the possibility that the albuminuria could be due to diabetic nephropathy. POINTERS TO A "NON DIABETIC" CAUSE OF RAISED UAE 1) a more rapid decrease in the GFR than is expected. 2) sudden development of nephrotic syndrome. 3) absence of retinopathy. 4) presence of hematuria ; although red cell casts have been described in some patients. 5) renal bruit. 6) absent pedal pulses. 7) disproportionately high serum potassium. 8) sudden deterioration in renal function after starting ACE inhibitors. 9) presence of cardiac failure, and the use of drugs, like diuretics, in its management. 10) testing after heavy exercise. 11) testing during acute illness. 12) high protein intake. 13) decompensation of metabolic control, including recent ketosis. Diabetic nephropathy should only be diagnosed when seen to be present on repeat testing and when other causes of raised urinary albumin have been excluded. I feel that checking for microalbumin levels and especially repeat testing is usually not feasible in most cases. I usually start the patient on a small dose of an ACE inhibitor or an Angiotensin Receptor Blocker (ARB) or a combination of both irrespective of whether the patient has hypertension or not. There is overwhelming evidence to suggest that the use of these agents can reverse the early or incipient diabetic nephropathy or at the very least slow down significantly the progression.

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Strict blood sugar control is important in the protection of kidney function. Onset of diabetic nephropathy may be avoided with good glycemic control. Interventional and epidemiologic studies have confirmed the benefits of tight glycemic control in avoiding or delaying onset of diabetic nephropathy in patients with type 1 diabetes. In one often quoted study, the DCCT, (average HbA1c level, 7.l%), in the primary-prevention group, who had had type 1 diabetes for less than 5 years and had no retinopathy, patients who received intensive versus standard insulin therapy had a 34% decrease in the frequency of microalbuminuria and no significant decrease in the frequency of macroalbuminuria. In the secondary-prevention group, who already had mild retinopathy, patients who received intensive therapy had a significant decrease in both microalbuminuria (43%) and macroalbuminuria (56%). In patients with type 2 diabetes, a recent interventional study showed a decrease in the frequency of development of both

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microalbuminuria (57%) and macroalbuminuria (70%) with intensive insulin therapy. However, since type 2 diabetes is diagnosed, on average, 8 years after onset, diabetic nephropathy may have already developed in many patients. There are some who feel that once diabetic nephropathy has set in, the importance of optimal glycemic control is little if any, in retarding the progression of the renal dysfunction. But this is far from true. Results from pancreatic transplant recipients in which true euglycemia is restored suggest otherwise. In fact, optimal glycemic control in these patients led to either an absence of albuminuria or a significant lowering of the urinary albumin excretion. To sum up this aspect, optimal glycemic control is important in delaying the onset of diabetic nephropathy and is also important in retarding the progress of the nephropathy once it has set in. Aggressive blood pressure control is by far the most important factor in protecting kidney function, regardless of the stage of DN. Even those who believe that there is a point of no return in so far as glycemic control is concerned agree that optimal control of the blood pressure does retard the progression of diabetic nephropathy. The goal of treatment is: 120 - 130 mm Hg systolic blood pressure and 70 - 80 mm Hg diastolic blood pressure.

We have already referred to starting an ACE inhibitor (ACEi) or an Angiotensin Receptor Blocker (ARB) even when the patient does not have hypertesnion in order to delay the onset of nephropathy. These drugs continue to be the mainstay in optimizing the raised blood pressure, but often combination therapy with other groups of blood pressure lowering drugs are necessary. I have discussed the management of hypertesnion in a patient with diabetes in a separate chapter. With an aggressive treatment approach, the decline in renal function can be reduced to half of the decline seen without treatment (ie, from 10% to 5% per year). Whilst this may not seem to be much, one should realize that this may mean that the patient reaches end stage renal disease state possibly 15-20 years later than he would without optimal management of the hypertension! Aggressive treatment of dyslipidemias, surprisingly have been shown to be beneficial. Hyperlipidemia is common in diabetic patients, a tendency that is increased by the development of renal insufficiency. In patients with type 1 diabetes, the incidence of myocardial infarction is not increased before age 35. However, after age 35, it is increased fourfold, and when proteinuria is present, it is increased by a factor of 140. The fourfold increase after age 35 could potentially be due to the presence of microalbuminuria. In patients with type 2 diabetes, diabetic nephropathy, or microalbuminuria, the incidence of myocardial infarction is also increased. Risk factors for ischemic heart disease, which occur in the presence of albuminuria, are hypertension, increased low-density lipoprotein (LDL) cholesterol and triglyceride levels, a decreased high-density lipoprotein cholesterol level, and increased platelet aggregation and clotting factors. However, albuminuria is a significant independent risk factor. The presence of albuminuria suggests that large-vessel walls are more permeable to lipoproteins or damage from local release of growth factors, as occurs in the glomerulus. Aggressive treatment of dyslipidemia in patients with diabetic nephropathy may have beneficial effects on not only macrovascular disease but also diabetic microvascular disease (ie, retinopathy and nephropathy). Several studies of treatment of dyslipidemia have shown improvement in retinopathy, and one double-blind study showed stabilization of renal function. Other studies have shown a positive effect of lipid lowering on other glomerular diseases. Dietary protein restriction is minimally protective. A high-protein diet can further damage the kidneys in people with diabetic nephropathy and/or chronic renal failure (CRF). Protein restriction must be cautiously implemented because of the risk for malnutrition. In general, dietary protein intake should be limited to 0.6 to 0.8 grams per kilogram (0.02 - 0.028 oz/lb) of body weight each day. A low-protein diet (0.6 g/kg of body weight) has the theoretical advantages of decreasing glomerular hypertension, reducing proteinuria, and slowing the decline in renal function. The efficacy of a low-protein diet in diabetic nephropathy has been questioned, but a recent meta-analysis found it to have a positive effect. Since high protein intake has the potential to accelerate the decline in renal function, at least some degree of protein restriction is indicated.

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There are, however, potential problems associated with a low protein diet. In addition to difficulty with compliance due to concurrent fat and simple carbohydrate restriction, diabetics are at increased risk for protein malnutrition because the reduction in intake may be associated with enhanced protein breakdown induced by insulin deficiency. Recent experimental studies also suggest that restricting all components of protein intake may limit the potential efficacy of this regimen. The amino acid L-arginine is the precursor of the vasodilator nitric oxide (endothelium-derived relaxing factor). The administration of L-arginine to diabetic rats with nephropathy ameliorates both the glomerular hyperfiltration and the degree of proteinuria. Thus, limiting L-arginine intake as part of a protein restricted diet may not be desirable. Maintain hydration In patients with diabetic nephropathy, avoidance of dehydration is an important factor in maintaining renal function, since a period of dehydration can cause an irreversible decline. Therefore, any acute illness that causes dehydration should be treated aggressively with intravenous fluids. The most common cause of dehydration in patients with diabetic nephropathy is overuse of diuretics. Diuretic doses should be adjusted so patients experience nocturnal ankle edema without morning ankle edema. All patients with diabetes should be examined for physical signs of dehydration at each clinic visit. It is absolutely essential that there should be adequate hydration. It is well known that dehydration can adversely affect the kidney. That is the reason why all diabetics should always be asked to drink an adequate amount of water so that normal quantities of urine are passed. I ask my patients to drink a glass of water at bedtime and to have some liquids on waking up. A problem that arises in our country is the fasts that people keep, especially those types of fasts where even water is not allowed. This in my opinion is harmful to some extent to a diabetic kidney, but one can only firmly advise in this matter as questions of religion are involved. But one area where doctors can definitely do something is regarding the advise we give the patient when they have to go for their blood tests. Often the patients are asked to go fasting and are told to have nothing from 10pm the previous night. By the time the patient finishes giving the blood it often happens that more than 12 hours have elapsed without any liquid intake. I have never understood the reason for not allowing the patient to have even water. I have come across no evidence that having a glass of water in the morning would in any significant manner affect the test results! Unfortunately, this standing instructions to go completely fasting have become the "order of the day" and is accepted without question. The problem even gets worse when the patient has to go for an X-ray examination on a fasting stomach. By the time these tests are over, more than 12-14 hours may have elapsed without water. Whenever my patient is called for an X-ray in the fasting stage, I usually make it a point to inquire whether even a glass of water would affect the quality of the X-rays. If this is so, then I insist that my patient be taken up first in preference to other non-diabetics. I also instruct the patient to have more than the normal amount of water the previous night. I am not implying that one occassion that the patient stays without water for about 12 hours will cause a renal shutdown, but when there is no need to be without water and when one knows that dehydration can harm the diabetic kidney, is it not better to take all precautions to avoid even mild dehydration? If one thinks of the number of times that we ask patients to go fasting for something or the orther, and one can well imagine the these small "insults" to the kidneys may well add up! And it is so simple to avoid these insults. Infections of the Urinary Tract must be treated adequately and the urine should be tested repeatedly and regularly for the presence of any infections which should be ruthlessly eradicated. By itself, this may appear trivial but they may add up over the years and avoiding them may make the crucial difference between the patient who remains at a stage where there is just albuminuria as compared to reaching a stage of full blown renal failure where life can be maintained only with dialysis or renal transplant. UTIs are detrimental to the diabetic kidney and the best solution to this is early detection and adequate management. Although such infections may be suspected from symptoms like burning micturation, dysuria, passing small but frequent urine, mild infections of the urinary tract may go unnoticed and may only be detected when the complete urine examination is done. Urinary tract infections are more common in diabetics. Besides the fact that poorly controlled diabetics, in general, have a tendency to infections, long- standing diabetics, have some degree of autonomic neuropathy which leads to bladder atony, incomplete emptying and stagnation of some urine. This coupled with the presence of glucose in the urine of poorly controlled diabetics favors the growth of bacteria and infection. The stagnation of the urine also makes it that much more difficult to eradicate any infection. I usually ask my patients, especially women who are more prone to chronic urinary tract infections, to have a complete urine examination done every three months or so irrespective of whether these have any signs and symptoms of urinary infection

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or not. If there is any evidence of infection, then I ask for a culture and sensitivity and treat the infection until the urine is sterile. In patients who are prone to recurrent urinary infections, the antibiotic to which the organism is sensitive may be continued in a small nighttime dose for a prolonged period. This often helps in avoiding frequent infections. The patient may also need to be taught methods which will help in a more complete emptying of the bladder. Occassionally drugs may be of some aid and in very severe case surgery may be required especially in male patients who may have some degree of an enlarged prostate that makes complete emptying of the bladder difficult. Smoking worsens hypertension and albuminuria by increasing catecholamine levels in patients with diabetes without autonomic neuropathy. Therefore, smoking cessation is imperative. Avoid renal damage from drug use. Some drugs should be avoided completely in patients with nephropathy whilst the dose of some other drugs needs to be carefully adjusted depending on the state of the renal function. It would be worthwhile to avoid the use of these drugs in cases with diabetic nephropathy especially if safer alternatives are available. Here again one may feel that occassionally taking a drug with a potential for renal toxicity may not have a significant effect on the final outcome of the renal disease, but these "minor" matters do add up and if one can avoid taking even these-minor risks, I really cannot find a valid reason for not doing so. One area where I would like to draw special attention is the use of radio-contrast media in investigations. Whenever possible, radiocontrast material should be avoided, since patients with diabetic nephropathy are at increased risk of radiocontrast-induced renal shutdown. Additional major risk factors for radiocontrast-induced renal shutdown are sepsis, dehydration, use of nephrotoxic antibiotics, use of antifungal agents or nonsteroidal anti-inflammatory drugs, and the presence of cardiac or pulmonary disease or other causes of hypoxia. However, the most predictive factor is the volume of iodinated radiocontrast material used. The risk of renal shutdown is minimal with intravenous urography or computed tomography of the head and greatest with coronary angiography. Coronary angiography is often considered in patients with diabetic nephropathy because their incidence of ischemic heart disease is increased; however, it should be performed only when absolutely necessary and with the lowest possible radiocontrast dose. Renal Replacement Therapy. Once patients with DN progress to stage 5 (end-stage renal disease, ESRD), renal replacement therapy (RRT) is implemented. The RRT options for DN patients include the following: Hemodialysis, removal of the blood's waste products through filtration outside of the body Peritoneal dialysis, filtration through the membrane lining the abdominal cavity; fluid is instilled into the peritoneal space, and then drained Kidney transplantation

MONITORING THE BLOOD GLUCOSE LEVELS Dr. S.M.Sadikot. Hon. Endocrinologist, Jaslok Hospital and Research Centre, Mumbai 400026 One of the major aspects of a good diabetic management is that the blood glucose levels should be optimally controlled. Whilst there are a few who may still question the role that hyperglycemia plays in the pathogenesis of the dreaded long term complications, most of the authorities are of the view that an optimal control of the blood glucose level will definitely help in retarding the progression of these complications even if one is not able to completely avoid the problems. By optimally, I would mean that they should be as close to normal as is possible without exposing the patient to the "peaks" of hyperglycemia as well as the "troughs" of hypoglycemia. But how are we to judge the adequacy, or otherwise, of the control of the glucose levels? What are the parameters available which enable us to get a correct idea of the control? Unfortunately, many of the so-called parameters which have traditionally been used to judge this control have so many shortcomings associated with them, that they should have no place in the modern management of diabetes. At the same time, one cannot accept all new methods of evaluating blood glucose control without inspecting their feasibility in our context. Having made this point, what are the methods that we commonly use to judge blood glucose control.

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Presently, the following methods are in vogue : 1. Testing the urine for the presence of glucose; 2. Occassional blood glucose test done in an laboratory ; 3. Estimation of Glycosylated Hemoglobin and serum Fructosamine levels ; 4. Self monitoring of the blood glucose levels. URINE TESTING FOR THE PRESENCE OF SUGARS This is still the most common method used for estimating the blood glucose control ! I feel that using this estimation is in today's context mostly unacceptable, especially when other, better, parameters are easily available. Urine tests are associated with too many shortcomings to give any reasonable answer about the glucose control. At the same time, it would be worthwhile to examine the reason why urine testing for glucose was advocated as a means of evaluating blood glucose control as a time when other methods were not routinely available. When blood flows through the kidneys, glucose that is present in it is filtered by the glomerulii. When this filtrate flows through the tubules, this glucose is reabsorbed back into the bloodstream and consequently, under normal circumstances, no glucose is found in the urine. The capacity of the tubules to reabsorb glucose is limited and if the amount of filtered glucose is more than this capacity, the excess glucose would be found in the urine, which would then test positive for the presence of glucose. As the amount of glucose found in the glomerular filtrate is dependent on the amount of glucose present in the blood, it follows that in cases where the blood glucose levels are increased, as in diabetes, more than normal amounts of glucose would be filtered out and if this overwhelms the reabsorptive capacity of the tubules, glucose would be found in the urine. This has lead to the concept of "renal threshold". This is the blood glucose level beyond which so much glucose would be filtered out by the glomerulii that the urine would test positive for the presence for glucose. The textbooks mention the renal threshold for glucose to be 180mg%. In other words, if the blood glucose levels were to increase above 180mg% then the urine would test positive for the presence of glucose. In view of this, it is easy to understand how testing the urine for the presence of glucose came to be used as a parameter to judge the blood glucose levels in the olden days. In the absence of wide availability to test for the blood glucose levels, it was felt that if the urine showed the presence of glucose, then it could be surmised that the blood glucose were above 180%. This is where the first fallacy creeps in. One must realise that the figure of 180% is just an average approximation and that the threshold differs markedly in every individual patient. Thus, there are those non-diabetics who will show the presence of glucose in their urine, even when the corresponding blood glucose level may be only 100mg% ! Conversely, some known diabetics may not show the presence of glucose in the urine, although their blood glucose levels may have reached as high as 300mg%. Most of the others would come in between these two extremes. Therefore, if urine testing is to have any relevance to judging the blood glucose control, then the renal threshold for every individual patient will have to be charted ! Unfortunately, the method for estimating the renal threshold is quite cumbersome and one should not be under the misconception that it just a simple matter of checking the urine for the presence of glucose and estimating the corresponding blood glucose levels. This "simple" method will invariably give wrong idea of the renal threshold as we shall discuss later. Even if we were to take the trouble to estimate the renal threshold for every individual patient, we are then faced with the problem that this value does not remain constant for that individual for all times. The threshold value changes with age, pregnancy, any kidney disease including diabetic nephropathy. More importantly, and this is not too well known, changes in the blood glucose level themselves can effect a change in the renal threshold values ! It is now well accepted that when the blood glucose levels are very high, the renal threshold values tend to be lower and this then increases gradually as the blood glucose levels are brought under control. In other words, the very parameter that we use to judge blood glucose control, itself undergoes changes as the blood glucose levels change !

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It should be obvious that such a labile renal threshold value should not have any important place to play in judging the blood glucose control in the modern context. There are many more reasons why we should not use urine glucose tests to evaluate blood glucose control. For the purposes of discussion, let us take a theoretical patient and accept that his renal threshold value for glucose is 180mg%. What this implies is that if the patients blood glucose values are below 180mg%, then no glucose would be found in the urine. Often, we test the urine in the fasting stage and feel gratified that is shows no glucose. But are we justified in accepting that this signifies good control ? It is possible that the blood glucose levels may be 165mg% and this value in the fasting stage would definitely be unacceptably high ! Looking at this from a slightly different angle, when the urine shows the absence of glucose, it would mean that the corresponding blood glucose level could range, in theory, from 0mg% to 180mg%, a complete range from the absurdly low to the unacceptably high. How is it possible to accept such a parameter to judge blood glucose control, leave alone making treatment changes ! Thus, testing the urine for the presence of glucose as an indirect parameter to judge blood glucose control is, at best, a crude method and should be accepted as such. Even if we are to accept that urine tests are only crude method and give us only a rough idea of the blood glucose levels, we would be erring. It should be realised that urine test for the presence of glucose does NOT give an estimate of the blood glucose levels at the very time of testing the urine. In simple terms, we test the urine for glucose, say, 2 hour after a meal, as patients are often asked to do. Let us for the sake of discussion accept that the renal theshold of the patient is 180mg%, 1 + urine sugar corresponds to 200mg%, a 2 + to 250mg% and so on. The patient tests his urine after two hours of a meal and finds that his urine shows a 2 + presence of sugar in the test. Can this be taken to mean that his blood glucose level 2 hours after the meal is 250mg% ? This could be completely off the mark. In this case, one may accept the blood glucose level at that time to be 250mg%, only if the urine that we are testing is that which is passed by the kidneys precisely 2 hours after the meal. But the urine that we are, in reality, testing is NOT the freshly passed urine but a mix of all the urine that has accumulated in the urinary bladder since the last time that the patient had voided. In other words, urine testing cannot give us a true idea of the blood glucose levels at the time that we test the urine. This point, though of utmost importance, is often forgotten by many of us. One way out of this problem would be to ask the patient to completely empty his bladder, say, 5 minutes before the test and discard this urine. He would then pass a fresh sample of urine after about 5 minutes and this could then be construed to be akin to a freshly passed specimen from the kidneys and this may give an idea of the corresponding blood glucose levels in an ideal situation. To do this, that is to completely empty the bladder and then pass some more urine within 5-10 minutes is more easily said than done. Most, if no all patients find this extremely difficult (not to say inconvenient) and many will refuse to do the test at all. I always ask doctors who advise their patients to do this, if they have ever tried to do it themselves. Only then they will realise how troublesome these instructions are ! Often, the patients are advised that after they have discarded the first urine completely, they should drink lots of water. This is done in the hope that it will help them offer the second sample easily. Unfortunately, the very fact that the patient drinks a lot of water, makes him pass dilute urine, and this dilution in itself, changes the renal threshold ! More commonly, many diabetics have some amount of autonomic nerve involvement and this leads to an inability to completely empty the urinary bladder. Such patients, and there are quite a few of them, would find it impossible to offer a second, fresh sample of urine, as any urine that they pass would invariable have been mixed with some of the urine that has remained in the bladder due to incomplete emptying caused by the neuropathy. This inability to completely empty the urinary bladder caused by the neuropathy, leads to some urine stagnating in the bladder and this urine is particularly prone to get infected especially in diabetics with a high blood glucose levels who would pass an increased amount of glucose in the urine. The infecting bacteria will utilise the glucose that is present in the urine and when we test the urine, under such circumstances, one would find an absence of sugars. This would lead to a completely erroneous idea that the blood glucose control is quite acceptable. In reality, the blood glucose may be very high but this would not be reflected in the urine tests just at the time when it would be important to correctly assess the diabetic control so that adequate measures can be taken to manage the blood glucose levels and help in the eradication of the urinary tract infection.

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Finally, let us briefly discuss the methods that are widely used in many parts of our country. The two most commonly used methods are the older Benedict's test and the "stick" test. The Benedicts test is the older test in which a certain amount of urine is added to a measured quantity of the blue copper sulfate solution, and the mixture is boiled after which the change in colour of the solution and precipitate, if any, is noted. This change in the color is supposed to indicate varying levels of sugars in the urine. This test is still very widely used here, the main reason being its cheapness. But, it is also very non-specific and will show a positive reaction with many a reducing substance besides glucose. To give a common example, breast feeding mothers excrete lactose in the urine and the Benedicts test will show a positive result even though the blood glucose of the mother are completely normal and she is not spilling any glucose in the urine. There are numerous drugs and medications that also interfere with the correct result as we shall discuss later. The "stick" has a special paper attached to one end. This paper is impregnated with certain enzymes and when it is dipped into the urine, the change in the color of the paper will denote the presence of, and the varying amounts, of glucose present in the urine. It has the advantage that it is quite specific for glucose and also does not require all the paraphernalia that one needs for the Benedicts test like test tubes, dropper, a source for boiling the solution etc. At the same time, it is costlier than Benedicts test, although the cost can be halved by cutting the strip longitudinally so that one can use each stick twice. It, too, has drawbacks, the chief one being that there are many drugs and medications which interfere with the correct result. These drugs may interfere with false positive or false negative results. Just to show how common the problem can be, two rountinely used drugs which can interfere with the results are aspirin and Vitamin C. Thus, doing urine tests for the presence of sugar when the patient is on any of these tablets would give a completely wrong result. These drugs are so commonly used even by patients themselves that doctors are often unaware that the patient is on these medications. I do not think that it would be possible to find a single diabetic patient who is not taking a vitamin tablet and aspirin is a common household remedy for aches and pains and also now routinely prescribed as a preventive measure against atherosclerosis. Does this imply that testing the urine for the presence of sugars has no role to play in the modern management of diabetes? Whilst, it would seem to be so, especially when other better methods are now available to judge blood glucose control, it should also be remembered that many of these methods are not easily accessible or affordable to many of our patients. They also have their inherent drawbacks. Therefore, I feel, that in spite of all the problems associated with the use of this mode of testing, it will continue to be used by many patients. One of the main reasons is the relative cheapness of the method, but more importantly, due to the fact that most of the patients are unaware of the useless results that one can get from such tests. Urine testing will continue to be important to look for the presence of ketones and albumin in so far as diabetes management is concerned as well as to rule out mild, asymptomatic, urinary tract infection. Some authorities feel that urine testing for glucose may be an adequate parameter to judge blood glucose control in the elderly diabetic who does not have any other complication. The reasoning behind this is that elderly diabetics tend to have a higher threshold and are also quite averse to having the blood tested frequently. Under such circumstances, if the urine shows the presence of glucose, then it could be surmised that the blood glucose levels must be quite high and need to be brought down. Conversely, many young diabetics have a low threshold and a consistent absence of glucose from their urine should be a pointer to the possibility that they many be undergoing subclinical hypoglycemia. Frankly, I am not convinced about either of these aspects. From a practical compromise view point, a newly diagnosed patient with a blood glucose of 400mg% and a urine glucose of 4+, may be monitored by testing the urine glucose till it comes down slightly, to say 2+, and then one must shift to monitoring the blood glucose levels. Finally, if one is going to utilise these tests to evaluate diabetes control it would be better to use the "stick" method, as this is somewhat specific for glucose. At the same time, it is essential that one be aware of the pitfalls associated with these urine tests so that one is not lulled into a false sense of complacency about the glycemic control when the tests for the presence of sugars in the urine are negative. Conversely, drastic changes in the treatment schedule should be avoided just on the basis of

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urine test results Urine testing, is at best, a very crude method for evaluating blood glucose control and should be accepted as such. OCCASSIONAL BLOOD GLUCOSE TESTING This is the parameter that is most commonly used to judge blood glucose control. Patients are usually seen at 2-3 monthly intervals and the fasting and the 2 hour post lunch blood glucose levels are estimated. On the basis of these levels, it is presumed that one can judge blood glucose control, compare this with previous values and judge whether the control is better or has deteriorated and, also make adjustments in the treatment regimen of the patient. Such occasional blood glucose estimations cannot give adequate information to allow us to rationally make these suppositions. The results of any blood glucose estimation are subject to quite a few variable factors which may interfere with the correct estimation and give a variation on the same sample of blood to the tune of 30-50mg%! Firstly, it should be clear that, at present times in our country, there is no accepted standard method to estimate the blood glucose levels. Many laboratories and even some hospitals still continue to use the outdated Folin-Wu method for the estimation of the blood sugar levels. This is the oldest method that was used to estimation of the blood sugar levels and its real place should be in the archives or a museum! It should never in the present time, be used to estimate the blood glucose levels. Like the Benedicts test for urine sugar, it is not very specific and estimates not only glucose but evaluates the presence and amount of any reducing substance in the blood. Therefore, besides, many drugs and medications, even substances which are normally present in the blood stream will give rise to abnormal results. The Somogyi-Nelson and the Hoffman methods although better that the Folin-Wu method should also be discarded and only the methods which will give the true glucose values like those using the Glucose oxidase system should be used. When the patient goes for his blood glucose one must make sure that the laboratory does utilize the oxidase method. Until we reach a stage where the method of estimating the blood glucose levels becomes unversally standardised, we would have to take the method by which any blood glucose is reported into consideration whilst interpreting a report especially if the report is to be compared with any previous results. I have often come across patients who come with two or three previous results and it becomes impossible to compare results because the methods by which the blood glucose have been estimated each, time are entirely different! One of the reasons why this occurs, besides the absence of a standard method, is that many of our patients do not have a fixed place where they get themselves tested. Often they go to the nearest place available to where they are on the day the test has to be done. Thus one of the reports may be from the hospital where the patient may be seen, the next may be from a laboratory near the house of the patient and the third, especially if it is a post meal report, would be from a place of work of the patient. It is possible that these places may use different methods. Even if the same method is used, other variables come into play. Some laboratories estimate the glucose levels in whole blood whilst others may do the estimation on plasma or even serum. It is quite well known that the glucose levels estimated in the plasma can be about 15% (not 15mg%) more than the glucose levels that would have been reported if the whole blood had been used instead of plasma. Therefore, not only is the method of importance, but also the material on which the estimation is done. Unfortunately, if you check your reports, how many of these note down whether the glucose was estimated on whole blood, plasma or serum ? With such a significant discrepancy of 15% between plasma glucose and whole blood glucose, even in the same sample, is it really possible to get a correct idea of the true blood glucose levels, leave alone any worthwhile comparison with previous values. Even if the methods and the material on which the glucose is estimated are the same, the problem is still compounded by other factors. Did you know that if the blood is collected from the back of your hand, the glucose values will be about 1015mg% more than if the blood has been collected from the front of your elbow? Some laboratories have started using the pinprick method to collect a drop of blood from the fingertips and this capillary blood is known to show glucose values which are again anywhere between 10-20mg% higher than what would be estimated in a simultaneously collected venous sample! At the same time, it should be added that the newer glucose meters come calibrated to show the equivalent venous plasma glucose levels. One would have to make sure that the meter which one is using is properly calibrated and know what reading it gives in order to correctly analyse the test results. The time that elapses between the collection of the blood sample and its estimation also affects the results. The greater the

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interval between the time of collection of the sample and the estimation, the lower will be the glucose result. This is in spite of whatever preservative that many laboratories add. It is obvious that there is no standard time interval at which laboratories do the glucose estimation. In view of such variability in the test results, it is not possible to make any valid comparison between the latest and any previous report. Thus, it is not possible to judge whether the blood glucose levels of the patient are better or worse than before. More importantly, I do not feel that it is feasible to adjust the treatment on the basis of such variable, and occasional, blood glucose reports. We have seen that due to the presence of factors that cause so much variability in the blood glucose estimation, the same sample may show a discrepancy of around 30-50mg% ! Even if we are to take a conservative estimate and accept that the variation in the result is around 25mg% , what does this imply in clinical terms ? Let us suppose that we have estimated a fasting blood glucose level and this has been reported as 125mg%. If we accept a variation of even 25mg%, either way, it means that the true blood glucose could range from 100mg% to upto 150mg% ! Whilst a figure of 100mg% or even 125mg% in the fasting stage is acceptable, 150mg% isn't. So what adjustment in the management is to be made ? Are we to accept the result as acceptable and continue the same management ? If we were to do this, and the real blood glucose value is around 150mg%, then it is obvious that we are under treating the patient ! If we try and reduce the 125mg% still further and if the true blood glucose values were to be around 100mg% then we may be exposing the patient to the hazards of nocturnal hypoglycemia ! We would then be over treating the patient. Therefore, for the same figure of 125mg%, any decision that we make to treat the patient, may lead either to over treatment or under treatment of the patient. Such, occasional blood glucose estimates cannot be used to correctly adjust the treatment and these estimates should really be called guesstimates (as the Americans with their penchant for joining two words call it), and accepted as such. Any change in the treatment made on the basis of these random blood glucose reports can, at best be based on intelligent guess work, and not on solid clinical grounds. I would also like to point out the fallacy of presuming that one can judge blood glucose control on the basis of these occasional blood glucose reports. There is no way that such reports can give us an idea of the control. After all, what does a blood glucose report tell us? Say that the sample has been collected on 1/10/2002 at 3 p.m. The test report, even if it were to give a truly correct estimate, only allows us to judge the precise blood glucose levels at the precise time that the sample was collected. It does not reflect the blood glucose levels even 15 minutes previously or the blood glucose levels 15 minutes after the blood has been collected. Let us say that the patient may give the blood sample and go out and eat a lot of sweets. But the report may show, possibly, an acceptable level. Does this imply that the patient's control is adequate ? When we talk of control we mean the average blood glucose levels at all times and not only at the time of the test ! Let us say that three months have passed since the time of the last test for blood glucose levels. A particular patient does not keep to any diet, takes his medicines only when he feels like it and generally in poor control in the sense that his blood glucose levels at most times during these three months are unacceptably high . Two or three days before he knows that he has to go for the test, he keeps to a very strict diet, takes a heavier dose of the medications and somehow brings his blood glucose down. I know of patients who go for a post lunch test without having any lunch ! I also have come across patients who when they have to go for the fasting blood glucose estimation will inject themselves with some regular insulin early in the morning and then go for the test after about 2 hours of the injection. With all these manipulations, often the blood glucose results come in the acceptable control, we would obviously be mistaken as the patient has been in poor control throughout the three months and has just brought down the blood glucose levels prior to the time of the test ! Conversely, we take the example of a patient who has kept to his diet, exercise and medications in the months since the last test and has been in acceptable control in he sense that his blood glucose levels have been in a good range throughout the three months. A few days prior to the test, he may have come down with flu and this will show up in the test as a high blood glucose level. Are we then to accept that this patient has been in poor control for the three months since the time of the previous test ? Blood glucose control is to be judged over a span of time and it is obvious that occasional blood glucose test will NOT give us any idea about the true control. Thus, such blood glucose reports do not have any role to play in judging blood glucose control over any span of time, and it may not even be feasible to correctly adjust treatment on the basis of such random reports. ESTIMATION OF THE GLYCOSYLATED HEMOGLOBIN LEVELS An estimation of the glycosylated hemoglobin (HbA1c) levels allows us to assess the blood glucose control over the previous two months. In common with many other proteins, some of the amino acids in the hemoglobin molecule can bind the glucose molecules to which they are exposed. In very simple terms, let us say that for every five glucose molecules, one

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would get attached to an amino acid. If ten glucose molecules are present, then it would follow that two amino acids would get glucose attached to them, then it would mean that the amino acids had been exposed to a greater than normal amount of glucose! Therefore, if one were to estimate the amount of amino acids (protein) to which glucose has become attached, one would be able to gauge the amount of glucose to which the protein had been exposed. This is the basic principle behind the use of glycosylated hemoglobin levels in judge blood glucose control. Since the hemoglobin is found in the circulating red blood cells, the glucose to which it would be exposed would be the glucose present in the blood. If more than the normal amount of hemoglobin becomes glycosylated, this would imply that if had been exposed to more than normal amounts of glucose and therefore, the blood glucose levels had been higher than normal ! How is the figure is 60 day or 8 weeks arrived at? A red blood cell has an average life span of 120 days, and therefore, more red blood cells are being constantly made and released into the bloodstream. If we were to analyse the red blood cells taken from any blood sample, it would follow that some of the red blood cells would have been in the circulation for almost 120 days and others would be newly released cells. The other red blood cells would have been in the circulation for periods in between these two extremes. The longer the red blood cells has been in circulation, the greater has it been exposed to the blood glucose and the greater would be the amount of glucose that is attached to it. Conversely, newly released red blood cells would not have any glucose attached to them. In order to average out these extremes, it is presumed that the average bed blood cell has been in the circulation for about 60 days (the midpoint of 0-120 days), and therefore the amount of the hemoglobin that has become glycosylated would give an idea of the blood glucose levels over these 60 days. If the average blood glucose levels has been normal, than the estimated amounts of glycosylated hemoglobin would be within normal limits. If hyperglycemia has been present, than the degree of this hyperglycemia would be reflected in the increased amount of the hemoglobin that would become glycosylated. In other words, the levels of the estimated HbA1c reflect the prevailing blood glucose levels over a period of 60 days, or 8 weeks. If all this sounds confusing, another way of looking at this would be to imagine that a needle has been inserted into the blood stream and this needle leads into a computer. This computer estimates the blood glucose levels every second and all the results are stored in the memory of the computer. At the end of 60 days, all the results are added up and the computer gives an average figure for the prevalent blood glucose levels over this time. HbA1c levels are akin to this average blood glucose levels. Estimation of the HbA1c levels has some definite advantages over the occasional testing for blood glucose levels at intervals of 2-3 months, that we have previously discussed. It was seen that even if the numerous drawbacks associated with the estimation of the blood glucose levels are overcome, such occasional test for the blood glucose levels will only tell us about the blood glucose levels and glycemic control at the precise time of the testing! When we talk about control of the levels we mean that the blood glucose levels would under acceptable control at all times and not only at the time of the test. By giving an idea of the average blood glucose levels over a period of 60 days, HbA1c determination is a better indicator of blood glucose control. Let us take the same two examples that we considered to show the fallacy of trying to judge blood glucose control by the occassional test for blood glucose levels. We took the examples of a patient who does not keep to his diet, does not exercise and takes his medications only when he feels like it. Two or three days before he knows that he has to go for the test, he keeps to a very strict diet, exercises heavily and also takes a larger than necessary dose of medications. With these manipulations, he manages to bring his blood glucose levels down so that when the blood is tested for the glucose levels, they may be found to be in the acceptable range. Before we could estimate the HbA1c levels, this would imply that the control of the patient was optimal although this is far from true. If in such a patient, the glycosylated hemoglobin levels were to be estimated, these would have been seen to be much higher than normal as they reflect the blood glucose levels over the previous 60 days when the patient had obviously been in poor control and all the wiles of the patient would not allow him to mask the true state of his control ! Conversely, the patient who has been in good control, but due to some reason like suffering from a 'flu' attack, shows a higher than acceptable blood glucose level would manifest a basically an acceptable HbA1c level as the deterioration in the blood glucose values in the past couple of days would not significantly alter the levels. This would enable us to understand that the patient is basically in good control but possibly for some reason presently has a high blood glucose levels. This would make us search for the cause of the deterioration rather than make a blind increase in the medications which may expose the patient to a risk of hypoglycemia. The estimation of HbA1c levels is also more convenient for the patient. The blood for the estimation can be collected at any time and the patient does not have to be in a fasting stage or at any fixed interval after a meal. Thus, the blood collection can

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be done even when the patient comes for his routine checkup at any convenient time. You must make sure that what is estimated is the HBA1c, which is the accepted norm today. It is possible to get a fairly good idea of the average blood glucose levels over the past two months based on a correctly carried out HbA1c reading.

Although, HbA1c levels do give an excellent idea of the blood glucose control over the previous 60 days, there is one other, clinical aspect that needs to be considered. Usually, the patient would come to the doctor after a period of two months with blood glucose tests and also HbA1c levels. If these levels are seen to be in the high range, then it is obvious that the patient has been in poor control over the previous 60 days. One can then only take corrective measures and even when these are taken, changes in the HBA1c levels would only be reflected after a further period of 60 days. Thus, at least four months would pass before the patient was known to be back in the good control. In case, as often happens, the HbA1c level at the second visit is not yet normal, then a further period of two months would be lost! In my opinion, if we are to talk of the correct, modern management of diabetes, then one cannot allow the patient to remain without optimal control for such a long time just because we are waiting for the glycosylated hemoglobin levels to be normalised. Rather than take corrective measures, it would be better to take immediate measures to optimise the blood glucose control if this is seen to be poor, rather than wait for a few months for changes in the HbA1c levels. One way to overcome this problem is to estimate serum fructosamine levels. This is basically the same as HbA1c estimations, but estimates the attachment of glucose molecules to albumin in the blood. Due to the relatively shorter half life in the blood of albumin, serum fructosamine estimations give an idea of the average control over the past fortnight. Unfortunately, this estimation is not widely available and should preferably be done in special situations such as pregnancy where one wants a tight control throughout, without having the luxury to wait for 2 months to decide if the patient is in good control as would be seen with HbA1c estimations! The other, and definitely better alternative is for the patients to self monitor their blood glucose levels (SMBG). SELF MONITORING OF BLOOD GLUCOSE LEVELS (SMBG) SMBG by the patient himself has, in my opinion, completely revolutionised the modern management of diabetes. Such self monitoring tests are extremely convenient for the patient. He can carry out the test at home, work or even elsewhere without having to take the trouble to go to any laboratory. Thus, these tests can be done at varying times of the day and night so that one can get an idea of the blood glucose profile throughout the day. As the test can be done so conveniently and frequently, one can take corrective measures to optimise the blood glucose levels almost as soon as they occur without having to wait two months for the HbA1c levels or take the recourse either having to go a laboratory often and at odd hours or even get admitted to a hospital!

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Ideally, all patients should self monitor their blood glucose levels, using test trips and meters which are now available. If it is not feasible, SMBG should be carried out by : 1. All patients on insulin therapy, especially those on multiple dose regimens; 2. patients with widely fluctuating blood glucose levels; 3. patients prone to severe ketosis or recurrent hypoglycemia; 4. those manifesting hypoglycemia "unawareness"; 5. patients in whom a "tight" control is essential, i.e. pregnancy, etc.; during acute illness; 6. in the perioperative period; 7. those with abnormal renal thresholds It should be clear that in many these conditions one would not have the luxury of waiting for HBA1c levels, it may not be possible to go to the laboratory at odd times and so frequently, and in many of such conditions, the urine tests are fraught with too many errors for them to be of any use. I am often asked as to how often a patient should monitor the blood glucose levels. I feel that patients on multiple insulin injection regimens, patients with critical problems such as those with sight threatening macular edema and infections, and pregnant patients in whom a tight control is mandatory should preferably monitor their blood glucose two to three times daily. They should be taught how to adjust their doses depending on the levels. If in spite of this, the blood glucose remain high, them they should consult their doctor at once. It is clear from this that poor control would be detected early and corrective measures can be taken at the earliest, which is as it should be. Patients who may not fall in these "critical" categories, are asked to test the blood glucose daily at different times for about 1-2 weeks or until they are confident about the method of testing and are optimally controlled. Once this is done, they are asked to test the blood twice or thrice a week just to make sure that the control remains at an optimal level. In case, they find that the control has deteriorated, then they should revert back to a more intensive frequency of testing and take the corrective measures until the control is back to the original optimal levels. Thus, here again, one would be fast off the mark in initiating corrective measures before the hyperglycemia has persisted for any significant time. At the same time, frequent testing for the blood glucose levels would also help in preventing any hypoglycemic attack in our quest for optimal control. Once the control has been optimised, the frequency of testing can be reverted back to twice or three times a week. All doctors treating patients who have diabetes must use a glucose meter as a part of their medical equipment, just as they carry a stethoscope and a BP apparatus. Not only will this allow you to diagnose diabetes in your patients at an early stage before complications have set in, but even in your patients who are known to have diabetes, you would be in a unique position to test their blood glucose levels at different times of the day. This would allow you to get a profile of the blood glucose values, allowing a more rational adjustment of their treatment. Carrying a meter with you would also be of help in certain emergencies which you may attend. Let us say that you are asked to see a diabetes patient at home, who is comatose. Is this hypoglycemia or is this caused by a hyperglycemic state? Correct and early treatment can save the person's life and this differential diagnosis can easily be made if you have a glucose meter with you. One should also remember that hypoglycemia can mimic many other critical states such as strokes etc., If you find a low blood glucose in such a patient and are able to administer glucose, the patient may show a " miraculous" recovery of the paralysis was due to hypoglycemia! One problem with the use of glucose meters and strips is that the strips may spoil rapidly in the high ambient temperatures and the degree of humidity that occurs in our country. This is in spite of the desiccating materials that are incorporated in the bottles. Although manufacturer's advise that the strips can be used for about 3-4 months after the bottle is opened, in my experience, the strips spoil within 2-3 weeks. I hope that the manufacturers of the strips will make the individually packed strips available here soon. This should not be problem as they do market them in such individually wrapped foils abroad. Although there may be some additional cost, patients would rather pay this little extra rather than have their money wasted on spoilt strips. More important than the wastage of the money, is the fact that if the strips are spoilt even a bit, they may

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register low readings and their may be a false sense of complacency that the blood glucose levels are under good control. Patients especially if they have to test themselves often complain about the pain of pinpricks. This usually occurs when the older all metal triangular lancets are used. A number of fine point, plastic coated lancets are available which are definitely easier to use and less painful especially if used with a companion lancet plunger. Even if the lancets are not.used, disposable needles will do fine. I find that the thinner needles, like No.23 give a much better drop of blood as compared to the thicker needles. Pricking on the lateral aspect of the middle three fingers further to the distal finger joint often causes less pain. One fear that has been expressed with the routine use of self monitoring is that one may make patients neurotic about their blood glucose control. Such patients have been reported and have been called as "blood glucose junkies". A rational discussion about the need and the importance of self monitoring, the need not be to be very upset about a high reading but to calmly carry out the corrective treatment and a more humane and friendly approach by the doctor can go a long way to protect against this. There are some who will get very emotional about testing, but these are patients who will invariably have an over reaction not to the self monitoring of the blood glucose levels, but to the fact that they have diabetes per se. I do not think that self monitoring should be blamed for this tendency. The benefits of self monitoring far outweigh the occasional patient who may over react to this method for judging blood glucose control. In conclusion, self monitoring of the blood glucose levels by the patient along with an estimation of the HbA1c level at 2-3 monthly intervals allows us to offer the most optimal method to judge blood glucose control at present. Most importantly, it must be realized that monitoring blood glucose levels is not the same as monitoring diabetes. Besides glycemic control, optimal monitoring in diabetes, implies optimising weight, blood pressure, lipid abnormalities, and importantly, the diagnosis of the presence of long term complications in their early, initial stages. FASTING HYPERGLYCEMIA: SOMOGYI AND DAWN PHENOMENON Dr. S.M.Sadikot. Hon. Endocrinologist, Jaslok Hospital and Research Centre, Mumbai 400026 Case Report Mr. P.F.A, a male aged 38 years was admitted in a comatose condition around 6 a.m. The accompanying relative informed the resident on duty that due to the fact that the patient regularly got up by 5.30 a.m., efforts had been made to wake him up, and when this failed, he had been urgently shifted to the hospital The only history that the relative could give was that the patient had diabetes, was taking insulin, and the family physician had told them that the blood glucose control of the patient was poor, possibly due to the erratic eating habits. O/E, the patient was comatose with a pulse of 110/minute, regular but "racy". The BP was recorded as 180/90. The patient felt cold and clammy and his clothes were drenched. The heart sounds were well heard, there was no murmer. The examination of the chest and the abdominal system was normal except for sinus tachycardia, and the examination of a catheter specimen of urine showed the presence of a trace of glucose but no ketones. The random blood glucose estimation done using a bedside glucose meter showed the levels to be 45mg%. Once blood had been collected for other tests, 100c.c. 25% dextrose was slowly infused intravenously followed by a 5% dextrose drip. The patient gradually regained consciousness and in a few hours seemed to be back to normal. At this time, a further detailed history was elicited. The patient informed us that he had been diagnosed as having diabetes about 2 months previously and had been put on a single pre-breakfast dose of 20 units of an intermediate acting insulin. This had been gradually increased to 32 units and a week back, when his blood glucose had been examined, the fasting blood glucose was found to be 160 mg% whilst the post lunch values were 172 mg%. Surprisingly, his HbA1c levels were in mid to high normal range. In view of the fasting hyperglycemia, the pre-breakfast dose of the insulin had been increased to 36 units, and 3 days later to 40 units. In spite of this, the fasting blood glucose levels could not be controlled, and in fact there was some rise seen. At this time, the patient volunteered the information that he had been feeling quite unwell, and when seen by his doctor had complained of tiredness and early morning headache. For the first time, his BP was found to be slightly high. His tiredness had been attributed to the uncon- trolled diabetes and the headache to the high blood pressure.

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The previous morning, he had been asked to take his usual dose of 40 units of the intermediate acting insulin. In addition, he was asked to take 10 units of the same insulin before his evening meal and also asked to halve the bedtime milk. It was hoped that this would decrease the raised early morning blood glucose levels. Discussion This case report illustrates a relatively common dilemna seen when patients are treated with "conventional" insulin regimens. The fasting blood glucose levels tend to be in the unacceptable high range whilst the control throughout the day may be quite fair! From practical viewpoint, there seem to be three main causes for this: 1)A simple waning of the insulin effect so that there is not enough insulin at nighttime to maintain control over the blood glucose levels in the early morning period; 2) The Dawn phenomenon; and 3) The Somogyi phenomenon; It is of greater importance to correctly distinguish between the Dawn and the Somogyi phenomenae as the management of these are radically different and a misdiagnosis can lead to quite a catastrophe, as happened to this patient. DAWN PHENOMENON When Type 1 patients were closely monitored during intensive conventional therapy or whilst being on continuous subcutaneous insulin infusion (CSII), overnight monitoring of the blood glucose levels showed that the blood glucose levels rose and the insulin requirements increased between 3 a.m. and 7 a.m. and this increase in the insulin requirements and the hyperglycemia that followed was referred to as the "Dawn" phenomenon. Later, this phenomenon was also reported in Type 2 patients and even in people who did not have diabetes. It is now fairly well established that many hormones undergo a diurnal variation. These changes in hormonal levels occur both, in people with and even in those who do not have diabetes. Soon after the onset of sleep, there is a surge in the secretion of growth hormone. Cortisol shows a significant increase between 2 a.m. and 4 a.m. and reaches peak values shortly after waking up. The catecholamines gradually increase overnight whilst glucagon remains relatively constant. Growth hormone, cortisol and the cathecolamines are all potent insulin antagonists and these changes in the secretion of the antagonists seen during the overnight period could explain the increased insulin requirements and the consequent early morning hyperglycemia. Recent studies have shown that it is the growth hormone surge seen soon after a person falls asleep, which seems to be the determining factor in the Dawn phenomenon. Although the increase in the cortisol and the cathecolamines may not by themselves be essential for the Dawn phenomenon, it is quite plausible that they have an added or even synergistic effect. The obvious consequence of the rise in the levels of these insulin antagonist hormones leads to a relative insulin "deficiency" and unless more insulin is secreted by the body (or is administered), hepatic neoglucogenesis would not be finely controlled and more and more glucose would be delivered to the bloodstream leading to early morning hyperglycemia. SOMOGYI PHENOMENON The Somogyi phenomenon is a manifestation of hyperglycemia following, possibly unrecognised, hypoglycemia. The clinical picture here, is one of worsening control in the face of increasing insulin doses and is manifested especially by early morning hyperglycemia. Excessive insulin dosage could lead to hypoglycemia, which occurring at night-time when the patient is asleep, may go unrecognised. But the counter-regulatory hormones (cathecolamines, glucagon, growth hormone and cortisol) rise as a consequence of the hypoglycemia and cause the blood glucose to rise. As there does not seem to be "fine tuning" of the magnitude of the counter regulatory responses and because these hormones are also insulin antagonists, there is an often an overshoot of the blood glucose which tend to go much higher than normal. Increasing the amount of insulin in order to counter the fasting hyperglycemia serves to intensify the nocturnal hypoglycemia and increase the counter regulatory response. This may be seen as a further increase in the fasting hyperglycemia in spite of increased insulin doses. Too much of an increase in the insulin dose could of course lead to a level of hypoglycemia from which the counter regulatory hormones may not be able to increase the blood glucose levels

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and the patient may manifest with frank hypoglycemic coma. WANING OF INSULIN EFFECT The third condition which commonly leads to a fasting hyperglycemia is a waning of the insulin effect seen overnight. In other words, the amount of insulin in the body decreases overnight and this decreased amount of insulin is not enough to prevent a rise in the blood glucose levels. In fact, at one time, it was thought that the Dawn phenomenon could be caused by an increase in the metabolism of insulin at night so that there would be less "active" insulin available to control the blood glucose levels. But studies in which insulin was infused in patients such that the insulin levels were kept constant throughout the night did not prevent the Dawn phenomenon. Fortunately, the management of the Dawn phenomenon and the problems of waning insulin levels is basically the same and therefore, the main clinical prob1ems is the differentiation between the Dawn phenomenon and the Somogyi phenomenon. DIFFERENTIAL DIAGNOSIS The best way to distinguish between the two would be to estimate the blood glucose levels at different times throughout the night. The patient could do self monitoring of the blood glucose levels at home, or if hospitalised, this could be done by more conventional methods. The estimations should be done at bedtime, at midnight and at 3 a.m. In patients showing the Somogyi phenomenon, a typical pattern would be normal or near normal, blood glucose levels at bedtime and midnight which decrease appreciably around 3 a.m. It has been shown that a value of around 70 mg% at 3 a.m. would suggest the presence of the Somogyi phenomenon. In patients manifesting the Dawn phenomenon, the blood glucose levels at bedtime, midnight and at 3 a.m. would tend to be similar and after this time, the blood glucose levels would increase to reach hyperglycemic levels by early morning. If it is not possible to do the blood glucose estimations, one method that may give a clue to the presence of the Somogyi phenomenon is to do a urine glucose estimations (in a double voided specimen) around 3 a.m. and in the early hours. If the former shows no glucose but the latter is MARKEDLY positive, the patient may be experiencing posthypoglycemic hyperglycemia. There are several other clues that may also point to this diagnosis. Rapid fluctuations in the results of the urine tests showing negative results and then suddenly changing to maximal values. Wide swings in the blood glucose levels which are not related to meal intake is another pointer to the diagnosis. It is also impera- tive that one should be able to recognise the subtle symptoms and signs of nocturnal hypoglycemia. The patient may complain of enuresis, nightmares, unusual sweating during the night, early morning headaches. A typical patient may also show a raised blood pressure in the early hours which tends to normalise after breakfast! MANAGEMENT STRATEGIES Once the diagnosis of the problem is clear, the management does not offer any difficulty. In patients with the Dawn phenomenon, one needs to increase the overnight insulin whilst the reverse seems to be the case with the Somogyi Phenomenon. How this is done would obviously depend on the individual patient. For the management of the Dawn phenomenon, one or more of the following could be done: 1) Give a small pre-dinner dose of intermediate acting insulin, if the patient is not already taking one; 2) If the patient is taking a dose of an intermediate acting insulin before dinner, this could either be judiciously increased or the timing of the injection delayed so that the maximum activity could be seen around 2-4 a.m.; 3) A small dose of regular insulin could be given before the post-dinner(bedtime) snack; The purpose of all these manipulations would be to increase the amount of insulin available in the body during the crucial 2-4 a.m. period. It is obvious that if an additional injection is given or the dose of the insulin is increased, corresponding changes must be made in the dose of insulin given at other times in order to prevent daytime hypoglycemia. The strategies to manage the Somogyi phenomenon could be: 1) Decrease the dose of the evening insulin injection; 2) Add, or increase, the amount of dinner or, preferably, the bedtime snack;

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3) Decrease the amounts of intermediate or long acting insulin given during the morning; The patient, Mr. P.F.A. was obviously manifesting the Somogyi phenomenon in the previous days. There were several clues present which could have pointed to the correct diagnosis. There was a worsening of blood glucose control in spite of increasing the insulin dose as could be seen from the increase in the levels of early morning hyperglycemia. The patient also complained of feeling extremely tired in the morning and of having a headache. His BP was found to be high for the first time after the increase in the insulin doses. An indirect clue could be the mid to high normal levels of HbA1c of unacceptable fasting blood glucose levels. Since HbA1c tends to "average" out the ambient blood glucose levels, his level in context of raised fasting blood glucose levels and "fair" post-meal values should have pointed out to the possibility that the patient may have been undergoing episodes of very low levels of blood glucose at some time during the 24 hours.

CRITERIA FOR DIAGNOSIS

Table
Glucose Concentration (mg/100ml) Whole Blood Venous Diabetes Melittus Fasting 2 hours post Glucose Load or both >/=110 >180 >/=110 >200 >/=126 >200 Capillary Plasma Venous

Impaired Glucose Tolerance Fasting(If measured) 2 hours post Glucose Load <110 <110 <126

>/=120 & </=180 >/=140 & </=200 >/=140 & </=200

Impaired Fasting Glycemia Fasting 2 hours PG (If measured) >/=100 & </=110 >/=100 & </=110 >/=110 & </=126 <120 <140 <140

When analyzing the results, it becomes apparent that all the test results can be divided into three main categories: people who have diabetes, people who do not have diabetes and an intermediate category which depending on the method of testing is known as having either Impaired Glucose Tolerance (IGT) or Impaired Fasting Glycemia (IFG). Before the ADA changed the procedures for testing, one had to carry out the full 2 hours GTT. When the results of this are analysed, one could be diagnosed as having IGT. This is an intermediate category between those who have frank diabetes and those whose results fall clearly in the normal range. Some of these patients will later go on to have diabetes, whilst others may not progress to the stage of frank diabetes. Patients falling in this category should be closely followed such that, if they progress to the diabetic stage, this would be diagnosed at an early stage. At the same time, many of the patients who are in the IGT category tend to be overweight, have problems with their lipid levels, are hypertensive and have a higher than acceptable serum uric acid level. I.G.T. is risk factor for the development of macrovascular disease. Thus even if these patients are not diabetics, they should undergo management for these problems. If one uses only the fasting values as suggested by the ADA, it would not be possible to diagnose IGT as the 2 hours postglucose values needed for a diagnosis of IGT would not be available. Impaired Fasting Glycemia (IFG) is an entity which has recently been introduced to delineate persons in whom only the fasting blood glucose has been done, but who do not come in the normal or diabetic category. Many of the associated disorders we mentioned as being possibly present

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in those with IGT are also true for those with IFG. In fact, IFG is felt to reflect a higher average glycemic burden than IGT. It is considered a marker for the development of diabetes and its long term complications. Although there is still some controversy about using only the fasting blood glucose values for diagnosis, it is now felt that this would be acceptable to pinpoint those with diabetes in prevalence studies. The WHO feels that in most cases this should be followed by a full GTT, if feasible. Most people tested would show "normal" values. But, "A NEGATIVE TEST RESULT ONLY SHOWS THAT THE PERSON DOES NOT HAVE DIABETES AT THE TIME OF TESTING. IT DOES NOT MEAN THAT THE PERSON WILL NEVER GET DIABETES IN THE FUTURE. WHICH IS WHY AN ANNUAL CHECKUP IS ESSENTIAL" DIAGNOSIS OF GESTATIONAL DIABETES (GDM) Gestational Diabetes Mellitus (GDM) is defined by abnormal glucose tolerance during pregnancy; the glucose tolerance test is normal before, and which will usually be normal, after pregnancy. Present in around 3-4% of all pregnancies, GDM can be associated with significant morbidity and mortality in the fetus and newborn. Thus, it is important for gestational diabetes to be ruled out in all pregnancies. Ideally, all pregnant women should be tested to rule out gestational diabetes, but if this is not feasible, all high risk patients must undergo the test. HIGH RISK Patients 1. Women who had GDM during a previous pregnancy. 2. Women with a first degree relative who is a diabetic. 3. Women who gave birth to large weight babies in a previous pregnancy. 4. Women whose newborn, in a previous pregnancy, showed any complication known to be associated as arising from maternal GDM. 5. Women who gave birth to still born babies or infants with congenital abnormalities. 6. Women with a bad obstetric history, including recurrent fetal wastage, hypertension, eclampsia, hydramnios, etc. 7. Women with repeated or persistent urinary tract infection. 8. Women manifesting glycosuria during pregnancy. 9. Women over the age of 30 years. When Should One test for GDM The test should be carried out at the time of initial visit and at the start of every trimester; high risk patients may require more frequent testing SCREENING METHODS for GDM Initial screening produce may be done by estimating the fasting glucose levels and the levels 1 hour after an oral dose of 50 gms. of glucose. This test can be carried out in the fasting stage or at any time; in the latter case, only the one hour blood glucose value is taken into consideration for diagnosis. Patients with a fasting venous whole blood glucose level of more than 80 mg% (venous plasma glucose more than 90 mg%). OR

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a 1 hour post 50 gms. glucose load venous whole blood glucose value greater than 120 mg/% (venous plasma glucose more than 140 mg% require a more comprehensive test. OR A "random" venous blood glucose level exceeding 105 mg% (plasma glucose >120 mg%) also merits a more comprehensive test. COMPREHENSIVE TEST for GDM The comprehensive test is the same as described for the diagnosis of diabetes in non pregnant persons. BUT, the criteria differ. In addition to blood glucose levels in the diabetic range, values suggestive of IGT, in a pregnant female, should be taken to be diagnostic of gestational diabetes Many centres still utilise the O'Sullivan Criteria. O'Sullivan Criteria. In this test, blood is collected in the fasting stage and then at 1, 2 and 3 hours intervals after an oral load of 100 gms. of glucose. Plasma Glucose (mg/100ml) Fasting 1 hour 2 hour 3hour 105 190 165 145 90 165 145 125 Whole Blood Glucose (mg/100ml)

Two of the four values must be met to diagnose GDM As a matter of interest, about 30-40% of women who are diagnosed as having gestational diabetes will later go on to have full fledged diabetes within 5-10 years of the pregnancy. Thus, they would automatically come into the High Risk category and must have annual check ups as discussed above. I am often asked whether an estimation of Glycosylated Hemoglobin level can be used as the parameter to diagnose diabetes. Let me make it quite clear that, at the present times it is not possible to accurately make this distinction between those that are normal and those that have diabetes or may be in the IGT or IFG category. Although the estimation of these levels are excellent to give an idea of the overall control of the blood glucose levels in the preceeding 6-8 weeks, they CANNOT be used for the diagnosis of diabetes, in most patients. The argument that a very high glycosylated hemoglobin level would be diagnostic for diabetes can be very easilv countered by the fact that if the glycosylated hemoglobin level were indeed to be so high, then it is apparent that even a random estimate of the blood glucose levels would show it to be in the distinctly "diabetic" range, and this can be done at much less cost to the patient! Lastly, once a patient has been diagnosed as being a diabetic, he need NEVER undergo a Glucose Test. This test is only for diagnosis. A known diabetic needs to know whether he is under optimal control or not and stressing him with a glucose load will definitely not give an answer to this problem. This is an important aspect as many doctors, including "specialists", have the patient undergo repeated G.T.T's! When a diabetic comes for a follow up with a fresh G.T.T., it is of absolutely no help in his management.

HYPOGLYCEMIA IN A DIABETIC PATIENT

Hypoglycemia is considered by many to be the most common emergency associated with the management of diabetes. Some call it an acute "complication" whilst others deem it to be a "side-effect" of the treatment. The latter feel that as the

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aim in the treatment of diabetes is to bring the blood glucose levels to as near normal as possible, hypoglycemia should be considered as a greater than required effect of the treatment! Whether it is a "complication" or a "side- effect", no one disputes the fact that hypoglycemia is very much an emergency that should be, if not avoided completely, at least recognized at the earliest so that vigorous steps can be taken to prevent any damage to the patient. Today, when "tight" control seems to be the mantra of glucose management, there are many who feel that it is not really possible to achieve tight control without the patient experiencing some episodes of hypoglycemia, especially those of a relatively mild nature. Without entering into a debate about this, it is well accepted by everyone that the patient should not have severe, prolonged or even numerous mild episodes of hypoglycemia. Whilst it is fairly widely recognized that a severe attack can lead to significant morbidity and even death, it is much less widely known that even recurrent so-called "mild" attacks of hypoglycemia can lead to complications which are similar to those that have been termed as long term diabetic complications. Ironically, these are the very same problems we would like to avoid by offering the patient a good and tight control! I would like to discuss the traditional signs and symptoms of hypoglycemia with a special emphasis on the very early and subtle manifestations. Later we will see what are the measures which one can take faced with the likelihood of experiencing hypoglycemia. Let us first discuss the classical signs and symptoms of hypoglycemia. These fall into two main categories: the sympathoadrenal (those caused by the increased activity of the autonomic nervous system) and the neuroglucopenic (caused by a decrease in the activity of the brain due to a decreased supply of glucose). Classical Signs and Symptoms of Hypoglycemia Adrenergic Weakness Sweating Tachycardia Pdyitations Tremor Nervouness Irritability Tingling of mouth and fingers Hunger Neuroglucopenic Headache Hypothermia Visual disturbances Mental dullness Confusion Amnesia Seizures Coma

The adrenergic signs and symptoms are weakness, sweating, increased heart rate, palpitations, trembling especially of the fingers, feeling of nervousness, irritability, a tingling or a funny sort of feeling in the mouth and fingers, hunger and sometimes nausea and vomiting. It is very important to realise that these signs and symptoms of "sympathoadrenal" activity occur whenever the blood glucose levels are falling very RAPIDLY! In fact, the faster the rate of fall of the blood glucose levels, the greater the manifestations of this over activity. In other words, these signs and symptoms may not necessarily reflect the actual levels of blood glucose but are significantly dependent on the rate of its fall. Thus, they may occur even if the blood glucose levels are low, normal or even higher than normal! I should be admitted that there are some experts who do not completely agree with this and feel that these signs and symptoms would only occur with a low blood glucose. Most of the others feel that whilst, often these manifestations are accompanied with a low blood glucose, they are dependent on the rate of fall of the blood glucose rather than its level per se. In any case, what one has to remember is that whilst these signs and symptoms should warn of a possible hypoglycemic reaction and corrective measures should be taken, it should also keep in mind that they may be due to treatment itself which is causing the blood glucose levels to fall too rapidly although they may not as yet be in the low range.

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In my experience, this is usually seen if the patient is using heavy doses of regular insulin or in some normal or underweight patients who are initially on heavy doses of oral hypoglycemic agents. In such circumstances, a decrease in the amount of insulin and/or oral agents may alleviate the signs and symptoms completely! In contrast, the signs and symptoms associated with "neuroglucopenia" are only seen when the blood glucose levels are truly in the hypoglycemic range. They do not seem to have any relationship with the rate of fall of the blood glucose levels. The manifestations are caused by a lower supply to the brain of glucose than its requirements. The signs and symptoms include headaches, low temperatures, visual disturbances, mental dullness, confusion, forgetfulness, convulsions and coma. In the classical manifestation of hypoglycemia, both, the "sympathoadrenal" and the "neuroglucopenic" signs and symptoms are seen, although some may not show the former manifestations. Once again, it is important to realise this, due to the fact that many patients are under the impression that unless they exhibit the signs and symptoms associated with sympathoadrenal overactivity, they cannot be undergoing a hypoglycemia episode! Therefore, problems such as headaches, confusion, forgetfulness, sight disturbances, convulsions etc. are not diagnosed correctly. I have seen patients who have undergone intense and expensive investigations, made to wear spectacles, had their nasal sinuses operated, given psychiatric treatment or even shunned off as being senile when the root cause of their problems was simply hypoglycemia! All this expense, stress and mental agony could have been averted if the blood glucose had been estimated! I am not trying to imply that all these problems cannot occur in a patient with diabetes, they can. But, as I will stress again later, in any patient who presents with medical problems, hypoglycemia should always be near the top of the differential list. Having made this point, let us consider some of the common situations where a patient may not exhibit the signs and symptoms of "sympathoadrenal" overactivity. As mentioned earlier, if the blood glucose levels fall very slowly, these manifestations may be absent even if the actual level of blood glucose is in the hypoglycemic range. Many diabetics have neuropathy and its presence may not allow the sympathoadrenal signs and symptoms to manifest. Others who have high blood pressure are put on quite high doses of drugs like beta blockers. These drugs can also lead to a blocking of the signs and symptoms that we traditionally associate with hypoglycemia. Quite a few patients will exhibit signs and symptoms when they are truly hypoglycemic which do not come into the categories of the "classical" manifestation of hypoglycemia as described above. If patients become excessively quiet, show a lack of interest, is unnaturally good or conversely becomes fretful, highly irritable and prone to throw "temper tantrums", hypoglycemia should be ruled out. This is especially true in children with Type 1 diabetes. Similarly, when adult patients become morose, ambitionless, are. depressed without adequate reason, complain of feeling weak and faint, become very irritable and are apt to lose their tempers without any real or worthwhile provocation especially if in the past, they have been relatively calm persons, or behave abnormally, 1qw blood glucose levels should be ruled out as a first step. In other words when any person with diabetes shows behaviour which is not in keeping with his "usual" self, one should consider hypoglycemia as the cause of the problem. Very often, the patients themselves are completely unaware of this change in attitude and behaviour and therefore, it is imperative for the family and fellow workers to be aware of these aspects so that they can draw attention to this and corrective measures could be taken. In my experience, it is usually the family that is able to see the change in behaviour of the patient. To give an example, one wife of a patient complained to me that her husband was very irritable and was very rough with his children who previously used to be the "apple" of his eyes. He always used to complain that the children were noisy and that he had no peace and would beat them up on the slightest provocation. It had reached such a stage that the young children had been sent off to their grandparents house and there was a distinct possibility of the marriage breaking up! Hypoglycemia was the cause of this behaviour and a decrease in the dose of oral agents that he was taking solved the problem completely and the family is back happily together.

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One of the most difficult diagnosis to make is that of "subclinical" hypoglycemia. One example that we could take is that of hypoglycemia occurring at night during sleep. This may not be severe enough to cause coma, or even cause the patient to sweat so that he complains that when he gets up, his clothes and even the bed sheet is drenched. In my experience, asking the patient whether he experiences night sweats, has early morning headaches or has vivid and bizarre dreams and nightmares often offers subtle clues to the fact that the patient may be undergoing hypoglycemic episodes in his sleep. At the same time, let me make it clear that the level of blood glucose estimated in the morning at the fasting state, even if this higher than normal, is not proof that one may not be having hypoglycemia at night. This fasting blood glucose levels may be manifestation of the Somogy Effect, where hypoglycemia at night, during sleep, can cause a reactive (or rebound) hyperglycemia. One point of great clinical importance is that most patients have their own characteristic pattern of showing hypoglycemia reactions and this pattern often remains constant for the patient, It is imperative that patients, their family and the treating doctor be thoroughly familiar with this characteristic pattern so that any hypoglycemia can be recognized at the earliest and treatment given before there is any serious and long lasting damage. I would like to discuss a couple of situations that may lead one into thinking that we are not dealing with hypoglycemia, in spite of the fact the patient is truly hypoglycemic and also exhibits all the typical signs and symptoms of hypoglycemia These situations should be known as they needlessly delay the diagnosis and treatment of hypoglycemia and may thus lead to serious consequences. Often, the patient or the doctor will examine the urine for sugar when the patient complains of hypoglycemia manifestation. One may be surprised to see that the urine does contain a moderate or even high concentration of sugars. This, leads to the wrong conclusion that the patient does not have hypoglycemic as many feel that when the sugars are present in the urine, it shows a high blood glucose level. Conversely, some are under the false impression that in hypoglycemia, the urine should not show any sugar. What we forget is that what one examines, may have been in the bladder for quite a while and that, during this period, the patient may have had a high blood glucose level with a consequent leak of the glucose in the urine. Therefore, the urine that has been in the bladder will not correlate to the situation at the time that the manifestation of hypoglycemia occur! If one were to completely empty the bladder and then after a few minutes pass some more urine, one may find it to be devoid of any sugars! Also there are some diabetics who have a low renal threshold for glucose. In other words, they leak glucose into the urine even when the blood glucose levels may be as normal or even lower than normal. Again in these patients, there may be sugar in the urine during hypoglycemia. In these patients, if the threshold is sufficiently low, even the second void specimen of the urine may show the presence of sugar! Therefore, the presence of sugar in the urine should not mislead us to rule out the possibility of hypoglycemia. If there is any doubt about the matter, an immediate blood glucose estimation may give the correct clue to the diagnosis. Unfortunately, sometimes, even the estimation of blood glucose levels may obscure the true story. Many patients live near a laboratory and may go there quite easily and hurriedly, if required. When these patients estimate the blood glucose levels around the time they had manifestations of hypoglycemia, especially the signs and symptoms of "sympathoadrenal" overactivity, some are surprised to find the blood glucose levels to be normal or even much higher than normal! Thus, they are confused whether they are really experiencing hypoglycemia or not. This, in spite of the fact, that they were truly hypoglycemic. Here again, it must be rea1ised that when a patient undergoes a hypoglycemic reaction, especially if it is associated with quite a rapid fall in the levels of the blood glucose, the body tries to fight the hypoglycemia by using counter measures like over activity of the sympatho-adrenal system and other hormones like cortisol and growth hormone. When fighting hypoglycemia by these counter measures, there is no way that the body can finely regulate the counter response such that the blood glucose levels reach only to a normal value. Often and especially if the rate of fall in the blood glucose is very rapid there is an overshoot of the counter measures and this may push the blood glucose to a level much higher than normal! Thus when this blood glucose level is estimated and the results are found to be high the patient wrongly feels that he does not have hypoglycemia. This, in spite of the fact, that the patient manifests all the signs and symptoms of hypoglycemia and was truly hypoglycemic! This again leads to a crucial delay in the diagnosis and consequent treatment of hypoglycemia with all its attendant problems. Scarily if, in view of the higher than normal blood glucose levels that are seen, the patient increases the doses of insulin and/or oral agents, it is quite possible that he may go into a worse episode of hypoglycemia or even be in coma.

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In view of the above mentioned situations, I feel that it would be better to go by clinical judgement rather than depend blindly on the laboratory results which may put us on a false trail. It is always worthwhile to treat any such manifestations as hypoglycemia, take the necessary treatment for the same and also decrease the dose of insulin and/or oral agents and see whether the problems are still present. It is quite possible that were the manifestations due to hypoglycemia, these would stop with a decrease in the dosage. Many patients are worried that if the problems were not due to low blood glucose level, the decrease in the dosage would further increase the blood glucose levels I do not think that this is a very important matter as one would be just as capable of normalising these raised blood glucose levels as one would the original high levels. But at least the patient would be protected from the damage the hypoglycemia may and does have the potential to cause. The management of hypoglycemia in a diabetic patient is fairly simple when the diagnosis is done at an early stage and this should be explained to all the patients as well as to a member of the family. All that one may have to do is to have a meal, snack or even a beverage with some easily absorbed carbohydrates. In an emergency, one could also take some simple sugars or a drink with simple sugars. In later stages, especially if the patient has become stuporous and the teeth are tightly clenched, the mouth may not open. Some doctors advocate that under such circumstances one could try and push some thick form of sugar solution or honey between the teeth and the cheeks, in the hope that some of this may be absorbed from the inner lining of the cheek and this may allow the patient to become slightly more conscious so that simple sugars can then be taken by mouth. I would like to warn against this. It is possible that the solution may be aspirated and lead to serious respiratory problems. It is very important that after patients have taken simple sugars and become better, they must take a meal having complex carbohydrates. This will be slowly absorbed and help in keeping the blood glucose levels even after the rapid effect of the simple sugars has worn off, especially when the hypoglycemia causing agent is still present in the body. This is an extremely important point and unless this is followed, it is quite possible that the patient may recover from one episode of hypoglycemia and later relapse again, possibly in a more severe form and at a time when help may not be forthcoming in time! This is specially true when the hypoglycemia is caused by long acting insulin preparations and by oral agents, especially chlorpropamide. Although, most of the books and even the literature that comes along with these tablets mention that the drug is effective for 36 hours, it is my clinical experience that when a patient goes into hypoglycemia caused by this drug, the effect may be prolonged up to 5 days. The patient keeps going into repeated attacks of quite severe hypoglycemia and I feel that if the hypoglycemia is caused by such an agent and especially if it has been of a serious nature, the patient should be admitted to hospital as many of such patients even need glucose drips for 4-5 day's in order to recover and prevent any further attack of hypoglycemia. I do not accept the statement that a diabetic cannot be well controlled without exposing him to the hazards of hypoglycemia, even though these be of a mild nature. At the same time, it is also possible that many patients will sometime or the other experience some episodes of hypoglycemia. With the modern management of diabetes, these episodes of hypoglycemia should be rare and mild. With an understanding of the various ways by which hypoglycemia may manifest, it would be possible to diagnose hypoglycemia at an early stage. The mild attacks of hypoglycemia, especially when diagnosed in the incipient stages can be quite easily managed using some of the measures detailed above, which not only would help in the early treatment of hypoglycemia but would also help in preventing further episodes of hypoglycemia, due to the same cause, from taking place. But what does one do when faced with a very severe hypoglycemia reaction, especially one in which the patient becomes comatose? Whilst such situations should not theoretically arise with the modern management, unforeseen problems may arise and it would be worthwhile for the family members of the patient to be aware of what needs to be done in these circumstances. Of course, one could always shift the patient to a hospital. But this takes time, and every minute counts when dealing with a severe hypoglycemic reaction if one is to prevent any major and irreversible damage. It is obvious that the patient requires glucose, but the difficulty is in administering it to an unconscious patient. The obvious thing to do would be to give glucose intravenously, but this is not feasible for most families. Even if one manages to get a doctor in a hurry, it is an unfortunate fact that many of us do not carry vials of glucose in our emergency bags! Therefore, it may be worthwhile for

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patients, especially those who are "brittle" and prone to frequent and severe episodes of hypoglycemia to keep a few vials of glucose and the materials for injection so that a doctor could use them in an emergency. A better option for such patients is to keep a vial of glucagons with them. As this is to be injected intramuscularly, anyone can easily be taught to give this injection. This is especially true as most of the families where a member is on insulin, have other members who know how to give the injection. I also feel that glucagons should be on the emergency medicine list of every doctor. 0.5 mg -1mg given intramuscularly is often sufficient to raise the blood glucose levels in comatose patients by about 20-25mg%. This enables many of the comatose patients to regain slight consciousness so that they are able to take sugars orally. Although the dose in adults is 1mg., it is better to initially inject 0.5 mg and see the result. If there is no improvement, the other 0.5 mg can then be injected. The reason for this is that in some patients glucagons can cause nausea and vomiting and this would not allow the patient when he does regain some consciousness to take any sweets orally. If in spite of these measures, if the patient does not recover, a shift to a hospital is essential. The patient would require, besides glucose, intravenous steroids and mannitol. I feel that the doctor who may see the patient at home before transfer to the hospital should be in such circumstances inject 100mg. of hydrocortisone, both intravenously as well as through the muscular route. This can be a life saving measure. In fact, I feel that even if the patient seems to recover completely from what seems to have been a very severe attack of hypoglycemia, it may be better to hospitalise the patient for any further management and observation, especially if the hypoglycemia has been caused by a long acting insulin or by chlorpropamide. One should also insist that all diabetes patients carry a card with them which clearly states that they have diabetes along with the contact phone number. This would prevent the very common occurrence of bystanders not giving any help as they feel that the patient is drunk. THE EYE AND DIABETES In India, today, diabetes ranks the second most common cause of blindness, right after cataracts! In many Western countries, it is already the most common cause of blindness. Almost all patients with Type 1 DM, as well as in patients Type 2 DM which occurs in the younger age group, in whom diabetes has been present for around 15 years will have some evidence of retinopathy, and about half have proliferative retinopathy. Type 2 diabetics in whom the diabetes starts at a slightly older age have less risk for retinopathy, but in many of these patients retinopathy may be the first sign of diabetes. In these older patients, those who require insulin are at higher risk for retinopathy than those who do not require insulin. Amongst insulin requiring Type 2 patients, 80% will show evidence of retinopathy as compared to 20% in those who do not require insulin. The corresponding figures for proliferative retinopathy are 40% and 5% respectively. The risk of clinically important macular edema is 10 to 15 percent after diabetes has been present for 15 to 20 years, regardless of the age at onset or whether insulin is required. Blindness occurs not only as a result of the sequelae of proliferative diabetic retinopathy and macular edema, but also because of an increase propensity for cataracts and glaucoma. Due to the fact that retinopathy can be present in many Type 2 diabetes patients, it is essential that all patients have a baseline visual evaluation. This MUST include: a) History of visual symptoms. b) Measurement of visual acuity and intraocular pressure : refractive errors should always be corrected after a period of stable control ; cataract and glaucoma (with special focus on open angle glaucoma) are more common in diabetics and should be actively looked for. c) Ophthalmoscopic examination through dilated pupils. This examination should be done at the time of diagnosis and repeated on an annual basis. It should be carried out by a person killed in diagnosing diabetic eye involvement.

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Patients at special risk, and those who show the presence of abnormalities, may require more frequent checkups; these patients should be seen along with a specialist. PATIENTS AT SPECIAL RISK include: a) women who are planning a pregnancy, must have a detailed eye examination b) all pregnant women must have a detailed eye examination for the presence of retinopathy at the time of diagnosis and then as frequently as warranted. c) patients with unexplained visual symptoms deterioration in visual acuity increased intraocular pressure any retinal abnormalities any other ocular abnormality that threatens vision. d) patients with preproliferative retinopathy (multiple cotton wool spots, multiple intraretinal hemorrhages, intraretinal microvascular abnormalities venous beading.) e) patients with proliferative retinopathy (retinal neovascularisation, preretinal or vitreous hemorrhage, fibrosis, traction retinal detachment.) f) macular oedema (hard lipid exudates and/or retinal thickening in side the temporal vascular arcades). g) presence of microalbuminuria, hypertension and smoking. I personally feel that doctors who have many patients with diabetes, must learn to use an ophthalmoscope, so that they can diagnose the presence of retinopathy, especially in the early stages. If this is not possible, then expert help should be taken for the retinal examinations. Often when I ask patients whether they have their eyes examined, they say that their eyes have been examined recently. What they usually mean is that they have had their vision checked to see if they need "glasses" or if there is a change in the "number". Such an examination in no way examines the retina and therefore, it is essential that the patient be told what a retinal examination means. They must also be told that it is possible that the doctor who examines the eyes may put some drops in them and that the vision would be blurred for a few hours. Therefore, it would be better for them to be accompanied by someone and it is obvious that they should not be driving a car! How often should the retina be examined? I feel that patients with Type 1 diabetes should have their retina checked 5 years after diagnosis or at puberty, (which ever is earlier) and annually thereafter. Patients with Type 2 diabetes should have their retina checked at the time of diagnosis and annually thereafter. The annual checkup recommendation is only valid if there is no significant problem. If the patient does show significant changes, then the frequency would have to be individualized. Diabetic women who are planning a pregnancy should have their retina checked before conception. If this is not possible, it should be done as soon as possible after she gets pregnant and should be carried out every semester at the very least. In case you do examine the retina with an ophthalmoscope, what would be looking for? This is what one would see with an ophthalmoscope

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If the patient has non-proliferative or background retinopathy, this is what you would see.

The small red dots are 'microaneurysms', tiny damaged capillaries. The red lines are small haemorrhages, little flecks of blood. The number of microaneurysms, the little red dots the doctor sees, indicate the likelihood of more severe problems in the years to come. The patients may have more serious form of a diabetic retinopathy. In the preproliferative stage, the retina has been damaged by the higher than normal sugar levels over several years. Small haemorrhages (flecks of blood) and tiny abnormal blood vessels are present.

If this progresses and many new vessels start developing in the retina, one has progressed to the proliferative stage. These new vessels are weak and can leak blood, blocking vision, which is a condition called vitreous hemorrhage. The new blood vessels can also cause scar tissue to grow. After the scar tissue shrinks, it can distort the retina or pull it out of place -- this is called retinal detachment.

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New blood vessels growing on the retinal surface and slightly in front of the surface If the macula is involved, this is a very serious matter, as the very central part of the vision would be affected! What are the symptoms? There are usually no symptoms in the early stages of diabetic retinopathy. Vision may not change until the disease becomes severe. An exam is often the only way to diagnose changes in the vessels of your eyes. This is why regular examinations for people with diabetes are so important. But it may not be feasible to carry out a retinal examination at every visit. Thus, one should tell the patient to look out for signs and symptoms which may herald a serious problem and they should be told that they should seek medical attention urgently. vision becomes blurry

trouble reading signs or books see double one or both of the eyes hurt the eyes get red and stay that way feel pressure in your eye see spots or floaters straight lines do not look straight

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can't see things at the side as you used to The macula is an area of the retina very near the optic disc. It seems to be devoid of blood vessels but is one of the most important areas of the retina as it is responsible for "central" vision. One can well understand the role of central vision if one reflects that if the macula is affected and one tries to see or read anything, the very central part on which the eyes would focus would appear either distorted or as a black spot! When the vessels surrounding the macula are affected by diabetic microangiopathy the condition is known as diabetic maculopathy or diabetic macular edema. I consider this as an acute emergency and immediate corrective steps need to be taken to rectify the problem. When the retina is examined, the macular area would also be looked at. But the next examination may be a year away and what happens if there is any problem in the meantime. Often the initial signs and symptoms may be very subtle and in my opinion, most of the patients who have macular problems come to us at a relatively late stage when the chance of normalising the vision may be that much harder. I usually give patients an Amslers Chart which they can use to test for macular vision. This chart is given alongside. I ask the patients to test central vision daily or at least twice a week and to seek immediate attention if there seems to be any problem. I have found that this is an extremely useful chart and allows the patient to be diagnosed at the every early stages of macular involvement.

AMSLER RECORDING CHART

1. Look at the square (grid). 2. Wear your reading glasses (if you use one) and cover one eye. 3. Focus on the center dot for one full minute. 4. While looking directly at the center, be sure that all the lines are straight and clear, and all the small squares are the same size. 5. Repeat the test in the other eye. 6. If any lines or squares appear distorted, wavy, blurred, discolored, or otherwise abnormal, call your eye doctor right away. 7. In healthy eyes the lines are straight. The Amsler's chart is very useful for early detection of macular problems and thus is very important as this may be an early sign of macular problems and lead to a loss of central vision! But one must know its limitations.The Amsler grid will NOT detect proliferative diabetic retinopathy, most preproliferative changes and other types of damage that may threaten vision, nor is it useful for detecting any of the early changes. Remember: a normal Amsler grid test does not rule out the presence of retinopathy that can threaten your vision.It cannot replace routine eye exams. Only regular eye exams can do this.

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What can be done to prevent serious eye problems? Meticulous management of the risk factors and an early diagnosis would go a long way towards averting diabetic retinopathy or retarding the progression of the retinal changes even if one is not able, to revert the changes that have occurred. The risk of retinopathy is directly related to the degree and duration of hyperglycemia. The prevalence of proliferative retinopathy - and of blindness related to this condition - is directly associated with the duration of diabetes and the degree to which blood glucose concentrations have been elevated Thus, all efforts must be made to keep a "tight" control on the blood glucose levels. Many studies have shown the importance of a good glycemic control. If one does not have diabetic retinopathy but does not keep the blood glucose under optimal control, one would have FOUR times the chances of getting retinopathy as compared to someone who does keep the blood glucose well controlled! Moreover, in people who already have retinopathy, the condition progresses in those with good control only half as often as those not well controlled. In fact, it has been shown that for each 1% rise in the HbA1c, the retinopathy gets worse at the rate of 32%. So if one's HbA1c is 9%, the retina is getting damaged twice as fast as someone with a level of 6% (3 x 32% = 92% additional deterioration). High blood pressure is fairly common in people with diabetes. Again one should aim for a good control of the blood pressure 130/80 or less (lower still if there is protein in your urine). With blood pressure, for each 10mmHg rise, the retinopathy gets 11% worse. So if one's blood pressure is 150/90, their retina is getting 22% worse that someone whose pressure is 130/80. Patients with diabetes who have high serum lipid concentrations have an increased risk of both proliferative retinopathy and vision loss from macular edema and associated retinal hard exudates. Reducing the hyperlipidemia may lower this risk. Similarly Smoking literally doubles the rate of damage that diabetes causes to the bodies larger arteries, making amputations and heart disease far more likely. Smoking triples the rate of retinopathy progression These impressive results show that we can do a tremendous amount to prevent serious deterioration of the diabetic retinopathy. To sum up, 30-60 minutes exercise a day, moderate alcohol consumption only, avoid obesity if possible, balanced diet including 5 portions of vegetables or fruit a day, with the minimal of animal or 'hard' vegetable fats, and very low salt. 130/80 or less125/75 or less if protein in urine present 6.5% or less with very few or preferably no hypos.If hypos develop, see expert advice.ACE inhibitors or AT11 unless young/pregnant/very low blood pressure/poorly tolerated smoking 20 a day triples retinopathy (passive smoking: roommates inhale at least 25%)

lifestyle

blood pressure HbA1c

Cholesterol <5.0mmol/l, and statins recommended for most adult patients Smoking

Specific Management of Diabetic Retinopathy Prevention of retinopathy is the best approach to reducing the risk of blindness among patients with diabetes, but this is not yet possible in many patients. At the outset it should be made clear that there are no drugs available to treat diabetic retinopathy. Hopes raised previously by a group of drugs called the Aldose reductase Inhibitors have not been borne out and neither has antioxidant treatment.

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Treatment with aspirin did not affect the progression of retinopathy, the risk of visual loss The two treatments are laser surgery and vitrectomy. They are very effective in reducing vision loss from this disease. In fact, even people with advanced retinopathy have a 70-80% chance of keeping their vision when they get treatment before the retina is severely damaged. Which again brings into focus the importance of regularly examining the retina of the patients! Laser photocoagulation therapy is effective in reducing the risk of further visual loss and is generally useful in preventing blindness in diabetics with high risk proliferative retinopathy and macular edema. There is now evidence that early treatment with laser photocoagulation, without waiting for the development of severe changes, may lead to a better prognosis in preventing vision loss. Vitrectomy may restore vision in some patients with recent traction retinal detachment or vitreous hemorrhage It is important to note that although these treatments are successful, they do not cure diabetic retinopathy. ORAL HYPOGLYCEMIC AGENTS Life was so much simpler 25 years back. That is all the more true when one considers oral agents used in treating diabetes. I remember when I passed my M.B.,B.S., that if one knew a little bit about tolbutamide and chlorpropamide, that was more than enough to satisfy the examiners. Things really did not change even during the M.D. examinations, with the exception that glibenclamide was then the "hot" oral agent! That was then. Today, five classes of oral agents are available for treating Type 2 diabetes and at last count more than 40 formulations were in the market! And they keep increasing day by day. Is any one oral agent better than the others? More importantly, when treating a person with diabetes, how does one choose the type of drug to be used! In order to make some sense of the plethora of oral agents available, it becomes essential to basically understand a few important points. The first, and probably, the most important point is that none of the oral agents is insulin, no matter what name may be given to the drug by a company. One should also understand that Type 2 diabetes is characterized by three basic abnormalities that contribute to the development of hyperglycemia: Impaired insulin secretion by the pancreas Peripheral insulin resistance mainly in the skeletal muscle Excessive glucose production by the liver

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Type 2 patients that one sees in practice would have a combination of these three mechanisms which cause the high blood glucose levels. The problem is that the extent and severity of each of these mechanisms varies in different individuals, and the oral agent which would be most optimal for any patient would depend on which of these three mechanism plays a major role in their hyperglycemia. Although there is no hard and fast rule for this, it is widely accepted that in lean type 2 patients, impaired insulin secretion is the predominant defect, while insulin resistance tends to be less severe than in the obese variety. Insulin resistance and hyperinsulinemia are the classic abnormalities of obese individuals with type 2 diabetes. All the oral agents available do not have the same mechanism of action. Thus, one must know how a class of oral agent acts in order to choose the appropriate drug. Before, we discuss the modalities of how to manage a patient using an oral agent, it would be worthwhile to understand the types of oral agents available for use. MAIN GROUPS OF OHAs SULFONYLUREAS The sulfonylureas have been available since the 1950s and have historically been the first line of pharmacologic therapy for diabetes. During World War II, French scientists working on the antibiotic potential of modified sulfonamides found that the mice that they were experimenting upon died unexpectedly. Such unexplained deaths also occurred amongst a few of the soldiers who had been administered these modified sulfonamides as an antibiotic. On closer examination, the cause of the deaths was found to be due to hypoglycemia. Unfortunately, in the milieu of the war scene, this effect of the sulfonamides was not paid much attention to and it was only as late as 1955 that the first oral sulfonylurea, carbutamide, was first introduced in the market as an oral hypoglycemic agent. The following year, tolbutamide and chlorpropamide were also introduced. In later years, the so-called "second generation" sulfonylureas, glibenclamide and glipizide amongst them, were brought into the market. Relative late comers on the sulfonyurea scene are gliclazide and glimepiride. Agent Daily dosage range Number of doses per day First-generation agents

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Tolbutamide Chlorpropamide Tolazamide Acetohexamide Second-generation agents Glipizide Glibenclamide Gliclazide Glimepiride

500-3,000 mg 100-500 mg 100-1,000 mg 250-1,500 mg 2.5 - 20mg 2.5 - 20 mg 80-240mg 1-8 mg

2 or 3 1 1 or 2 1 or 2 2 or 3 1 or 2 2 or 3 1

The sulfonylureas are often classified as belonging to the first or second generation. The first generation sulfonylureas are rarely used now. Sulfonylureas work primarily by stimulating pancreatic insulin secretion, which in turn reduces hepatic glucose output and increases peripheral glucose disposal. There is some evidence that the newer sulfonylureas such as gliclazide and glimepiride may also have some action in reducing insulin resistance. Biguanides The precursors of the biguanides have been around for much longer. Way back in 1918, guanidine derivatives were used as oral hypoglycemic agents. Synthalin A, a homologue of guanidine, continued to be used for many years and would have been still more frequently used if insulin had not become available for routine use. Synthalin A is the precursor of the modern day biguanides, two of which are commonly used here being phenformin and metformin. Although some doctors continue to use phenformin, it's use has declined to such an extent that for most purposes, when one takes of biguanides, one is usually referring to metformin.

Metformin works primarily by inhibiting hepatic glucose production and improving insulin sensitivity. It does not stimulate insulin secretion from the pancreas and, when used alone, does not cause hypoglycemia or hyperinsulinemia. Metformin may increase glucose utilization in peripheral tissues to a lesser degree, by decreasing insulin resistance in muscle cells. Metformin may also improve glucose levels by reducing intestinal glucose absorption. Metformin should be started with a single daily dose of 500 mg, taken with a meal. The patient's response to therapy can be checked at one- to two-week

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intervals and will guide how the dosage should be increased. Metformin dosage can be increased by one tablet (500 mg) per day at one- to two-week intervals until glycemic control is obtained or a total daily dose of 2,000 mg is reached. The maximal daily dosage should not exceed 2,550 mg; most patients get little additional benefit from dosages of more than 2,000 mg per day. Alpha-Glucosidase Inhibitors Acarbose is an alpha-glucosidase inhibitor that slows down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides. The enzymatic generation and subsequent absorption of glucose is delayed and the postprandial blood glucose values, which are characteristically high in patients with type II diabetes, are reduced with acarbose. AGIs do not prevent the absorption of carbohydrates and complex sugars, but they do delay their absorption. Delaying the absorption of carbohydrates is a unique mechanism among oral diabetic medications for lowering HgbA1c levels. The effectiveness of this mechanism is one of the physiologic characteristics of type 2 diabetes. Patients with type 2 diabetes demonstrate a delayed or sluggish insulin response from the pancreas to a glucose (a meal) load. By delaying the absorption of glucose, the insulin response is more matched to the serum glucose, resulting in less postprandial hyperglycemia and a lowering of the HbA1c. The AGIs also demonstrate a lowering of total insulin output of the pancreas, increased insulin sensitivity, a variable but mild decrease in triglycerides, with no effect on patient weight. One disadvantage with the use of acarbose is that it is to be taken along with the first bite of a meal. Moreover, it has to be taken three times daily with meals. These factors often lead to non compliance and a decrease in the efficacy of the drug. Acarbose may be started at 25 mg three times daily, taken at the beginning of each main meal. The dosage can be adjusted at four- to eight-week intervals. The maximal recommended dosage is 100 mg three times daily (50 mg three times daily if the patient's body weight is 132 lb [60 kg] or less). Meglitinides Repaglinide from the meglitinide drug class, acts like an extremely short-acting SU (an insulin secretagogue) and is potentially useful as a SU replacement. The effect of repaglinide on the pancreas is very similar to that of the SUs. Repaglinide, like the SUs, blocks the potassium channels on the pancreatic islet beta-cells, which causes an influx of calcium into the cell and increasing the secretion of insulin. There appears to be 2 similar potassium channels on islet betacells, one of which is predominantly affected by repaglinide and the other is predominantly affected by SUs. The repaglinide-affected potassium channel appears to be glucose dependent, which may partially explain why repaglinide is associated with a much lower incidence of hypoglycemia. What makes repaglinide clinically different from the SUs is its ultra-short half-life (1 hour). Repaglinide is taken just before or with meals, and the stimulation of the pancreas is limited only to a brief time around meals. Because of the short duration, the patient does not have continuous high levels of insulin and the resulting adverse effects. Its biggest advantage over the other oral hypoglycemic medications is that it allows for flexible timing and missed meals. Repaglinide stimulates the release of insulin from the pancreatic beta cells by closing ATP-sensitive potassium channels. It is rapidly absorbed, allowing for a rapid onset of action. It was found to be three to five times more potent in stimulating insulin release than the sulfonylurea glibenclamide. However, it does not stimulate the release of insulin in the absence of glucose. Repaglinide augments the early insulin response and decreases prandial and postprandial glucose excursions. Repaglinide's rapid onset and short duration of action make multiple daily doses necessary. The physician can often turn this characteristic to good use by instructing patients to take repaglinide immediately before each meal. This approach is especially useful for patients who eat at irregular hours or sometimes skip meals altogether. For patients who are just beginning treatment with oral medications or whose HbA1c is less than 8 percent, the recommended starting dose is 0.5 mg taken 15 minutes before each meal. For patients who have previously been receiving oral medication for diabetes and who have an HbA1c of 8 percent or more, a starting dose of 1 or 2 mg taken 15 minutes before each meal is recommended. The maximal recommended dosage is 4 mg per meal, for a maximum of four meals (16 mg) a day. If a patient skips a meal, he or she should not take the tablet. If a patient adds a meal, a tablet should be added for that meal.

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Thiazolidinediones (Glitazones) The thiazolidinedione (TZD) class of oral hypoglycemics ( popularly known as glitazones) was developed in 1997 and offers a new mechanism for treatment of type 2 diabetes. The first, troglitazone was taken off the market in 1999 because of its association with hepatic toxicity. Rosiglitazone and pioglitazone have been available since 1999. The primary effect of TZDs is peripheral, with increasing insulin sensitivity and increased glucose uptake. The TZDs have some effect on hepatic glucose uptake and sensitivity to a lesser degree. They do not stimulate the pancreas to produce more insulin. TZDs are hepatically metabolized and thus can be used safely in patients with renal dysfunction. They can be dosed once daily, although rosiglitazone works better with twice-daily dosing. Reports have suggested that rosiglitazone works better in women, but the reason for this is not known. Both pioglitazone and rosiglitazone are approved for monotherapy and in combination with metformin, SUs, and insulin. Besides their effect in lowering the blood glucose levels, both drugs also have notable effects on lipids. The current data show that pioglitazone has a minimal effect on low-density lipoprotein (LDL) cholesterol levels and a favorable effect on high-density lipoprotein (HDL) cholesterol and triglyceride levels. Rosiglitazone is thought to be basically lipid neutral. With use of glitazones, patience is required. Blood sugar levels may show a significant reduction statistically in as little as two to four weeks, but the maximum effects are not seen until two or three months have passed.

Having discussed some basic aspects of the oral agents available today for use in diabetes, the next step would be the treatment plan itself. A simple plan is given in the Figure below.

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Diet and exercise remain the mainstay of diabetes management and all patients should be advised about the changes in their diet and prescribed an exercise schedule. The next critical step would be to find out those patients in whom it would be mandatory, or better, to initiate further management with insulin. Such patients have been discussed in the section dealing with Insulin Therapy. Having done this, one would then be faced with the vast majority of patients who may need oral hypoglycemic agents. Theoretically, one should put all such patients through a trial with diet and exercise before starting them on any oral agent. This is precisely what all of us have been taught in medical college. In practice, one needs to have a slightly different approach. I feel that any patient who comes with an initial fasting blood glucose value which exceeds 250mg% or who is severely symptomatic with polyuria and polydipsia or who is losing weight inspite of an adequate diet, can be started of with an oral agent along with diet and exercise. In fact, some of these patients may do better if insulin is started initially. If we decide to start an oral agent initially due to these reasons, my oral agent of choice would be a sulfonylurea. Why a sulfonylurea, and not another class of oral agent? Metformin would not be ideal as the patient is already losing a lot of weight and metformin will only increase this weight loss. The glitazones have a significant time lag before showing their full activity whilst the others are too mild for such patients. For the purposes of our discussion, let us accept that we have decided to initiate treatment with glimepiride, although this should not be taken to mean that glimepiride is the best sulfonylurea available. I usually start with a relatively small dose, say 2mg. per day. The patient is then monitored closely. I usually see them after a week with the fasting and the postmeal blood glucose levels or preferably with results of self monitored blood glucose levels. NON OBESE

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SCENARIO 1. In quite a few patients, the blood glucose would have decreased significantly and there is a significant amelioration of the symptoms. If the values have reached acceptable levels, then I usually decrease the dose of the oral agent. In many cases this would mean managing the patient on diet and exercise alone or halving the dose of the sulfonylurea till the next visit after about two to three weeks. Many patients who have been off the oral agent will continue to show acceptable control at this time and they would continue to be managed with diet and exercise alone. Patients who had been given a decreased dose of the oral agent, if they show such an acceptable level of control at the second visit would be taken off this smaller dose to see whether they can subsequently be managed on diet and exercise alone. If at a subsequent visit, the control seems to have worsened in spite of adequate dieting and exercise, then the oral agent should be reintroduced at the small dose at which the patient had been started.

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SCENARIO 2. A few of the patients will show a decrease in the blood glucose levels and some amelioration of the symptoms but this may not have reached an acceptable level. Such patients would be continued on the same small dose to see whether this would cause a further lowering of the blood glucose levels. At the next visit, if the control is within acceptable limits, then the patient is managed as discussed in Scenario 1. In case, there is no further improvement in the control, then I would treat the patient as in Scenario 3. b SCENARIO 3. Quite a few patients may show some improvement in the control parameters, but this may not be to any significant extent. Such patients would need an increase in the does of the oral agent. I would increase the dose of the glimepiride to say 4 mg per day and follow them after 3-4 weeks to judge control. At this time, some of these patients may show an adequate control and they would then undergo a decrease in the dosage to see whether they could be managed with the smaller dose. If at the next visit, the control is maintained, then they may be continued on this small dose or one may even try a trial with a still further decrease of the oral agent. If the control in spite of taking 4mg of glimepiride per day is still not at acceptable levels, it would be possible to further increase the dose to say 6mg of glimepiride per day. In a few patients this increase may lead to an acceptable control, and the patient is then managed with this dose. It should be realized that only a few patients who did not show an acceptable control at 4mg per day would then go on to show a good control with 6mg. per day. Most of these patients would be better managed as in Scenario 4 The point that I would like to stress upon is that one should try and achieve adequate control with the SMALLEST possible dose of the oral agent. SCENARIO 4. A number of patients may not be optimally controlled even when the patient is 4mg of glimepiride. At this stage, it would be more prudent to review the patient clinically rather than make a further blind increase in the dose of the tablets. In my opinion the maximum dosage of the oral agents, given by the drug manufacturer's and also mentioned in the text books is not valid for our patients. These dosages are too high and in Table 1, I have given the maximum doses of the oral tablets as mentioned in the books and literature and the dose at which I feel the patient warrants a close review. For instance, the maximum dose of glibenclamide is reportedly 20mg per day (4 tablets). I feel that this is too high for most our indian patients and that it would be the very rare person who did not show a substantial response to two tablets of glibenclamide (10mg per day) and then would go and show "control" with a higher dose. TABLE 1 The commonly used oral hypoglycemic agents, the dosage at which it would be prudent to "review" the patient, as well as the maximum advisable dose which may be used are: Drug Initial Dose SULFONYLUREAS Glibenclamide 2.5 - 5mg Glipizide 2.5 - 5mg Gliclazide 40 - 80mg Chlorpropamide 125mg Tolbutamide 250mg BIGUANIDES Metformin 250 - 500mg Phenformin 12.5 - 25mg Dose at Whichreview is essential Maximum dose advisable 10mg 10mg 120mg 250mg 1000mg 750mg 37.5mg 20mg 20mg 320mg 500mg 2000mg 1500mg 50mg

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In the detailed review that I carry out in such circumstances, the first point is to see whether the patient is complying with his diet and exercise. This is obviously not easy to judge as most of the patients would tend to swear that they are following their prescribed diet. In the section dealing with diet, I have discussed ways through which it would be possible to judge the pationts dietary compliance. If one finds that the patient is not keeping to his diet, then the focus of management would be to increase the dietary compliance rather than increase the dose of the oral agent. When faced with a patient who is complying with the diet and exercise prescription and who does not show the neccessary response to say, 4mg. per day of glimepiride, it would be worthwhile to rule out the presence of associated conditions which may interfere with the action of the oral agents and not allow for good control. The commoner of these conditions are detailed in Table 2 and have been discussed in detail in the section on "Insulin therapy". TABLE 2 Conditions that may interfere with the effectiveness of oral Sulfonylureas. Patients with low insulin reserve; Infections, especially look for T.B. and urinary tract inf.; Use of drugs which increase blood glucose levels; Thyrotoxicosis; Hormone excess: cortisol, growth hormone

After having ruled out the presence of these conditions, one would be faced with one of the following three scenarios in the vast majority of such cases. SCENARIO A. The patient may be an insulin-requiring diabetic. In this condition, although the patient does not go into ketosis if not given insulin, he cannot be optimally controlled without the addition of some exogenous insulin. These patients, and there are a number of such patients in our country, are usually normal or even slightly underweight. The therapeutic strategy in such circumstances would be to give the patient a small dose of exogenous insulin in addition to a small dose of the oral agent. In practice, I usually start with a small mixture of a short acting and an intermediate acting insulin (say 8 units of each) given before breakfast along with an oral agent. Often, with slight modification of the doses, one finds that the patient can not only be optimally controlled, but the patient himself says that he feels much better! SCENARIO B. If the patient is overweight, then I consider using a small dose of metformin or a glitazone along with the sulfonylurea. In practice, I give the patient 250mg of metformin two to three tijes a day with the meals in addition to the sulfonylurea. If a glitazone is used, this could be 15mg. of pioglitazone given once daily or 2mg. of rosiglitazone given twice a day. The combination often shows good results and the doses are then carefully adjusted so that the patient maintains the control with the smallest possible doses of the tablets. If the patient shows a relatively high postprandial levels, then addition of an alpha-glucosidase inhibitor, such as acarbose may help Managing the Overweight (Obese) Patient A stringent regimen of diet and exercise should be the main stay therapy of all obese patients. OBESE If the patient does not show the desired results, Scenario A. Metformin is the drug of choice as the initial oral agent in patients who are overweight, especially those with a raised waist to hip ratio, if diet and exercise fail to achieve the aims of control. Phenformin is available in India but its use is on the

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decline and metformin should be preferred to phenformin when a biguanide is decided upon. In order to minimize the side effects such as nausea and other abdominal problems, I usually initiate therapy with small doses of metformin, 250mg once or twice daily, taken with meals. If desired result is obtained, decrease the dose of metformin by half tablet (250mg) decrements, to maintain control at smallest possible dose of the OHA. Scenario B If the target control is not observed, the importance of diet and exercise is re-enforced. Increase metformin in small doses (250mg) at a time and monitor control. Further increments are usually made every 2-4 weeks till the dose of metformin (500 mg twice a day) is reached. At this time, check for diet and exercise compliance. Change in weight is an excellent parameter to judge diet and exercise compliance. If patient is following his diet and exercise schedule: Scenario C Check for the presence of any condition which may interfere with the action of metformin. These conditions are given above. If any of these conditions are present, they should be treated. After treatment, patient may show optimal control. In this case, the procedure outlined in Scenario A is followed. Scenario D In the absence of any condition interfering with the action of metformin, re-enforce diet and exercise regimens, the dose of metformin can be gradually increased to the maximum. But this rarely leads to better control in most patients. Scenario E Usually when the dose of metformin has reached around one gram per day in divided doses and the desired control is not seen, it would be better to combine this regimen with other drugs. In an obese person, a glitazone would be ideal but care is to be taken about the weight gain which is associated with the use of glitazones. 15mg of pioglitazone daily, or 2mg. of rosiglitazone taken twice a day, often leads to a significant lowering of the blood glucose levels. Combination therapy with a sulfonylurea can be started. In this case, a small dose of metformin (250mg two to three times a day) is combined with, say, glimepiride ( 2mg daily). Such a combination therapy with slight adjustment in doses also often leads to target levels. If the patient shows very high postprandial levels with fairly acceptable fasting and preprandial levels, one could think of the additional use of an alpha-glucosidase inhibitor such as acarbose. If the desired levels are achieved, doses of the oral agents should be slightly decreased gradually to observe if control can be maintained at the smaller doses. The aim, again, is to manage the patient with the smallest doses of the drugs. Scenario F Some patients do better with a combination of metformin with insulin. SIDE-EFFECTS I would now like to discuss some of the more important side effects of the oral agents.

Pathophysiologic Basis of Treatment of type 2 Diabetes

The primary goals of managing type 2 diabetes are to : * Eliminate symptoms of hyperglycemia

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* Achieve and maintain normal or near normal metabolic and metabolis parameters(both fasting & postprandial blood glucose levels glycated Hb,Fasting LDL and HDL Cholesterol and Triglycerides ) * Assist the patient in achieving and maintaning a reasonable body weight * Prevent or delay the development and progression of microvascular and macrovascular complications. Therapeutic efforts to achieve these goals involve using a variety of treatment modalities: * Dietary Modifications * Regular physical activity * Oral Antidiabetic agents * Insulin An individualised approach is recommended based on: * Patient age * Presence of coexisting disease and /or diabetes related complications * Lifestyle , including - .Attitudes .Habits .Cultural / Ethnic status * Financial considerations * Ability to learn and follow self - management skills * Level of patient motivation The cornerstone of effective diabetes management is maintaining good glycemic control.Compelling evidence indicates that long term glycemic control can prevent or delay the development of complications .The DCCT Trial demonstrated definitely the value of intensive therapy of Type 1 Diabetes in delaing the onset and progression of microvascular complications of diabetes . The UKPDS demonstrated the same for the type 2 Diabetes. It is likely that no single genetic defect willemerge to explain type 2 diabetes , thus the disease is heterogenous and possibly multigenetic , and likely has a complex etiology.Even though the disease is genetically heterogenous, there appears to be a fairly consistent phenotype once the disease is fully menifested. Most patients with type 2 diabetes and fasting hyperglycemia are characterised by : * Insulin Resistance * Impaired Insulin Secretion * Increased Hepatic glucose production Although these metabolic abnormalities have been well studied ,the etiologic sequence has only recently come into focus.It is clear that the increased hepatic glucose production of type 2 diabetes is secondary and can be fully researved with a variety of antidiabetic treatment options . The proposed etiological sequence is that insulin resistance is manifested initially , leading to increased insulin secretion to maintain the compensated IGT state .Later the compensation fails and beta cell functon declines ,leading to hyperglycemia .In addition , the conversion of IGT to type 2 diabetes can be influenced by : * Ethnicity * Degree of obesity * Distribution of body fat * Sedentary lifestyle * Ageing CONSIDERATIONS FOR CHOICE OF OHA : * Age * Weight * Duration of diabetes * Presence of Dyslipidemia * Severity of hyperglycemia * Presence & degree of Renal / Hepatic Disease

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* Ulcer or other GI problem Obese patient with recent diabetes with /without Dyslipidemia * Metformin / Rosi / Pioglitazone * Acarbose * Sulfonylurea -- only if signs of glucotoxicity Thin Elderly patient : * Acarbose * Repaglinide * Glitazones ( if Normal Hepatic functions ) Acceptable FBG but high HbA1c * Acarbose * Repaglinide * Metformin Non Obese (lean ) Type 2 DM * Glibenclamide * Glipizide * Glimipiride * Insulin Prolonged , severe Hyper glycemia * Short term insulin , then OHA * Any SU + Glitazone + Metformin Severe Renal / Hepatic Dysfunction * Repaglinide * Acarbose * Insulin Taking patients with type 2 diabetes Off Insulin You may be successful if : * Duration < 10 Years * Obese Persons * FBg > 200 and PPBG < 250 * Diabetes diagnosed after 35: add & Substitute -Glitazones + Metformin + Acarbose + ? Repaglinide / Glimipiride TARGETS FOR CONTROL All the target levels given below are generalisations and individual targets MUST be established. Laxity may be allowed in

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elderly patients; certain conditions require a much tighter control, e.g. pregnancy, maculopathy, etc.

BODY MASS INDEX (BMI)

Body Mass Index (BMI) is an excellent indicator of the weight status of a person. Its significance also lies in the fact that the normal values are based on the effect of body weight on disease and death, irrespective of the age and gender of an adult person. A healthy BMI for adults is between 19 and 24.9. A high BMI is predictive of death from cardiovascular disease. Diabetes, high blood pressure, some forms of cancer, osteoarthritis and many other ailments are also common consequences of overweight, and obesity in adults. Obesity itself is a strong risk factor for premature death. The BMI also allows us to judge the nutritional status of an individual. A BMI of less than 18.5 is considered to denote undernutrition. Recently, it has been shown that the BMI used along with the Waist-Hip Ratio (WHR) is better in predicting risk for many of the serious disorders such as diabetes, high blood pressure, lipid disorders and atherosclerosis leading to heart attacks and strokes etc. Research has shown that much more than the weight of a person, it is the shape of the body which is important in determining risks for the development of many serious disorders such as diabetes, high blood pressure, lipid disorders, atherosclerosis leading to heart attacks and strokes, and many other ailments. Research shows that people with "apple-shaped" bodies (with more weight around the waist) face more risks than those with "pear-shaped" bodies that carry more weight around the hips.

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Are YOU an Apple or a Pear? To determine if you have a healthy waist to hip ratio, use a measuring tape to measure the circumference of your hips at the widest part of your buttocks. Then measure your waist at the smaller circumference of your natural waist, usually just above the belly button. ( See Figure ) Recently, it has been shown that the Waist-Hip Ratio (WHR) used along with the BMI is better in predicting risk for many of the serious disorders such as diabetes, high blood pressure, lipid disorders and atherosclerosis leading to heart attacks and strokes etc.

So what exactly is diabetes?

To put it very simply, diabetes mellitus is a chronic and currently incurable condition in which too much glucose (sugar) is present in the blood. Why should this be so? Since diabetes is a disease that affects your body's ability to use glucose, let's start by looking at what glucose is and how your body controls it. Glucose is a simple sugar, which is normally necessary to provide energy to the cells in your body. The various cells in your body take up the glucose which is in the blood and break it down using various biochemical pathways into "energy". Whilst in the absence of glucose, many cells and organs can use other substitutes for a while, important cells such as those of the brain, the red blood cells and the those of kidneys can only use glucose and nothing else. Where does the body get glucose from. It come from the food we eat.

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When you eat food, the carbohydrates in the food, and remember most of the diet is full of carbohydrates (starch, in popular parlance), gets broken down in the intestines into simple sugars such as glucose which are then absorbed into the bloodstream and get distributed all over the body for it to be used. When you have something with simple sugars, the glucose gets absorbed that much faster! But we do not eat continuosly. So our body has a mechanism which closely regulates the level of glucose in the bloodstream so that the cells of the body can get their required supply at all times. Unless this is done, your cells would have too much glucose right after a meal and starve in between meals and overnight ! So, when you have an oversupply of glucose, your body stores the excess in the liver and muscles by making glycogen, long chains of glucose. When glucose is in short supply, your body mobilizes glucose from stored glycogen and/or stimulates you to eat food. The key is to maintain a constant blood-glucose level. Think of this as some sort of a "depot" where you store excess materials for later use. So how does the body fine tune this mechanism by which a normal amount of glucose is available for use by the body at all times? To maintain a constant blood-glucose level, your body relies on two hormones produced in the pancreas that have opposite actions: insulin and glucagon. Although things are not that simple and many other mechanisms do come into play, it will suffice for our purposes to understand the basic role played by these two hormones.

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The Pancreas The pancreas is composed of two main parts, the exocrine part and the endocrine pancreas. The exocrine part secretes substances into the intestinal tract which help in digestion of the eaten food. These include lipase, which helps to digest fat, and amylase that helps to digest starchy foods. It also releases 'bicarbonate of soda' to neutralise any stomach acid that may otherwise damage the lining of the gut. The exocrine pancreas is directly connected to the intestinal tract through the pancreatic duct as seen below.

But we are basically concerned in diabetes with the endocrine pancreas which is the source of insulin, glucagon and other hormones, secreted directly into the bloodstream.

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The pancreas is full of tiny cluster of cells called the Islets of Langerhans, which surround the cells of the "exocrine" pancreas.

The islet of Langerhans contains many types of cells

The pancreas has many islets that contain insulin-producing beta cells and glucagon-producing alpha cells.

Proinsulin, secreted as insulin and C-Peptide Insulin is made and secreted by the beta cells of the pancreatic islets, small islands of endocrine cells in the pancreas. In the beta cell, the insulin is made and stored as a precursor called proinsulin. When the B cell is appropriately stimulated, insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood. C peptide is also secreted into blood, but has no known biological activity. Insulin is a protein hormone that contains 51 amino acids After a meal the digestive system breaks some food down into glucose. The blood carries the glucose or sugar throughout the body, causing blood glucose levels to rise.

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Insulin Release

In response to this rise the hormone insulin is released into the bloodstream to signal the body tissues to metabolize or burn the glucose for fuel, causing blood glucose levels to return to normal.

Glucose the body doesn't use right away goes to the liver, muscle or fat for storage. Under normal circumstances the hormone insulin, which is made by the pancreas, carefully regulates how much glucose is in the blood. Insulin stimulates cells to absorb enough glucose from the blood for the energy, or fuel, that they need. Insulin also stimulates the liver to absorb and store any glucose that's left over. After a meal the amount of glucose in the blood rises, and this triggers the release of insulin.

When blood glucose levels fall, during exercise for example, insulin levels fall too. A second hormone manufactured by the pancreas is called glucagon. It stimulates the liver to release glucose when it's needed, and this raises the level of glucose in the blood.

ERECTILE DYSFUNCTION
Blood Supply and Innervation The diagram below on the basic mechanisms of erection and flaccidity of the penis also shows the blood supply and

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innervation of the penis.

The mechanisms of erection and flaccidity are shown in the upper and lower inserts, respectively. During erection, relaxation of the trabecular smooth muscle and vasodilatation of the arterioles results in a severalfold increase in blood flow, which expands the sinusoidal spaces to lengthen and enlarge the penis. The expansion of the sinusoids compresses the subtunical venular plexus against the tunica albuginea. In addition, stretching of the tunica compresses the emissary veins, thus reducing the outflow of blood to a minimum. In the flaccid state, inflow through the constricted and tortuous helicine arteries is minimal, and there is free outflow via the subtunical venular plexus. Physiology of Penile Erection Penile erection is a complex physiologic process that occurs through a coordinated cascade of neurologic, vascular, and humoral events.

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In the flaccid penis, a balance exists between blood flow in and out of the erectile bodies.

Mechanics of erection. (A) In the flaccid state, arterial vessels are constricted and venous vessels are noncompressed. (B) On erection, smooth muscle relaxation in the trabeculae and arterial vasculature results in increased blood flow, which rapidly fills and dilates the cavernosal spaces. Venous outflow drops as the expanding cavernosal spaces compress the venous plexus and the larger veins passing through the tunica albuginea. Erection With sexual arousal through imaginative, visual, auditory, tactile, olfactory, and other erotic stimuli, nitric oxide (NO) is released by nonadrenergic, noncholinergic (NANC) neurons. Originally termed endothelial-derived relaxing factor, NO is known to be the most important physiologically occurring vasoactive molecule in the entire cardiovascular system. This also applies to corpus cavernosum function, where local smooth muscle relaxation, and in turn erection, is mediated predominantly by NO release. On arousal, parasympathetic activity triggers a series of events starting with the release of nitric oxide and ending with increased levels of the intracellular mediator cyclic guanosine monophosphate (cGMP). Increases in cGMP cause penile vascular and trabecular smooth muscle relaxation. Blood flow into the corpora cavernosa increases dramatically. The rapid filling of the cavernosal spaces compresses venules resulting in decreased venous outflow, a process often referred to as the corporeal veno-occlusive mechanism. The combination of increased inflow and decreased outflow rapidly raises intracavernosal pressure resulting in progressive penile rigidity and full erection

1: Mechanism of erection

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Non-adrenergic, non-cholinergic nerves and vascular endothelium release nitric oxide in response to sexual arousal, which activates cytoplasmic guanylate cyclase, converting GTP into cGMP. The increased levels of cGMP alter transmembrane calcium ion flux, resulting in cavernosal smooth muscle relaxation, dilatation of cavernosal and helicine arteries and engorgement of lacunar spaces. The expanding lacunar spaces compress the subtunical venous plexus against the tunica albuginea, decreasing cavernosal venous outflow, increasing intracavernosal pressure, with resulting penile rigidity. Cyclic nucleotides, such as cGMP, are hydrolysed by cyclic nucleotide phosphodiesterases. GTP=guanosine monophosphate. triphosphate; GMP=guanosine monophosphate; cGMP=cyclic guanosine

So the basic mechanism underlying is the relaxation of the penile smooth muscle.

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Molecular Mechanism of Penile Smooth-Muscle Relaxation. Cyclic AMP (cAMP) and cyclic GMP (cGMP), the intracellular second messengers mediating smooth-muscle relaxation, activate their specific protein kinases, which phosphorylate certain proteins to cause opening of potassium channels, closing of calcium channels, and sequestration of intracellular calcium by the endoplasmic reticulum. The resultant fall in intracellular calcium leads to smooth-muscle relaxation. Sildenafil inhibits the action of phosphodiesterase (PDE) type 5, thus increasing the intracellular concentration of cGMP. Papaverine is a nonspecific phosphodiesterase inhibitor. GTP denotes guanosine triphosphate, and eNOS endothelial nitric oxide synthase. It is well established that NO and cGMP are the most important transmitters for onset and maintenance of erection. Finally, cGMP is metabolized to GMP via phosphodiesterase, of which four isoforms (types 2, 3, 4, and 5) have been identified in human penile tissue. Phosphodiesterase type 5 (PDE 5) is the predominant isoform in human corporal smooth muscle. We shall refer to this again when we discuss the action of sildenafil citrate. Detumescence and return to the Flaccid state Detumescence.After ejaculation or cessation of erotic stimuli, sympathetic tonic discharge resumes, resulting in contraction of the smooth muscles around sinusoids and arterioles. Arterial flow is diminished to flaccid levels, much of the blood from the sinusoidal spaces is expelled, and the venous channels reopen During the return to the flaccid state, cyclic GMP is hydrolyzed to GMP by phosphodiesterase type 5. Other phosphodiesterases are also found in the corpus cavernosum, but they do not appear to have an important role in erection.

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Molecular Mechanism of Penile Smooth-Muscle Contraction. Norepinephrine from sympathetic nerve endings, and endothelins and prostaglandin F2 from the endothelium, activate receptors on smooth-muscle cells to initiate the cascade of reactions that results in elevation of intracellular calcium concentrations and smooth-muscle contraction. Protein kinase C is a regulatory component of the calcium-independent, sustained phase of agonist-induced contractile responses. Smooth Muscle The key to the entire system is smooth muscle. The percent of smooth muscle dictates the ability to achieve and maintain erections. Roughly 45 percent of the cavernosal body is made up of smooth muscle.The common mechanism of these agents may be via regulation of smooth muscle calcium. Penile erection or flaccidity is determined by the state of relaxation or contraction of trabecular and arteriolar smooth muscle, which is influenced, in turn, by several factors, including: Adequate levels of neurotransmitters, hormones, and endothelium-derived substances Adequate expression of receptors Integrity of the transduction mechanisms Calcium homeostasis Interaction between contractile proteins Effective intercellular communication among smooth muscle cells.

Trabecular muscle tone is controlled and penile blood vessel smooth muscle tone may be influenced by three neuroeffector systems. Adrenergic nerves, which constrict penile blood vessel and corporal smooth muscle via norepinephrine or similar adrenergic agonists acting on alpha-1 adrenoreceptors

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Cholinergic nerves, which appear to modulate the other two neuroeffector systems rather than act directly on smooth muscle Nonadrenergic-noncholinergic (NANC) nerves, which control blood vessel and corporal smooth muscle relaxation.

Local Penile Smooth Muscle Physiologic Mechanisms. To sum up In the flaccid state, the smooth muscle cells of the penile arteries and the corpora cavernosa are in a state of tone (contraction). Relaxation of the smooth muscle (arterial and cavernosal) causes increased inflow of blood into the lacunar spaces of the corpora cavernosa. The arterial pressure expands the relaxed trabecular walls, thus expanding the tunica albuginea with subsequent elongation and compression of the draining venules. This mechanism of veno-occlusion restricts the outflow of blood through these channels. After ejaculation or cessation of the erotic stimuli, the smooth muscle surrounding the arteries and the lacunar spaces contracts. The inflow of blood is reduced and the venous drainage of the corporeal spaces is opened, returning the penis to the flaccid state. Erection of the penis is thus a haemodynamic event under the control of the autonomic nervous system. Coordination of the neuronal activity from psychogenic stimuli occurs in the hypothalamus while reflexogenic erection involves a polysynaptic coordination in the sacral parasympathetic centres. The mechanisms of erection and detumescence are much more complex than that described above with many other factors and secondary messengers playing a role. But the description above gives the more important an salient points.

SCHEMATIC DIAGRAM OF PENILE ERECTION

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PERIPHERAL NEUROPATHY IN DIABETES: A CLINICAL APPROACH

Dr. S.M.Sadikot. Hon. Endocrinologist, Jaslok Hospital and Research Centre, Mumbai 400026 The relationship between diabetes and the peripheral nerves has been known for quite a long time. Rollo is credited as being the first to record this association almost two hundred years ago. In fact, most of the observers in the 19th Century felt that diabetes was caused by the involvement of the nervous system through some unknown mechanism. It was only in 1864 that Michael de Calvi first suggested that diabetes may be the cause of, rather than be caused by, neuropathy. He also recorded the occurrence of pain in the distribution of the sciatic nerve and loss of peripheral sensations. Later, Bouchard noted the loss of tendon reflexes, and Pavy and Althus provided a further account of the nerve involvement. As late as 1945, Rundles first definitively ascribed diabetes to be the cause of peripheral nerve involvement and gave the first comprehensive description. Estimates of the prevalence of diabetic neuropathy vary widely with studies showing a range from 0% to as much as 93%. This is due to the fact that the criteria used for the estimation of prevalence are not standardised and also to the differences in the duration of diabetes before one tests for the presence of neuropathy. Pirart's classic 25 year prospective study of 4400 unselected patients would give the best idea about the prevalence. He defined neuropathy as the loss of the ankle reflex and/or patellar reflex plus diminished vibration sense irrespective of other clinical signs and symptoms of nerve involvement. Neuropathy was detected at the time of diagnosis of diabetes in 12% of the patients, mostly in those with mild Type 2 diabetes. These were patients in whom it is the most difficult to rule out pre-existing hyperglycemia. In the series reported by Pirart, prevalence increased linearly with the duration of diabetes, reaching about 50% of the patients after 25 years of diabetes. He also reported that patients with retinopathy and/or nephropathy were more likely to have evidence of neuropathy. Our own study CINDI carried out by DiabetesIndia showed a prevalence of around 15% in patients who were evaluated within three months of initial diagnosis. In Type I patients in whom the onset is usually easy to pinpoint, Eng has reported that it is quite rare for neuropathy to be detected within the first five years of diabetes. Although various classifications of diabetic neuropathy have been published, none of them have gained wide acceptance. From a review of the different classifications, I have compiled a clinical classification, which is arbitrary but would help in understanding the various clinical manifestations of diabetic peripheral neuropathy. It should be clear that the different categories are not absolutely independent and patients may show the signs and symptoms of more than one of the classified categories. Clinical Classification of DIABETIC NEUROPATHY ACUTE ONSET- TYPE Painful symmetrical polyneuropathy This is the commonest form of painful neuropathies having a relatively acute onset. It is extremely painful and like all diabetic neuropathies, the pain is more at night, a diagnostic pointer to its diabetic roots. Curiously, it tends to develop about three weeks after a stressful episode like surgery, heart attack, ketosis, severe infection etc. It may develop after the initiation of insulin therapy especially in those patients in whom the blood glucose is dropped very rapidly and more so if this is accompanied by frequent and/or severe episodes of hypoglycemia. A severely curtailed diet may also play a role, especially in those patients who are already slightly undernourished. Typically, this form a diabetic neuropathy generally lasts for about 6-18 months and then disappears. Motor involvement is commoner with this neuropathy in comparison to that associated with the gradual onset distal symmetrical polyneuropathy. The motor involvement also tends to be more severe. Depression and loss of appetite is seen so often that this should be considered as a part of the clinical picture in this type of neuropathy. Diabetic Amyotrophy (Plexopathy)

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This commonly seems to attack men in their 60's with a history of diabetes of a relatively short duration. It is associated with a severe pain and like other painful diabetic neuropathies, it may have a time relationship with a stressful situation. Diabetic plexopathy is typically associated with painful weakness and atrophy of the pelvic girdle and thigh musculature. The weakness commonly affects the ilio-psoas and the quadriceps muscles with a relative sparing of the hip extensors and the hamstrings. Thigh flexion and the stability of the knee is affected although the clinical picture does have a resemblance to femoral neuropathy, the associated weakness of the gluteii, thigh adductors and the occasional involvement of the distal muscles like the peroneal and the tibial, gives a distinct differential feature in diabetic pelvic plexopathy. Sensory signs and symptoms may also occur and include paraesthesias and dysthesias of the anterior thigh and anteromedial leg, and may radiate down to the dorsum of the leg. The pain may start from the sacroiliac region and radiate down the back of the leg. The knee jerk is commonly absent, the ankle jerk being present, whilst the planter may be extensor. The plexopathy is usually unilateral in onset, but the other side may also be affected whilst sometimes involvement of the contralateral side is seen to manifest after the episode has disappeared from the initial side. The shoulder girdle may be affected in rare cases but if bulbar involvement is seen, then a search must be made for another cause. The main differential diagnosis is lumbar nerve root compression, although neoplastic infiltration of the lumbosacral canal, motor neuron disease, myopathy and vasculitis may have to be kept in mind in atypical cases. Indeed laminectomies have been carried out in quite a few of these patients in order to treat nerve root compression! But the lack of mechanical manifestations, the nocturnal exacerbation of pain with failure to respond to bedrest, the extreme muscular wasting and the types of muscle groups involved may help in the correct diagnosis. MONONEUROPATHIES Cranial nerve involvement Isolated or multiple lesions of the nerves occur more frequently in people with diabetes than in the general population, and this may frequently be seen even in the absence of signs and symptoms of peripheral nerve involvement. The 3rd and the 6th cranial nerves are the ones commonly affected whilst the 4th cranial nerve would rarely be affected alone, if ever. The onset of diplopia is acute and is often seen to be associated with pain behind and above the affected eye. (It is felt that this pain is caused by involvement of the first and second parts of the trigeminal nerve, as the occulomotor nerves are purely motor). An important diagnostic point in distinguishing this from the involvement of the third nerve in other pathologies such as cavernous sinus thrombosis is that the pupils are spared in diabetic involvement, whilst in other cases pupillary dilation is one of the first features. Another important differential diagnosis is with temporal arteritis. In this condition, the muscles are involved in a random manner whilst in diabetic third nerve involvement, all the muscles supplied by the nerve are affected. After the cranial nerves supplying the external ocular muscles, it is the 7th cranial nerve that seems to be the most affected in diabetes. There seems to be a less favorable prognosis for recovery as compared to a similar non-diabetic case. This is in contrast to the clinical picture seen with the third and sixth nerve involvement, where the pain gradually subsides and the recovery is mostly complete in a while. In fact, it should be made clear that many authorities doubt whether the seventh nerve is really affected in diabetes but feel that diabetes could be a coincidental finding. Other upper cranial nerves may be rarely affected, whilst the lower cranial nerves are almost never the site of diabetic cranial mononeuropathy. Isolated Peripheral Nerve Lesions Isolated peripheral mononeuropathy is relatively more common in diabetes. The pathological basis may be a vascular lesion, entrapment or trauma to a superficially placed nerve. Any major nerve trunk may be affected and when several are affected at the same time, the entity is called "mononeuritis multiplex". The signs and symptoms would obviously depend on the site and type of nerve that is involved. They may be purely sensory as when the lateral cutaneous nerve of the thigh is involved, but more commonly, the clinical manifestations are of a mixed type although pure motor nerve involvement is known to occur. The onset is usually acute, but may rarely be insiduous. The acute onset varieties are invariably quite painful, but satisfactory recovery seems to be a part of the clinical picture. The nerves that are most commonly affected are the median, ulnar, radial, femoral, sciatic and the peroneal, (the nerves are not listed in any particular order).

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Detailed descriptions about the signs and symptoms associated with involvement of individual nerves are beyond the scope of this book and the reader could refer to any standard text for these descriptions. What is interesting is that many of the nerves involved are those that are capable of being involved in compression and/or entrapment pathologies and it is possible that diabetes in some manner makes the entrapment much more plausible. Radiculopathy This is a relatively uncommon form of diabetic mononeuropathy, but its correct diagnosis is tremendously important in order to save the patient from unnecessary therapeutic intervention. When the thoracic or upper abdominal radicals are involved, the clinical picture may definitely mimic an acute chest or abdominal emergency. In fact, patients have been admitted in the intensive care units with a provisional diagnosis of myocardial infarction whilst some have even undergone emergency abdominal laparotomy. A careful examination showing that the pain is limited to a dermatomal distribution (with an EMG of the paraspinal muscles if needed) would have avoided this diagnostic gaffe. The cause for this type of neuropathy is not well known although it is felt that ischemic infarction of the nerve may play an important role. In any case, the patient may be comforted with the fact that, invariably, the pain subsides after a period and that there is no residual damage, although the complete recovery may take upto a few months. Diabetic Neuropathic Cachexia This disorder has been recognised as a clinical entity only in relatively recent times. It resembles the syndrome of painful, acute onset symmetrical neuropathy but is associated with an incredible weight loss which has even been known to be in the range of 100 lbs. in some affected individuals. This often leads to an incorrect tentative diagnosis of malignancy and the patient is extensively investigated for the root of the malignant problem. The irony is that this type of nerve involvement usually disappears within 6-12 months and the patient recovers even as the extensive investigations are still going on! To date, all the patients with this type of syndrome have been men in their 60's and despite the clinical severity of the neuropathy, most have mild degree of hyperglycemia which often is diagnosed only when they are investigated for the cause of the neuropathy and the weight loss. It could be that the mild degree of hyperglycemia may mislead the physician who is unaware of this clinical entity. AUTONOMIC NEUROPATHY Diabetic autonomic neuropathy usually accompanies the gradual onset type of distal symmetrical polyneuropathy. It may, in some patients, be so mild that it is not even taken into consideration, whilst in some cases the degree of involvement of the autonomic nerves may overshadow all other clinical manifestations of peripheral neuropathy. At the same time, it should be realised that even mild degrees of clinical involvement of the autonomic nerves can give size to significant problems to the patient. Clinical Manifestations of Autonomic Neuropathy Cardiovascular Tachycardia, exercise intolerance Cardiac denervation, painless myocardial infarction Orthostatic hypotension Heat intolerance Alterations in skin blood flow Gastrointestinal Esophageal dysfunction Gastroparesis diabeticorum Diarrhea Constipation Fecal incontinence

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Genitourinary Erectile dysfunction Retrograde ejaculation Cystopathy Neurogenic bladder Sweating disturbances Areas of symmetrical anhydrosis Gustatory sweating Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness Pupillary Decreased diameter of dark-adapted pupil Argyll-Robertson-type pupil

Cardiovascular system Postural hypotension is the commonest form of cardiac autonomic neuropathy in diabetes, and a postural drop of more than 20mm of Hg. is seen in many diabetic patients. In fact, this drop often is used as a test for the presence of autonomic neuropathy. Interestingly, postural hypotension may be made worse after an insulin injection. It has been shown that significant changes occur in the blood pressure after an insulin injection and that this tends to peak within one to three hours after the injection, so that the greatest effect on the postural drop in systolic blood pressure is seen at these times. At the same time, it should be noted that many patients do have a slight drop in systolic blood pressure but this is not large enough to cause any symptoms. Diabetics with significant degree of autonomic neuropathy may show a partial or complete cardiac denervation with a fixed pulse rate of about 80-90 which does not change with stress, exercise or sleep as it does in normal people. Cardiac autonomic neuropathy also changes the autonomic tone in the heart and one sees adrenergic supersensitivity as a result. Both, the partial or complete cardiac denervation and the adrenergic supersensitivity are blamed for the greater incidence of coronary artery spasms, painless myocardial infarcts and sudden deaths seen in diabetics. Diagnostic Tests of Cardiovascular Autonomic Neuropathy Test Resting heart rate Beat-to-beat heart rate variation Heart rate response to standing Method/Parameters > 100 beats/min is abnormal. With the patient at rest and supine (no overnight coffee or hypoglycemic episodes), breathing 6 breaths/min, heart rate monitored by ECG , a difference in heart rate of > 15 beats/min is normal and < 10 beats/min is abnormal. During continuous EKG monitoring, the R-R interval is measured at beats 15 and 30 after standing. Normally, a tachycardia is followed by reflex bradycardia. The 30:15 ratio is normally > 1.03.

Although, exercise is an important aspect in the management of diabetes, it is not without danger as the capacity to exercise may be severely compromised in a diabetic with significant autonomic neuropathy. We have seen that the heart is relatively

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incapable of making adjustments to stress and exercise when it may be partially or completely denervated. There may also be associated problems with peripheral vascular adjustments. Normally, when a person exercises, the heart rate increases and there is also an increase in the contractility. Peripherally, changes take place in the vessels such that blood flow is diverted from the viscera to the muscles. In diabetics with a significant autonomic neuropathy, besides the problems in the heart, changes in the autonomic tone may prevent an adequate rerouting of the blood flow thus starving the muscles and decreasing the capacity to exercise. Conversely so much blood may be diverted that the internal organs may be starved of blood and there have been reports that acute renal shutdown has occurred when a diabetic has undergone sudden and severe exercise. This should not be taken to mean that exercise should be eschewed by all diabetics, but points to the need for greater pre- exercise evaluation and also for a graded and well prescribed exercise therapy in the management of diabetes. Gastrointestinal tract Diarrhoea is one of the most disturbing manifestations of autonomic nerve involvement, and in its most severe form can be quite disabling, both, from a physical as well as a social viewpoint. The attacks of diarrhoea may be preceeded by abdominal rumbling and discomfort. There is a significant increase in the nocturnal frequency of stools and there may be such a severe degree of urgency that this may be accompanied by fecal incontinence. The stools are usually thin and watery but may be steatorrhic. The patient passes stools, often in the range of 25-30 times a day. These attacks are intermittent and may be followed by periods of normality or even by episodes of severe constipation. In fact, some studies have noted constipation as the most common manifestation of diabetic autonomic neuropathy. One of the most emotionally disabling problem is that the patient is unaware about when he may get an attack of diarrhoea and this clouds his social and economic outlook to the possible exclusion of all else. The diarrhoea is multifactorial in its causation and may reflect hypermotility from decreased sympathetic inhibition, bacterial overgrowth, pancreatic insufficiency, diabetic sprue and bile salt malabsorption. Oesophageal motility disorders have been reported and whilst they may cause dysphagia, the more significant problem seems to be related with the decrease in the tone of the lower oesophageal sphincter allowing regurgitation and the sense of retrosternal fullness and discomfort. Problems with gastric emptying and decreases in acid production have also been reported, as has dysfunction in the contractility of the gall bladder causing it to dilate, although it has not been shown that this increases the risk of infection or stone formation. Genitourinary system Bladder dysfunction is commonly seen in diabetic neuropathy. In the early stages, the patient may complain of a diminished frequency of urination and this may be associated with nocturia. Later, the problem of decreased frequency of urination increases, and this is accompanied by a difficulty in emptying the bladder, incontinence and overflow dribbling. Residual urine in the bladder leads to increased urinary infection. Impotency is one of the most troubling aspects of diabetic neuropathy and is present in more than 50% of male diabetics; retrograde ejaculation may also be seen. Neurogenic sexual dysfunction is present also in about 25-30% of female diabetics. Inspite of such a high prevalence and the great emotional and social trauma that it causes, this is one aspect that is often ignored by most of us. This is unfortunate as today, there is so much that can be done for erectile dysfunction. I have discussed this aspect in separate chapter. Sudomotor problems Sweating disturbances may be seen in diabetics with autonomic neuropathy. This may be manifest as abnormal and bizzare sweating patterns, the commonest being the absence of sweating in the distal parts of the lower extremities. This could be accompanied by compensatory hyperhydrosis on the trunk and face and the patient may show heat intolerance. Drenching night sweats have been described which an unknowing physician could attribute to nocturnal hypoglycemia. The cause for this nocturnal sweating is obscure, but the distal anhydrosis is akin to the distal symmetrical neuropathy and is said to be caused by involvement of the autonomic nerves regulating peripheral vascular flow and tone of the vessels. Facial sweating at mealtimes is rarer than one thinks, but when present, it is a striking feature of diabetic peripheral autonomic neuropathy. In severe cases, this may be intolerable to the patient. Sweating usually begins moments after starting to chew tasty foods, specially cheese or other foods rich in tyramine. It starts on the forehead and then may spread to

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the face, scalp, back and occasionally to the shoulders and the upper part of the body. The patient may be compelled to keep a towel with him during mealtimes. There is very little that can be done about this disturbing condition, although anticholinergics have been useful but are often poorly tolerated. The patient may be advised to avoid the foods he know which bring about this phenomenon. Other Manifestations The pupils of the eye are seen to be constricted and this component of autonomic neuropathy, although not clinically significant in itself, is supposed to reflect duration of diabetes, metabolic factors as well as the presence of other diabetic complications. The ability of the body to stabilise the blood glucose levels during times of substrate deprivation as well as during mealtimes is dependent on certain finely tuned interplays. One of the most important of these, which goes a long way to warn about low blood glucose levels as well as to counterregulate the fall in the glucose levels, is the role played by glucagon and the adrenal medulla. These depend to some extent on the functional integrity of the autonomic nervous system and in diabetic autonomic neuropathy, this system is compromised so that the ability of the body to show the signs and symptoms of hypoglycemia are diminished as is the capacity of the body to overcome hypoglycemia and raise the blood glucose levels to an acceptable value. MANAGEMENT It is obvious that one should try and achieve an optimal control of diabetes. This would help in preventing the initiation of neuropathy and in the early stages, it has been shown that it may even help in the regression of the neuropathy. Would optimal control of the blood glucose levels help in cases where the neuropathy is well established. Although there is some controversy in this area, it is felt that one should strive for optimal control as this would definitely help in retarding further progression and in quite a few cases there may be improvement in the signs and symptoms of the nerve involvement. At the same time, I would like to add a word of caution. There have been numerous reports of worsening of the neuropathy when strict control has been sought especially with the use of insulin and insulin "pumps". A closer analysis of these reports has brought out the fact that this worsening was associated with patients undergoing severe and/or frequent episodes of hypoglycemia. This has to be avoided and one should understand that the routine use of these pumps is fraught with too many problems and in fact, even the American Diabetes Association has recommended that these pumps should only be used under very strict guidelines. Another problem that one sees in clinical practice is that diabetic patients are routinely put on a severely calory restricted diet and given high doses of the anti-diabetic medications in order to bring about a rapid decrease in the high blood glucose levels. Many of our patients are underweight or normal and their nutrition status is borderline. There is no need, and in fact, it may even be detrimental to severely restrict the calories. Also unless there is a definite indication for a rapid decrease in the blood glucose levels, there is no justification for trying to bring the blood glucose levels down rapidly. Both these factors may be associated with a worsening of the neuropathy. In fact, in quite a significant number of cases, there is a remarkable improvement in the neuropathy (especially in the burning feet type), when patients who were on a very severely calory restricted diet, were put on a high calory diet and the raised blood glucose levels controlled with small judicious doses of insulin with a resultant smooth control of the diabetes and weight gain in the patient. With regards to diabetic neuropathy per se, there is at present, no specific drug which is routinely available in our therapeutic armamentarium. Aldose reductase inhibitors have been tried abroad with mixed results. The rationale for using these drugs is the proposed role played by the polyol pathway in general, and the aldose reductase enzyme in particular, in the pathogenesis of diabetic neuropathy. Whilst some initial studies showed a significant effect on diabetic neuropathy, the more recent studies have shown some improvement, especially in the pain parameter and in improving the conduction in the nerve, whilst others have shown either very slight.improvement or none. Thus, the role that would be played by this group of drugs is still open to discussion. At the same time, the consensus evidence is of the opinion that these drugs would show a beneficial effect only if they were started in the initial stages of the diabetic neuropathy, whilst they may not be as useful once the neuropathy has become severe.

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The use of drugs such as alpha-lipoic acid, Gamma-linolenic acid and hydroxycobalmin, Vitamins C and E have not been shown to be very useful and would mostly seem to have a placebo like action except in those occasional patients who have a deficiency of these nutrients. Injections of B1, B6, and B12 are routinely used by many doctors when faced with a patient with diabetic neuropathy. Unless there is manifest evidence of the deficiency of these vitamins in the patient, the injections would be of use only as a placebo. Although quite a significant number of our patients are borderline in so far as the level of nutrition goes, I am sure that most of the vitamin injections that are used for the diabetic neuropathy have no real therapeutic role. One also has to accept that the management of neuropathies, especially those with a very painful component, is quite difficult. Telling a patient who is in great agony, that the prognosis for his painful neuropathy is quite bright and that he would get relief from his pain in about 12-18 months, is definitely no solace for the patient. During the very acute and painful stage, relative bed rest may be useful. In acute cases with a significant motor affectation, the strength and mobility of the weakened muscles must be maintained by graded exercises. Special circumstances, like foot drop or a claw hand, may require specially made artificial support up to the time that they recover. The pain may be so severe that I have seen patients willing to even cut off the affected part in order to get some relief. Due to this level of severity, there may be a tendency to use powerful narcotics analgesics. This should be avoided. The painful condition lasts for about 12-18 months and there is a significant chance that the patient may become addicted to these drugs. Many doctors feel that one may give a short course of these drugs, bring about some relief and then discontinue the drug and substitute it with a milder analgesic which is not addictive. This, in clinical practice does not work in most cases, Usually, the severe pain returns and the patient demands the powerful narcotic analgesic which may have given him some relief before, this viscious cycle definitely predisposing to addiction. Moreover, the use of narcotic analgesics for treatment of neuropathic pain is controversial. There is no evidence that nonsteroidal anti-inflammatory drugs or other nonnarcotic analgesics have much effect on neuropathic pain, and for a long time it was held that opioids are also ineffective. In fact, that is usually true if these agents are given at standard doses. Also many of the patients do not seem to get any significant relief even with the use of these drugs and the tendency would then be to either increase the dose of the drug or use even more powerful ones with an increased chance of making the patient addicted. The best compromise is to give relatively high doses of paracetamol and I have given up to 1 gm every four to six hours. There are some patients who do not find the pain very severe during the day but cannot bear it at night and this interferes with sleep. In such cases, the paracetamol may be given only at bedtime. This regimen works in some cases but in others this needs to be accompanied by other drugs like phenothiazines or tricyclic antidepressives, especially given at bedtime. One regimen is to start with very small doses and then titrate the dose against the response. Here again, it is often better to give just a nighttime dose. I use amitryptiline (10-20mg) at bedtime and have found this to give a good reponse. A bed-time dose induces sleep, rarely interferes with daytime wakefullness, especially at these small doses, and tends to break the terrible depression found with the onset of painful neuropathy. Although in some patients, the drug may have to be given round the clock (10mg t.d.s.), most patients do manage with a nighttime dose of antidepressives with non-narcotic analgesia during the day. Unfortunately, tricyclic antidepressants have only modest efficacy, and their use is limited. First, dose titration takes a long time. Second, these agents have a very narrow therapeutic window; beyond a certain dose, most patients experience intolerable adverse effects such as sedation, urinary retention, orthostatic hypotension, or cardiac arrhythmias. In contrast, narcotic analgesics or newer anticonvulsants do not have a dose ceiling. Higher doses of these agents are more likely to cause side effects but will not cause organ damage. Selected Drugs for the Treatment of Neuropathic Pain Syndromes Category ANALGESICS Opioids Morphine,30 mg/75 kg po qid Analgesic tolerance is not in-evitable; side effects include constipation Examples Comments

ADJUVANT ANALGESICS Tricyclic Antidepressants Nortriptyline, start at25 Side effects include sedationand mental mg/day po and titrate to 150 mg/day clouding

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Traditional Anticonvulsants Novel Anticonvulsants

Carbamazepine,400 mg po tid Valproate,750 mg po tid Gabapentin,600 mg po tid Lamotrigine,100 mg po tid

Side effects include ataxia Side effects include ataxia Requires titration; side effectsinclude ataxia Requires titration; side effectsinclude ataxia and rash Side effects include orthostatichypotension Limited experience intreatment of hyperalgesia; sideeffects include sedation Requires close monitoring;limited experience intreatment of hyperalgesia Requires close monitoring;limited experience in treatmentof hyperalgesia

Alpha-Agonists

Clonidine,0.2 mg/day po

ANTIHYPERALGESICS NMDA Antagonists Dextromethorphan,60 mg po tid SYSTEMIC LOCAL ANESTHETICS Lidocaine,1 mg/kg/hr continuoussubcutaneous infusion Mexiletine, 150-300 mg po tid

Carbamezapine and phenytoin sodium have been used for the relief of painful dysthesias with very variable results and most patients do not seem to get much relief with the recommended doses. At higher doses, the side effects of the drugs tend to contraindicate the use of the these drugs. Of the two, carbamezapine may be helful in some patients. The availability of novel antiepileptics renewed interest in this class of agents, especially since some have few side effects. Gabapentin is one such drug which has shown quite good results. It has been shown to relieve pain and sleep interference and improve mood and some aspects of quality of life The dose needs to be titrated and is usually around 600mg three times a day. In one study, treatment with gabapentin was initiated at 900 mg a day and the dose was titrated weekly to 1,800, 2400, and finally 3,600 mg a day. In clinical practice, titration can proceed much faster, but the need for slower titration should always be kept in mind when the patient has renal disease, as many do. However, gabapentin is very forgiving in this respect; if adverse effects occur, they are uncomfortable rather than dangerous. The range of effective doses is wide. Some patients respond to as little as 300 mg a day, while others require much larger doses. The thing is to start with a small dose and titrate upwards. It is usually evident within a few days whether gabapentin will be efficacious. Once an effective dose has been achieved, most patients can continue to take that dose. Perhaps 25% of patients will need dose adjustment. In some patients, the effectiveness of gabapentin diminishes within a few months or weeks, even if the dose is increased. The loss of efficacy may be due to the evolution of the disease or the development of tolerance. The oral antiarrhythmic mexiletine is occasionally given to patients whose pain is not well controlled with other medications. If mexiletine is selected, serum levels should be monitored. The management of the autonomic neuropathy is mostly symptomatic. Oesophageal manifestations usually respond to metoclopramide. Constipation may be managed by the use of high fiber diets or bulk laxatives. Care must be taken with the use of the latter so as not to push the patient into laxative abuse syndrome. Diabetic diarrhea is a diagnosis of exclusion and can be very difficult to control. Diphenoxylate, loperamide, or clonidine, can be helpful. Small bowel stasis contributes to bacterial overgrowth, causing diarrhea. Antibiotic treatment is recommended for a period of 2 weeks. Bacterial overgrowth does not have to be proven; it is prudent to treat the condition empirically. Doxycycline, amoxicillin, metronidazole, and ciprofloxacin are choices for the treatment of diabetic diarrhea secondary to bacterial overgrowth of the small intestine. In milder forms of the postural hypotension, the patient would have to be told to be careful whilst getting up and possibly sleep with a couple of pillows under the head. Symptomatic orthostatic hypotension can be very troubling in patients with diabetic neuropathy. Increasing the patient's salt intake, along with use of compression stockingsand sleeping with a couple

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of pillows under the head may help. If these modalities do not improve symptoms, then fludrocortisone may help. There is very little that can be done about cardiac denervation except to see that the patient avoid undue stress like severe attacks of hypoglycemia, severe exercise, unnecessary cardiac stress tests etc. In case, the patient has to undergo an operation, it may be preferable to avoid general anaesthesia but if this has to be given, the surgeon and the anaesthetist should be forewarned about this problem. Management strategies for urinary bladder problems include telling the patient to void at frequent fixed time intervals, teaching the patient manoevres to try and get the bladder emptied as much as possible and treating any urinary tract infection early and completely. Occassionally, a patient may be helped by giving a cholinergic drug like bethanechol (1020mg t.d.s. to q.d.s.) but frequently the side effects preclude the use of this drug. In certain patients, especially women who tend to get recurrent urinary tract infection, it may be worthwhile to put them on a small bedtime dose of an antibiotic to which the previous infection responded. The management of sexual dysfunction is discussed seperately. Neuropathic ulcers are a major source of morbidity associated with diabetic neuropathy. The best strategy is their prevention which is definitely better than cure. It is essential that all the patients be taught about the importance of, and the need for, constant care of the feet. It is also imperative that all the patients, each time that they are seen by the diabetic specialists, should have the feet closely examined. Foot care is also discussed in a seperate section. Finally, it would be worthwhile to reiterate the importance of an early diagnosis of diabetic neuropathy, the need for excellent foot care and lastly, but probably, the most important, the desirability of a smooth and optimal control of diabetes.

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