Endocrine/Reproductive Physiology Diabetes

Diabetes is a lifelong (chronic) disease in which there are high levels of sugar in the blood. To understand diabetes, it is important to first understand the normal process by which food is broken down and used by the body for energy. Several things happen when food is digested: A sugar called glucose enters the bloodstream. Glucose is a source of fuel for the body. An organ called the pancreas makes insulin. Paul Langerhans, a German student, identified clusters of cells within the pancreas responsible for the production of insulin called the islets of Langerhans. Insulin is a hormone produced by the pancreas to control blood sugar levels. The role of insulin is to move glucose from the bloodstream into muscle, fat, and liver cells, where it can be used as fuel. Diabetes is a disorder of insulin action/production and can be caused by too little insulin, resistance to insulin, or both. People with diabetes have high blood sugar because their body cannot move sugar into fat, liver, and muscle cells to be stored for energy. This is because either their pancreas does not make enough insulin or their cells do not respond to insulin normally. High blood sugar levels can cause several symptoms, including: Blurry vision, excessive thirst, fatigue, frequent urination, hunger, weight loss.

Diagnosis of Diabetes Mellitus A person may be diagnosed as diabetes if; random plasma glucose levels > 11.1 mmol and/or fasting plasma glucose levels > 7.5 mmol on 2 occasions and/or they have impaired glucose tolerance symptomatic (frequent urination, blurred vision etc) they have a family history of the disease

There are three main types of diabetes; Type 1 Diabetes, Type 2 Diabetes and Gestational Diabetes. There are also other rare forms of the disease that occur due to mutations.

Compare and contrast type 1 and type 2 Diabetes. (2010/2011)

Type 1 diabetes (Insulin-dependent Diabetes) Type 1 diabetes can occur at any age, but it is most often diagnosed in children, teens, or young adults. Type 1 diabetes accounts for 5-10% of all cases. In this disease, the body makes little or no insulin. It is an autoimmune destruction disorder where the body attacks its own B cells and suffers a loss of insulin production. Many complex metabolic derangements occur with this disease such as Hyperglycaemia (excessive amount of sugar in the blood), protein breakdown and Ketoacidosis.

Diabetic ketoacidosis occurs when the body cannot use sugar (glucose) as a fuel source because there is no insulin or not enough insulin. Fat is used for fuel instead. The By-products of fat breakdown, called ketones, build up in the body. As there is a loss of insulin production, this results in a reduced entry of glucose into various peripheral tissues. At the same time, there is an increase in hepatic glucose production and release into the circulation. Therefore there is an extracellular glucose excess and in many cells an intracellular glucose deficiency starvation in the midst of plenty. Because of this, the body thinks it is starving and starts to break down lean muscle. The only treatment is insulin replacement therapy and daily injections of insulin are needed. In addition to being an autoimmune disorder, diabetes also has some genetic susceptibility on chromosome 6 with linkage to HLA locus DR3 locus increases risk X3 DR4 locus increases risk X8

Type 1 Diabetes can also be triggered by environmental factors such as childhood viral infections, mumps, rubella and it is thought that some Cows milk antigens can contribute to the disease. Europe and South East Asia are hot-spots for type 1 Diabetes. Ketogenesis (synthesis of ketone bodies) and Ketoacidosis (excess ketone bodies) in T1DM. Complete insulin deficiency causes unrestrained lipolysis in adipose tissue resulting in increased fatty acid and ketone levels. Most fatty acids are oxidised to give acetyl co-enzyme A. Increased beta oxidation of fatty acids generates an excess of acetyl CoA, some of which is diverted from the TCA cycle into ketone body production. Acetoacetate, -hydroxybutyrate and acetone are three ketone bodies that are formed as by-products of fatty acid metabolism. Ketoacidosis is when too many ketone bodies are formed. It is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. In ketoacidosis, the body fails to adequately regulate ketone production causing such a severe accumulation of keto acids that the pH of the blood is substantially decreased. In extreme cases ketoacidosis can be fatal. It is most common in untreated type 1 diabetes mellitus. Ketoacidosis can be smelled on a person's breath. This is due to acetone, a direct by-product of the spontaneous decomposition of acetoacetic acid. It is often described as smelling like alcohol or nail polish remover. In some cases, ketones can spill over into the urine and cause ketonuria. Symptoms include; nausea and vomiting, confusion, excessive thirst (dehydration), headache, abdominal pain, drowsiness, acetone on breath, ketonuria, metabolic acidosis, hyperventilation.

Insulin Therapy for type 1 Diabetes Mellitus Insulin therapies were isolated from pigs/cows in the past but now are made as a recombinant human protein in bacteria. Insulin is degraded by the GIT therefore oral administration not successful. However, oral analogues are being developed. The Insulin usually administered (self) subcutaneously, intravenously or intramuscular. The half-life of insulin in the blood is 10 min. the main aim of insulin therapy is to avoid large fluctuations in the levels of insulin/glucose. Without insulin therapy, coma and death would occur. The best therapy for Type 1 diabetes is a mixture of short and medium lasting insulin which is injected before meals.

Type 2 diabetes (Non-insulin dependent) Type 2 diabetes is responsible for the majority of diabetes cases. It most often occurs in adulthood, but teens and young adults are now being diagnosed with it because of high obesity rates. In T2DM, fat, liver, and muscle cells do not respond correctly to insulin. This is called insulin resistance. As a result, blood sugar does not get into these cells to be stored for energy. When sugar cannot enter cells, it builds up in the blood causing hyperglycaemia. Type 2 diabetes usually occurs slowly over time. Most people with the disease are overweight when they are diagnosed and do not know they have it. Type 2 diabetes can also develop in people who are thin. This is more common in the elderly. Type 2 Diabetes also has some genetic susceptibility (Polygenic). Other contributing factors are Lifestyle risk factors Physical inactivity Obesity Family history

Characteristics of type 2 Diabetes Classical symptoms (50%) Metabolic Hyperglycaemia/ hyperinsulinemia Impaired glucose tolerance Dyslipidaemia -Increases LDL (proatherogenic) and decreases HDL (atheroprotective) Polydipsia - excessive thirst Polyphagia - excessive hunger Polyuria excessive urination

Lipotoxicity in Type 2 Diabetes. Lipotoxicity can occur in the liver of diabetic patients where excess lipids deposit in non-adipose tissue causing cell/tissue dysfunction and resulting in; increase in fatty acid b oxidation decrease in insulin sensitivity increase in gluconeogenesis increase in inflammation increase in oxidative stress

Diabetes long term complications Micro vascular complications such as retinopathy, nephropathy and neuropathy. Macro vascular complications such as arteriosclerosis which leads to Myocardial infarction and stroke. The latter are the leading cause of death in type 1 and type 2 diabetes. The risk of complications are diminished by good glycaemic control Retinopathy: Retinopathy is the leading cause of blindness in working age adults. Poor glycaemic control major risk factor for Diabetic retinopathy. DR results in changes in retinal microvasculature such as; increased vascular permeability/macular oedema (non proliferative retinopathy) retinal hypoxia and ischemia stimulate angiogenesis (proliferative retinopathy)

Nephropathy: Progressive disease caused by damage to the renal microvasculature. It is more common in type 1 diabetes than type 2. The main risk factor for nephropathy is poor glycaemic control. Nephropathy is the leading cause of end-stage renal disease as it causes pathological changes in the kidney such as; glomerular basement membrane thickening mesangial cell expansion ECM accumulation/fibrosis Progressive decline in glomerular filtration rate

Neuropathy: Neuropathy is the leading cause of non-traumatic lower extremity amputations. Its development is also closely related to glycaemic control. It causes abnormalities of the microvasculature that supplies peripheral nerves resulting in; endothelial hyperplasia basement membrane thickening increase in vasoconstriction and oxidative stress Hypoxia and ischemia

Describe the major actions of insulin in skeletal muscle, adipose tissue and liver. Discuss how these actions are altered in type 2 Diabetes. (2008/2009)

Metabolic Actions of Insulin Insulin has 3 major target organs in the body; skeletal muscle, adipose tissue and the liver. It causes cells in the liver, muscle, and fat tissue to take up glucose from the blood and store it as glycogen. These types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose uptake is concerned. Muscle cells because of their central role in movement, breathing, circulation, etc., and adipocytes because they accumulate excess food energy against future needs. Together, they account for about two-thirds of all cells in the human body.

In skeletal muscle, insulin increases the uptake of glucose from the blood. It drives glycogen synthesis and glycolysis. Insulin also promotes the uptake of amino acids and therefore increases protein synthesis. In the adipocytes, insulin also increases glucose uptake from the blood. It stimulates triglyceride synthesis from fatty acids. In the liver, insulin drives glycogen synthesis and the storage of glucose in liver in the form of glycogen. Lowered levels of insulin in diabetes cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin, which is directly useful in reducing high blood glucose levels as in diabetes. Insulin also decreases gluconeogenesis decreases production of glucose from non-sugar substrates, primarily in the liver.

Classification of Diabetes Mellitus into two types. (2007)

Type 1 Diabetes Age of onset Nutritional status Prevalence Genetic predisposition Defect Childhood/puberty frequently malnourished 10-20% of cases Moderate B cell / insulin deficiency

Type 2 Diabetes > 35y (middle age) frequently obese 80-90% of cases Very strong Target cell defect (Skeletal muscle) Insulin resistance Insulin insufficiency

Gestational diabetes is high blood sugar that develops at any time during pregnancy in a woman who did not have diabetes in the past. Pregnancy hormones can block insulin from functioning properly. When this happens, glucose levels may increase in a pregnant woman's blood. Women are at greater risk for gestational diabetes if they: Are older than 25 when pregnant Have a family history of diabetes Gave birth to a baby that weighed more than 9 pounds or had a birth defect Have high blood pressure Have too much amniotic fluid Were overweight before pregnancy

Oral hypoglycaemic agents Oral drugs can be taken to reduce and prevent hypoglycaemia. These help to treat Type 2 Diabetes Mellitus by lowering blood glucose levels. Examples include; Biguanides e.g. Metformin Biguanides lower blood glucose levels by increasing glucose uptake into skeletal muscle and inhibiting gluconeogenesis in the liver. Their actions are mediated by the AMP dependent protein kinase (AMPK). In the liver biguanides act to: decrease acetyl CoA carboxylase (inhibition of FA synthesis) decrease SREBP-1 (down regulates expression of lipogenic genes) increase FA oxidation and decrease hepatic lipotoxicity decrease gluconeogenesis

Sulfonylureas e.g. Glibenclamide Sulfonylureas stimulate first-phase insulin release from the pancreatic b-cells. Therefore, they are only useful if the islets are still functional. Sulfonylureas bind to the KATP receptor on b-cells and mimic ATP by blocking the channel. This triggers membrane depolarisation, Ca2+ entry and insulin release. -glucosidase inhibitors- e.g. Acarbose These control hyperglycaemia by inhibiting digestion of complex CHOs in the brush border of the villi and thus slowing their rate of absorption. They target post-prandial hyperglycaemia and have no effect on fasting blood glucose. Alpha-glucosidase inhibitors can cause GI distress. Thiazolidinediones (TZDs) e.g. Rosiglitazone