Type 1 Diabetes Mellitus in Pediatrics

After completing this article, readers should be able to: Diabetes mellitus is a disorder of the metabolic homeostasis controlled by insulin, resulting in abnormalities of carbohydrate and lipid metabolism. Type 1 diabetes (also called juvenile-onset diabetes mellitus and insulin-dependent diabetes mellitus) is caused by an absolute insulin deficiency, the result of a loss of the insulin-producing beta cells of the pancreas. Type 2 diabetes mellitus is characterized by two underlying defects. The earliest abnormality in an individual who develops type 2 diabetes mellitus is insulin resistance, which initially is compensated for with an increase in insulin secretion. Type 2 diabetes mellitus then develops due to a defect in insulin secretion that prevents such secretion from matching the increased requirements imposed by the insulin-resistant state. Thus, diabetes mellitus always is caused by insulin deficiency: in type 1 diabetes mellitus, the deficiency is absolute; in type 2 diabetes mellitus, the deficiency is relative.Although the percentage of cases of diabetes in children and adolescents caused by type 2 diabetes has risen in the past 1 to 2 decades, type 1 diabetes remains the most common form of diabetes mellitus in children.Recombinant insulin analogs, insulin pumps, and newer devices for home monitoring have drastically improved the ability to control glucose concentrations in patients who have diabetes. However, the feedback control in the healthy state that allows minute-to-minute regulation of insulin secretion cannot be recapitulated with current diabetes therapies, making full metabolic normalization not yet possible. Thus, some degree of hyperglycemia persists in virtually all patients who have diabetes. Long-term complications, including renal failure, retinopathy, neuropathy, and cardiovascular disease, are related to and likely caused by the hyperglycemia.In the United States, the prevalence of type 1 diabetes at 18 years of age is approximately 2 to 3 per 1,000. Type 1 diabetes typically has its onset in childhood, although it can present at any age from infancy to adulthood. Recent studies have documented an increase in the incidence, both in the United States and in other western countries, with the incidence in the United States approaching 20 cases per 100,000. There are small peaks in incidence at 2 and 4 to 6 years of age and a larger peak at 10 to 14 years of age. The incidence is approximately 1.5 times higher in American nonHispanic white people compared with African American or Hispanic individuals. There is seasonal variation in the incidence of type 1 diabetes, with more cases presenting in the cooler months of the year.Type 1 diabetes is caused by the autoimmune destruction of the beta cells of the pancreas. Autoimmune type 1 diabetes sometimes is referred to as type 1A; type 1B diabetes is a rare form of insulinopenic diabetes that is found most often in patients of African or Asian ancestry, in whom autoimmunity is not believed to cause the islet cell loss. In this review, “type 1” diabetes refers solely to type 1A diabetes.Type 1 diabetes is believed to develop when environmental triggers stimulate an autoimmune reaction against pancreatic beta cells in a genetically susceptible individual. The largest genetic component of the risk of diabetes is the major histocompatibility complex on chromosome 6, including the DR3-DQ2 and DR4-DQ8 alleles that increase risk and the DR2-DQ6 allele, which is protective. Because of the genetic component of risk for the disease, the risk for diabetes is increased in relatives of individuals who have diabetes (Table 1). In spite of this familial risk, however, only 10% to 20% of individuals who have type 1 diabetes have a similarly affected family member.A number of toxins, dietary components, and viral infections have been proposed as possible environmental factors contributing to the pathogenesis of type 1 diabetes. Except for congenital rubella infection, after which up to 20% of affected individuals develop type 1 diabetes, the identity of other specific environmental factors remains either unconfirmed or unidentified.The autoimmune destruction of pancreatic beta cells is a T-cell-mediated process. In addition, autoantibodies directed against beta-cell antigens usually are identified in the sera of patients who have type 1 diabetes. These substances include antibodies detected against whole islets (islet cell antibodies) as well as antibodies against specific proteins such as insulin, glutamic acid decarboxylase, and a protein tyrosine phosphatase, insulinoma-associated protein-2. These antibodies can be detected months to years before the development of diabetes. However, such antibodies are not likely to have a direct role in the beta-cell damage.Indeed, not all individuals who have beta-cell autoantibodies develop diabetes. Nonetheless, the presence of the antibodies indicates an increased risk of developing diabetes, with the presence of multiple such antibodies more predictive of future type 1 diabetes than is a single antibody. The increased risk is much higher in populations having additional risk factors, such as relatives of individuals who have type 1 diabetes or individuals who have high-risk human leukocyte antigen (HLA) haplotypes. Thus, the antibodies have very poor predictive utility as a “screen” in the general population.The autoimmune destruction of beta cells probably occurs over the course of months to years before diabetes develops. It is believed that more than 80% of beta cells must be lost before glycemic control is impaired significantly. As beta-cell loss progresses beyond that point, insulin is insufficiently present to maintain glucose and lipid homeostasis. When glucose concentrations in the blood rise above approximately 180 mg/dL (10.0 mmol/ L), glucosuria occurs, leading to an osmotic diuresis that causes polyuria. The polyuria stimulates polydipsia to maintain euvolemia. With further insulin deficiency, there is an increase in lipolysis from fat cells as well as protein breakdown, an exaggeration of the normal fasting state designed to provide alternative sources of fuel. These mechanisms, along with the caloric loss from glucosuria, result in the hyperphagia and weight loss typical of the undiagnosed diabetic state. With profound insulin deficiency, the process devolves into ketoacidosis, with marked hyperglycemia, dehydration driven by the glucosuric osmotic diuresis, and accumulation of ketoacids from the hepatic metabolism of the liberated fatty acids.The diagnosis of type 1 diabetes generally is straightforward, with the child's presenting symptoms suggesting the diagnosis and laboratory studies confirming its presence. The classic symptoms of diabetes are polydipsia, polyuria, polyphagia, and weight loss. Re-emergence of bedwetting, nocturia, and a need to leave classes in school to use the bathroom are complaints that suggest polyuria. The symptoms of undiagnosed diabetes typically are present for less than 1 month, although they may be present for several months in some. The other typical presentation for children who have type 1 diabetes is metabolic deterioration into diabetic ketoacidosis (DKA), presenting with nausea, vomiting, dehydration, and lethargy. Affected patients generally have a preceding history of the classic symptoms of diabetes. In both of these situations, a plasma glucose concentration greater than 200 mg/dL (11.1 mmol/L) confirms the diagnosis. A fasting glucose value of 126 mg/dL (7.0 mmol/L) or more also is diagnostic.It is highly desirable to diagnose type 1 diabetes before the child's metabolic state deteriorates into DKA to avoid the morbidity and mortality risk associated with this condition. Therefore, it is important to be attentive to children who have polydipsia and polyuria or weight loss in spite of polyphagia and to test such children for diabetes. However, although the autoimmune process that leads to beta-cell failure in type 1 diabetes may be present for many years prior to the clinical presentation of diabetes, the period of time from when abnormalities in glucose control can be identified until the development of symptoms generally is relatively brief. Therefore, screening for type 1 diabetes is not useful.In certain situations, the diagnosis of diabetes should be considered in the absence of the classic symptoms. Examples include an infant who presents with an acute febrile illness in whom a plasma glucose value obtained as part of a chemistry panel is elevated. This scenario may result from hyperglycemia as part of an acute stress response to the illness or it may be the coincident presentation of diabetes with a viral illness. Another example is the situation in which results of a urinalysis as a laboratory indicates glucosuria in the absence of a history of polydipsia or polyuria. This may renal also may be due to diabetes identified in a the absence of the diagnosis is on a fasting plasma glucose value at or above 126 mg/dL (7.0 virtually for the diagnosis of type 1 diabetes, a plasma glucose value at or above 200 mg/dL (11.1 mmol/L) on an glucose test also is In the absence of hyperglycemia, results of these on a to the the the diagnosis of diabetes in a to be type 1 diabetes. the however, the incidence of type 2 diabetes in children and adolescents has risen driven in part by the increased prevalence of a found that of diabetes cases in children 10 to years of age due to type 2 diabetes. of this increase due to the very of type 2 diabetes children in whom more than type 2 diabetes. A of nonHispanic white however, also type 2 diabetes. Thus, diabetes is at some of the has type 1 or type 2 diabetes of the more of is this may the of some children present with type 2 diabetes before most children develop type 1 diabetes. it generally is not to the diagnosis of type 2 diabetes in a nonHispanic white who presents in DKA or who is has a less than the for a who is with diabetes of as an is considered to have type 2 diabetes the need for additional for nonHispanic white children 10 years of age and as well as for most children in this age the that the diabetes is type 2 than type 1 should be considered in presenting with symptoms. 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