Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) is the second most common chronic disease of childhood. It has two peaks in presentation, the first between 4 to 6 years of age and the second between 10 and 14 years (early puberty). Boys and girls are affected equally. T1DM most commonly affects whites of Northern European descent. T1DM is uncommon among blacks living in sub-Saharan Africa but is far more prevalent among U.S. black children of African descent.

T1DM can involve a genetic predisposition. Having a sibling with T1DM increases a person’s lifelong risk by 3% to 6%, a parent increases the risk by 2% to 5%, and a monozygotic twin increases the risk by 30% to 50%. T1DM also occurs more frequently among individuals who have other autoimmune disorders, such as Addison’s disease and Hashimoto’s thyroiditis. These diseases are associated with increased frequency of certain human leukocyte antigens of the major histocompatibility complex (MHC). It is currently believed that T1DM is caused by a “two-hit phenomenon.” An increased risk for T1DM is conferred via genes inherited in the MHC. Then, a second “hit” occurs after birth, activating the immune system and causing an immunologic attack on the pancreatic islets of Langerhans. Unfortunately, the nature of this second “hit” is not clear, and researchers have hypothesized that it may be caused by pregnancy-related and perinatal influences, viruses, vitamin D deficiency, or early ingestion of cow’s milk and cereals.

Over a period of time, T cells infiltrate the islets and cause β-cell destruction with consequent insulin deficiency. However, clinical symptoms do not generally occur until insulin secretory capacity is reduced to approximately 30% of normal, although the exact percentage is controversial. Most patients with T1DM have circulating autoantibodies against a variety of islet cells proteins, including islet cells, glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase-like protein (IA2), and insulin. These antibodies can be used to aid in diagnosis and as markers of risk. Of individuals who have the first three antibodies present, 50% will develop T1DM within 5 years.

Insulin is an anabolic hormone that stimulates glucose uptake and hepatic glycogen synthesis and inhibits hepatic gluconeogenesis and glycogenolysis. It also stimulates lipogenesis, amino acid uptake, and protein synthesis (see Chapter 4, Figure 4-1). The absence of insulin triggers a series of biochemical events that emulate a starvation state even when food intake is adequate and that result in hyperglycemia and ketoacidosis (Figures 71-1 and 4-2). Glucose uptake by peripheral tissues is reduced, and hepatic glycogenolysis and gluconeogenesis are stimulated by insulin deficiency, which produces hyperglycemia. Lipolysis, proteolysis, and fatty acid oxidation lead to the accumulation of ketone bodies (β-hydroxybutyrate and acetoacetate), which eventually leads to metabolic acidosis.

Figure 71-1 Insulin deprivation.

As the serum glucose increases above 180 mg/dL, the renal threshold for glucose reabsorption, glycosuria results. Glycosuria causes an osmotic diuresis, resulting in polyuria and compensatory polydipsia. Over time, hyperosmolarity and dehydration develop, and decreased tissue perfusion can elicit a mild lactic acidosis. Patients without free access to fluid, such as infants and those with developmental disorders, are especially at risk. The osmotic diuresis also leads to the loss of crucial electrolytes, such as sodium, potassium, phosphorus, magnesium, and calcium. Metabolic acidosis and dehydration also stimulate counterregulatory hormones, such as growth hormone, cortisol, and epinephrine, further antagonizing insulin action. The end result is a serious metabolic disorder termed diabetic ketoacidosis (DKA; see Chapter 4).

Type 2 Diabetes Mellitus

Although still rare in children and adolescents, type 2 diabetes mellitus (T2DM) has become more prevalent with the increase in pediatric obesity. T2DM results from a combination of genetic and environmental factors. Risk factors include obesity (particularly visceral adiposity), insulin resistance, race or ethnicity (Native Americans, African Americans, Hispanic, and Asian Americans are at greatest risk), family history (74%-100% have a first- or second-degree relative with T2DM), and physical inactivity. T2DM affects girls more often than boys, and children with T2DM often present during puberty, when there is a physiologic increase in insulin resistance.

Obesity increases insulin resistance, resulting in a compensatory hyperinsulinemia. Increased pancreatic insulin secretion cannot be sustained to meet demand, eventually resulting in a relative insulin deficiency and a loss of first-phase insulin secretion. The relative contributions of insulin resistance and the insulin secretory defect in T2DM are controversial.

Type 2 Diabetes

The clinical presentation of T2DM in children can range from the incidental finding of glycosuria to severe acidosis or dehydration causing typical DKA. In addition to the signs described above for T1DM, children with T2DM often have specific characteristics that are related to insulin resistance, particularly obesity and acanthosis nigricans. In contrast to adults with T2DM, children with T2DM often have a shorter latency period of disease and commonly present with DKA. In addition, hyperglycemic hyperosmolar nonketotic coma (HHNK) is an extreme form of hyperosmolar dehydration seen more commonly in T2DM.