Background

Diabetes mellitus (DM) is a chronic metabolic disorder caused by an absolute or relative deficiency of insulin, an anabolic hormone. Insulin is produced by the beta cells of the islets of Langerhans located in the pancreas, and the absence, destruction, or other loss of these cells results in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]). Most children with diabetes have IDDM and a lifetime dependence on exogenous insulin. Type 2 diabetes (noninsulin-dependent diabetes mellitus [NIDDM]) is a heterogeneous disorder. Most patients with NIDDM have insulin resistance, and their beta cells lack the ability to overcome this resistance. Although this form of diabetes was previously uncommon in children, in some, countries 20% or more of new patients with diabetes in childhood and adolescence have NIDDM, a change associated with increased rates of obesity. Other patients may have inherited disorders of insulin release leading to maturity onset diabetes of the young (MODY). This chapter addresses only IDDM.

ketones. It also stimulates fat storage. Additionally, insulin inhibits the breakdown of protein and fat for glucose production (gluconeogenesis) in both liver and kidneys. Hyperglycemia (ie, random blood glucose concentration more than 200 mg/dL or 11 mmol/L) results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with IDDM wastes away and eventually dies from diabetic ketoacidosis (DKA). An excess of insulin prevents the release of glucose into the circulation and results in hypoglycemia (blood glucose concentrations of <60 mg/dL or 3.5 mmol/L). Glucose is the sole energy source for erythrocytes, kidney medulla, and the brain.

Frequency
United States

Pathophysiology
Insulin is essential to process carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and

Overall incidence is approximately 15 cases per 100,000 individuals annually and probably increasing. An estimated 3 children out of 1000 develop IDDM by age 20 years. International DM exhibits wide geographic variation in incidence and prevalence. Annual incidence varies from 0.61 cases per 100,000 persons in China, to 41.4 cases per 100,000 in Finland. Substantial variations exist between nearby countries with differing lifestyles, such as Estonia and Finland, and between genetically similar populations such as those in Iceland and Norway. Even more striking are the

differences in incidence between mainland Italy (8.4/100,000) and the Island of Sardinia (36.9/100,000). These variations strongly support the importance of environmental factors in the development of IDDM. Most countries report that incidence rates have at least doubled or more in the last 20 years. Incidence appears to increase with distance from the equator.

the interaction of factors such as metabolic control, genetic susceptibility, lifestyle (eg, smoking, diet, exercise), pubertal status, and gender.Long-term complications include the following: Retinopathy Cataracts Hypertension Progressive renal failure Early coronary artery disease Peripheral vascular disease Neuropathy, both peripheral and autonomic Increased risk of infection

Mortality/Morbidity
Information on mortality rates is difficult to ascertain without complete national registers of childhood diabetes, although agespecific mortality is probably double that of the general population. Particularly at risk are children aged 1-4 years who may die with DKA at the time of diagnosis. Adolescents are also a high-risk group. Most deaths result from delayed diagnosis or neglected treatment and subsequent cerebral edema during treatment for DKA, although untreated hypoglycemia also causes some deaths. Unexplained death during sleep may also occur. IDDM complications are comprised of 3 major categories: acute complications, long-term complications, and complications caused by associated autoimmune diseases. Acute complications reflect the difficulties of maintaining a balance between insulin therapy, dietary intake, and exercise. Acute complications include hypoglycemia, hyperglycemia, and DKA. Long-term complications arise from the damaging effects of prolonged hyperglycemia and other metabolic consequences of insulin deficiency on various tissues. While long-term complications are rare in childhood, maintaining good control of diabetes is important to prevent complications from developing in later life. The likelihood of developing complications appears to depend on

Associated autoimmune diseases are common with IDDM, particularly in children who have the human leukocyte antigen DR3 (HLA-DR3). Some conditions may precede development of diabetes; others may develop later. As many as 20% of children with diabetes have thyroid autoantibodies.

Race
Different environmental effects on IDDM development complicate the influence of race, but racial differences clearly exist. Whites have the highest reported incidence of IDDM; Chinese have the lowest. IDDM is 1.5 times more likely to develop in American whites than in American blacks or Hispanics. Current evidence suggests that when immigrants from an area with low incidence move to an area with higher incidence, their IDDM rates tend to increase toward the higher level.

Sex
The influence of sex varies with the overall incidence rates. Males are at greater risk in regions of high incidence, particularly older males, whose incidence rates often show seasonal variation. Females appear to be at a greater risk in low-incidence regions.

Age
Generally, incidence rates increase with age until mid-puberty then decline after puberty, but IDDM can occur at any age. Onset in the first year of life, though unusual, can occur and must be considered in any infant or toddler, because these children have the greatest risk for mortality if diagnosis is delayed. Their symptoms may include the following: Severe monilial diaper/napkin rash Unexplained malaise Poor weight gain or weight loss Increased thirst Vomiting and dehydration, with a constantly wet napkin/diaper

Where prevalence rates are high, a bimodal variation of incidence has been reported that shows a definite peak in early childhood (ie, 4-6 y) and a second, much greater peak of incidence during early puberty (ie, 10-14 y).

Hyperglycemia: Hyperglycemia alone may not cause obvious symptoms, although some children report general malaise, headache, and weakness. They may also appear irritable and become ill-tempered. The main symptoms of hyperglycemia are secondary to osmotic diuresis and glycosuria. Glycosuria: This condition leads to increased urinary frequency and volume (eg, polyuria), which is particularly troublesome at night (eg, nocturia) and often leads to enuresis in a previously continent child. These symptoms are easy to overlook in infants because of their naturally high fluid intake and diaper/napkin use. Polydipsia: Increased thirst, which may be insatiable, is secondary to the osmotic diuresis causing dehydration. Weight loss: Insulin deficiency leads to uninhibited gluconeogenesis, causing breakdown of protein and fat. Weight loss may be dramatic, even though the child's appetite usually remains good. Failure to thrive and wasting may be the first symptoms noted in an infant or toddler and may precede frank hyperglycemia. Nonspecific malaise: While this condition may be present before symptoms of hyperglycemia, or as a separate symptom of hyperglycemia, it is often recognized only retrospectively.

Symptoms of ketoacidosis Severe dehydration Smell of ketones Acidotic breathing (ie, Kussmaul respiration), masquerading as respiratory distress Abdominal pain Vomiting Drowsiness and coma

History
The most easily recognized symptoms are secondary to hyperglycemia, glycosuria, and ketoacidosis (KA).

Other nonspecific findings o Hyperglycemia impairs immunity and renders a child more susceptible to recurrent infection, particularly of the urinary tract, skin, and respiratory tract. o Candidiasis may develop, especially in groin and flexural areas.

cells are progressively destroyed, with insulin deficiency usually developing after the destruction of 90% of islet cells.

Genetic issues
Clear evidence exists for a genetic component to IDDM. Monozygotic twins have a 60% lifetime concordance for developing IDDM, although only 30% do so within 10 years after the first twin is diagnosed. In contrast, dizygotic twins have only an 8% risk of concordance, which is similar to the risk among other siblings. The frequency of diabetes developing in children with a diabetic mother is 2-3% and 5-6% if the father has IDDM. The risk to children rises to almost 30% if both parents are diabetic. HLA class II molecules DR3 and DR4 are associated strongly with IDDM. More than 90% of whites with IDDM express 1 or both of these molecules, compared to 50-60% in the general population. Patients expressing DR3 also risk developing other autoimmune endocrinopathies and celiac disease. These patients are more likely to develop diabetes at a later age, to have positive islet cell antibodies, and to appear to have a longer period of residual islet cell function. Patients expressing DR4 are usually younger at diagnosis and more likely to have positive insulin antibodies, yet they are unlikely to have other autoimmune endocrinopathies. The expression of both DR3 and DR4 carries the greatest risk of IDDM; these patients have characteristics of both the DR3 and DR4 groups.

Physical
Apart from wasting and mild dehydration, children with early diabetes have no specific clinical findings. Physical examination may reveal findings associated with other autoimmune endocrinopathies, which have a higher incidence in children with IDDM (eg, thyroid disease with symptoms of overactivity or underactivity and possibly a palpable goiter). Cataract is a rare presenting problem, typically occurring in girls with a long prodrome of mild hyperglycemia. Necrobiosis lipoidica usually, but not exclusively, occurs in people with diabetes. Necrobiosis most often develops on the front of the lower leg as a well-demarcated, red, atrophic area. The condition is associated with injury to dermal collagen, granulomatous inflammation, and ulceration. The cause of necrobiosis is unknown, and the condition is difficult to manage.

Causes
Most cases (95%) of IDDM are the result of environmental factors interacting with a genetically susceptible person. This interaction leads to the development of autoimmune disease directed at the insulin-producing cells of the pancreatic islets of Langerhans. These

Environmental factors
Environmental factors are important because even identical twins have only a 30-60% concordance for IDDM, and because incidence rates vary in genetically similar populations under different living conditions. No single factor has been identified, but infections and diet are considered the 2 most likely environmental candidates. Viral infections may be the most important environmental factor in the development of IDDM, probably by initiating or modifying an autoimmune process. Instances have been reported of a direct toxic effect of infection in congenital rubella. A recent survey suggests enteroviral infection during pregnancy carries an increased risk of IDDM in the offspring. Paradoxically, IDDM's incidence is higher in areas where the overall burden of infectious disease is lower. Dietary factors are also relevant. Breastfed infants have a lower risk for IDDM, and a direct relationship exists between per capita cow milk consumption and incidence of diabetes. Some cow's milk proteins (eg, bovine serum albumin) have antigenic similarities to an islet cell antigen. Nitrosamines, chemicals found in smoked foods and some water supplies, are known to cause IDDM in animal models; however, no definite link has been made with humans. Chemical causes: Streptozotocin and RH-787, a rat poison, selectively damage islet cells and can cause IDDM.

IDDM secondary to pancreatic damage (ie, cystic fibrosis, chronic pancreatitis, thalassemia major, hemochromatosis, hemolytic uremic syndrome) Wolfram syndrome (diabetes insipidus, DM, optic atrophy, deafness [DIDMOAD]) Chromosomal disorders such as Down syndrome, Turner syndrome, Klinefelter syndrome, or Prader-Willi syndrome (The risk is said to be around 1% in Down and Turner syndromes.)

Lab Studies
The need for and extent of laboratory studies vary, depending upon the general state of the child's health. For most children, only urine testing for glucose and blood glucose measurement are required for a diagnosis of diabetes. Other conditions associated with diabetes require several tests at diagnosis and at later review. (See Diabetic Ketoacidosis for information on laboratory studies needed to manage cases of DKA.) Urine glucose A positive urine glucose test suggests but is not diagnostic for IDDM. Diagnosis must be confirmed by test results showing elevated blood glucose levels. Test urine of ambulatory patients for ketones at the time of diagnosis. Urine ketones Ketones in the urine confirm lipolysis and gluconeogenesis, which are normal during periods of starvation.

Other causes
Congenital absence of the pancreas or islet cells Pancreatectomy

With hyperglycemia and heavy glycosuria, ketonuria is a marker of insulin deficiency and potential DKA. Blood glucose Apart from transient illness- or stress-induced hyperglycemia, a random whole-blood glucose concentration more than 200 mg/dL (11 mmol/L) is diagnostic for diabetes, as is a fasting whole-blood glucose concentration exceeding 120 mg/dL (7 mmol/L). In the absence of symptoms, the physician must confirm these results on a different day. Most children with diabetes detected because of symptoms have a blood glucose level of at least 250 mg/dL (14 mmol/L). Blood glucose tests using capillary blood samples, reagent sticks, and blood glucose meters are the usual methods for monitoring day-to-day diabetes control. Glycated hemoglobin Glycosylated hemoglobin derivatives (HbA1a, HbA1b, HbA1c) are the result of a nonenzymatic reaction between glucose and hemoglobin. A strong correlation exists between average bloodglucose concentrations over an 8- to 10-week period and the proportion of glycated hemoglobin. The percentage of HbA1c is more commonly measured. Normal values vary according to the laboratory method used, but nondiabetic children generally have values in the low-normal range. At diagnosis, diabetic children unmistakably have results above the upper limit of the reference range. Measurement of HbA1c levels is the best method for medium- to long-term diabetic control monitoring. The Diabetes Control and Complications Trial (DCCT) has demonstrated that patients with HbA1c levels around 7% had the best outcomes relative to longterm complications. Check HbA1c levels every 3 months. Most

clinicians aim for HbA1c values of 7-9%. Values less than 7% are associated with an increased risk of severe hypoglycemia; values more than 9% carry an increased risk of long-term complications. Renal function tests: If the child is otherwise healthy, renal function tests are typically not required. Islet cell antibodies Islet cell antibodies may be present at diagnosis but are not needed to diagnose IDDM. Islet cell antibodies are nonspecific markers of autoimmune disease of the pancreas and have been found in as many as 5% of unaffected children. Other autoantibody markers of type 1 diabetes are known, including insulin antibodies. More antibodies against islet cells are known (eg, those against glutamate decarboxylase [GAD antibodies]), but these are generally unavailable for routine testing. Thyroid function tests Because early hypothyroidism has few easily identifiable clinical signs in children, children with IDDM may have undiagnosed thyroid disease. Untreated thyroid disease may interfere with diabetes management. Check thyroid function regularly (every 2-5 years or annually if thyroid antibodies are present). Antithyroid antibodies: This test indicates risk of present or potential thyroid disease.

Antigliadin antibodies Some children with IDDM may have or develop celiac disease. Positive antigliadin antibodies, especially specific antibodies (eg, antiendomysial, antitransglutaminase) are important risk markers. If antibody tests are positive, a jejunal biopsy is required to confirm or refute a diagnosis of celiac disease. Imaging Studies No routine imaging studies are required. Other Tests Oral glucose tolerance test (OGTT)

diabetes show variable and substantial insulin production in the presence of hyperglycemia. Lipid profile

Lipid profiles are usually abnormal at diagnosis because of increased circulating triglycerides caused by gluconeogenesis. Apart from hypertriglyceridemia, primary lipid disorders rarely result in diabetes. Hyperlipidemia with poor metabolic control is common. Urinary albumin: Beginning at age 12 years, perform an annual urinalysis to test for a slightly increased albumin excretion rate (AER), referred to as microalbuminuria, which is an indicator of risk for diabetic nephropathy.

While unnecessary to diagnose IDDM, an OGTT can exclude the diagnosis of diabetes when hyperglycemia or glycosuria are recognized in the absence of typical causes (eg, intercurrent illness, steroid therapy) or when the patient's condition includes renal glucosuria. Obtain a fasting blood sugar level, then administer a PO glucose load (2 g/kg for children aged <3 y, 1.75 g/kg for children aged 3-10 y [max 50 g], or 75 g for children aged >10 y). Check the blood glucose concentration again after 2 hours. A fasting whole-blood glucose level higher than 120 mg/dL (6.7 mmol/L) or a 2-hour value higher than 200 mg/dL (11 mmol/L) indicates diabetes. Mild elevations, however, may not indicate diabetes when the patient has no symptoms and no diabetes-related antibodies. A modified OGTT can also be used to identify cases of MODY that often present as type 1 diabetes, if, in addition to blood glucose levels, insulin or c-peptide (insulin precursor) levels are measured at fasting, 30 minutes, and 2 hours. Type 1 diabetics cannot produce more than tiny amounts of insulin. People with MODY or type 2

Complications
1. Hypoglycemia Hypoglycemia is probably the most disliked and feared complication of diabetes, from the point of view of the child and the family. Children hate the symptoms of a hypoglycemic episode and the loss of personal control it may cause. Insulin inhibits glucogenesis and glycogenolysis, while stimulating glucose uptake. In nondiabetic individuals, insulin production by the pancreatic islet cells is suppressed when blood glucose levels fall below 83 mg/dL (4.6 mmol/L). If insulin is injected in a treated diabetic child who has not eaten adequate amounts of carbohydrates, blood glucose levels progressively fall.

The brain depends upon glucose as a fuel. As glucose levels drop below 65 mg/dL (3.2 mmol/L) counterregulatory hormones (eg, glucagon, cortisol, epinephrine) are released, and symptoms of hypoglycemia develop. These symptoms include sweatiness, shaking, confusion, behavioral changes, and, eventually, coma when blood glucose levels fall below 30-40 mg/dL. The glucose level at which symptoms develop varies greatly from individual to individual (and from time to time in the same individual), depending in part on the duration of diabetes, frequency of hypoglycemic episodes, rate of fall of glycemia, and overall control. Manage mild hypoglycemia by giving rapidly absorbed PO carbohydrate or glucose; for a comatose patient, administer an intramuscular injection of the hormone glucagon, which stimulates the release of liver glycogen and releases glucose into the circulation. Where appropriate, an alternative therapy is intravenous glucose (preferably no more than a 10% glucose solution). All treatments for hypoglycemia provide recovery in approximately 10 minutes. Occasionally, a child with hypoglycemic coma may not recover within 10 minutes, despite appropriate therapy. Under no circumstances should further treatment be given, especially intravenous glucose, until the blood glucose level is checked and still found subnormal. Overtreatment of hypoglycemia can lead to cerebral edema and death. If coma persists, seek other causes. Hypoglycemia is a particular concern in children younger than 4 years because the condition may lead to possible intellectual impairment later in life. 2. Hyperglycemia In an otherwise healthy individual, blood glucose levels usually do not rise above 180 mg/dL (9 mmol/L). In a child with diabetes, blood sugar levels rise if insulin is insufficient for a given glucose load. The

renal threshold for glucose reabsorption is exceeded when blood glucose levels exceed 180 mg/dL (10 mmol/L), causing glycosuria with the typical symptoms of polyuria and polydipsia. All children with diabetes experience episodes of hyperglycemia. 3. Diabetic ketoacidosis DKA is much less common than hypoglycemia, but it is potentially far more serious, creating a life-threatening medical emergency. Ketosis usually does not occur when insulin is present. In its absence, however, severe hyperglycemia, dehydration, and ketone production contribute to the development of DKA. DKA usually follows increasing hyperglycemia and symptoms of osmotic diuresis. Users of insulin pumps, by virtue of absent reservoirs of subcutaneous insulin, may present with ketosis and more normal blood glucose levels. They are more likely to present with nausea, vomiting, and abdominal pain, symptoms similar to food poisoning. 4. Injection-site hypertrophy If children persistently inject their insulin into the same area, subcutaneous tissue swelling may develop, causing unsightly lumps and adversely affecting insulin absorption. Rotating the injection sites resolves the condition. Fat atrophy can also occur, possibly in association with insulin antibodies. This condition is much less common but more disfiguring.

5. Diabetic retinopathy The most common cause of acquired blindness in many developed nations, diabetic retinopathy is rare in the prepubertal child or within 5 years of onset of diabetes. Prevalence and severity of retinopathy increases with age and is greatest in patients whose diabetic control is poor. Prevalence rates seem to be declining, yet an estimated 80% of people with IDDM develop retinopathy. Diabetic retinopathy's first symptoms are dilated retinal venules and the appearance of capillary microaneurysms, a condition known as background retinopathy. These changes may be reversible or their progression may be halted with improved diabetic control, although some patient's conditions may worsen initially. Subsequent changes in background retinopathy are characterized by increased vessel permeability and leaking plasma that form hard exudates, followed by capillary occlusion and flame-shaped hemorrhages. The patient may not notice these changes unless the macula is involved. Laser therapy may be required at this stage to prevent further visual loss. Proliferative retinopathy follows with further vascular occlusion, retinal ischemia, proliferation of new retinal blood vessels and fibrous tissue, then progressing to hemorrhage, scarring, retinal detachment, and blindness. Prompt retinal laser therapy may prevent blindness in the later stages, so regular screening is vital. 6. Diabetic nephropathy and hypertension Diabetic nephropathy's exact mechanism is unknown. Peak incidence is in postadolescents, 10-15 years after diagnosis, and may involve up to 30% of people with IDDM.

Microalbuminuria is the first evidence of nephropathy. The exact definition varies slightly between nations but an increased AER is commonly defined as a ratio of first morningvoid urinary albumin levels to creatinine levels that exceeds 10 mg/mmol, or as a timed overnight AER of more than 20 mcg/min but less than 200 mcg/min. Early microalbuminuria may resolve. Glomerular hyperfiltration occurs, as do abnormalities of the glomerular basement membrane and glomeruli. In a patient with nephropathy, AER increases until frank proteinuria develops, and this may progress to renal failure. Blood pressure rises with increased AER, and hypertension accelerates the progression to renal failure. Progression may be delayed or halted by improved diabetes control, by administration of angiotensin-converting enzyme inhibitors (ACE inhibitors), and by aggressive blood pressure control. Regular urine screening for microalbuminuria provides opportunities for early identification and treatment to prevent renal failure. A child younger than 15 years with persistent proteinuria may have a nondiabetic cause and should be referred to a pediatric nephrologist for further assessment. Diabetic neuropathy affects both the peripheral and autonomic nerves. Hyperglycemic effects on axons and microvascular changes in endoneural capillaries are amongst the proposed mechanisms. Autonomic changes involving cardiovascular control (eg, heart rate, postural responses) have been described in as many as 40% of children with diabetes. Cardiovascular control changes become more likely with increasing duration and worsening control.

In adults, peripheral neuropathy usually occurs as a distal sensory loss. 7. Macrovascular disease While this complication is not seen in pediatric patients, it is a significant cause of morbidity and premature mortality in adults with diabetes. People with IDDM have twice the risk of fatal myocardial infarction (MI) and stroke than people unaffected with diabetes; for women, the MI risk is 4 times greater. People with IDDM also have 4 times greater risk for atherosclerosis. The combination of peripheral vascular disease and peripheral neuropathy can cause serious foot pathology. Smoking, hypertension, hyperlipidemia, and poor diabetic control greatly increase the risk of vascular disease. 8. Associated autoimmune diseases are relatively common in children and include the following: Hypothyroidism affects 2-5% of children with diabetes. Hyperthyroidism affects 1% of children with diabetes; the condition is usually discovered at the time of diabetes diagnosis. Although Addison disease is uncommon, affecting fewer than 1% of children with diabetes, it is a life-threatening condition that may reduce the insulin requirement and increase the frequency of hypoglycemia. (These effects may also be the result of unrecognized hypothyroidism.) Celiac disease, associated with an abnormal sensitivity to gluten in wheat products, is probably a form of autoimmune disease and may occur in as many as 5% of children with IDDM.

Necrobiosis lipoidica is probably another form of autoimmune disease. This condition is usually, but not exclusively, found in patients with IDDM. Necrobiosis lipoidica affects 1-2% of children and may be more common in children with poor diabetic control. Limited joint mobility, primarily affecting hands and feet, is believed to be associated with poor diabetic control. Originally described in approximately 30% of patients with IDDM, limited joint mobility occurs in 50% of patients older than 10 years who have had diabetes longer than 5 years. The condition restricts joint extension, making it difficult to press the hands flat against each other. The skin of patients with severe joint involvement has a thickened and waxy appearance. Limited joint mobility is associated with increased risks for diabetic retinopathy and nephropathy. Improved diabetes control over the past several years appears to have reduced the frequency of these additional complications by an approximate 4-fold factor. More recent patients also have markedly fewer severe joint mobility limitations.