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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #15: Epidemiology and Geography of Type 2 Diabetes Mellitus Part 4 of 5

DeFronzoCoverType 2 diabetes in children

Prevalence and incidence

Type 2 diabetes was historically a rare occurrence in children but recent studies have reported marked increases in the prevalence of T2DM in children. Type 2 diabetes was first reported in a population-based study in 1979 of American Indian children in Arizona [86]. This American Indian community has one of the highest rates of T2DM in adults and obesity in both adults and children [87]. After 30 years of follow-up in this population, the youngest age of onset of T2DM was 4 years and the prevalence of T2DM in 15–19-year-old children increased from 2.4 to 3.8% in boys and from 2.7 to 5.3% in girls [88]. Data from the Indian Health Service (IHS) in the United States confirmed an increase in the prevalence of diabetes in American Indian populations in the United States,with a 68% increase in the prevalence of diagnosed diabetes in American Indian and Alaska Natives adolescents between the ages of 15 and 19 years between 1990 and 1998. Although these IHS estimates were for all diabetes and not only T2DM, T1DM is very rare in some of these American Indian populations [89,90].

The increase in T2DM is not limited to the American Indians. Very few population-based studies have been conducted in other racial and ethnic groups but results from diabetes registries, case reports, and cross-sectional studies from Canada [91], Cincinnati [92], Japan [93–95], Libya [96], Thailand [97], United Kingdom [98–100], India [101], Taiwan [102] and numerous case reports from the United States [103–107] have all indicated a significant increase in the prevalence of T2DM in children, although all these studies did not use a standard method to differentiate between type 1 and type 2 diabetes (see Table 3.2). The incidence of T2DM in African American adolescents in Cincinnati increased 10-fold from 0.7 to 7.2 per 100,000 over a 12-year period [92]. The proportion of T2DM in children diagnosed with diabetes has increased from 2–4% in 1992 to 8–45% in the last decade [108]. The proportion of type 1 to type 2 diabetic children is highly variable according to their different age and racial and ethnic groups (see Table 3.2).





ITDMTable3.2bCharacteristics and diagnosis

The majority of children with T2DM are non-Caucasian and in one review about 94% of cases were from minority groups [109]. The cause of this increased risk in non-Caucasian groups is unclear but will involve genetic predisposition and cultural and environmental risk factors. African American [110,111] and Hispanic [112] children, for example, have been shown to have higher insulin resistance than do non-Hispanic White children.

The majority of T2DM cases occur in overweight and obese children and they may have clinical signs of insulin resistance, such as acanthosis nigricans. The prevalence of T2DM in these children is higher in girls who may be two to six times more likely to have T2DM. The mean age of onset is around puberty in most populations.

Cases may present with classical signs and symptoms of diabetes but the disease may have an insidious on-et and may only be detected by opportunistic screening. In a series from a referral center in Cincinnati, 32% of children with T2DM were discovered by opportunistic screening [92]. Therefore, underreporting of cases of T2DM in children may be as common as in adults.

The differentiation of T2DM from T1DM may be difficult in some cases (see Table 3.3). Currently, the mainstay of differentiating diabetes in children is inadequate and includes the use of clinical characteristics such as obesity, severity of onset, use of insulin, age of onset, diabetic ketoacidosis, and family history of diabetes.With the rising prevalence of obesity in children, more T1DM cases are presenting with obesity [113]. In addition, some cases of T2DM may present with diabetic ketoacidosis [114,115]. Diabetes-related autoantibodies that include the glutamic acid decarboxylase (GAD), tyrosine phosphatase-like molecule (IA2), islet cell antibody (ICA), and C-peptide (which is co-secreted with insulin) concentrations are currently being investigated as a means of improving the differentiation of diabetes type in children. The use of diabetes autoantibodies is limited by problems with assay methodology and the transient nature of some of these autoantibodies in cases of T1DM [116,117]. The use of C-peptide to differentiate the type of diabetes in children is made especially difficult by varying levels of residual β-cell function in type 1 diabetic cases. Current efforts are underway in a CDC (Centers for Disease Control) and NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) sponsored study, the SEARCH for Diabetes in Youth Study, to develop cutoff points and algorithms that include diabetes autoantibodies and C-peptide concentration which may be used to diagnose and differentiate diabetes in children.











Risk factors

Very few studies have examined the risk factors for T2DM in children. Some of the established risk factors for adult T2DM, discussed in other sections of this chapter, may play a role in the development of T2DM in children. Overweight and obesity are some of the strongest risk factors for insulin resistance and T2DM in adults. The rising prevalence of overweight in children may thus play a role in the risk of T2DM in children. In the United States, the prevalence of overweight in children has increased sharply over the last three decades to 15% in a 1999–2000 survey [118]. Over 20% of Hispanic and African American children are overweight compared to 12% in non-Hispanic White children [119]. This difference in prevalence of obesity may in part explain the higher prevalence of T2DM in ethnic minority children such as American Indians, African Americans, and Hispanics in the United States [88,92,103] and Asian Indians in the United Kingdom [100].

Most cases of T2DM occur around puberty. The reason for this increased risk around puberty is unclear but may be related to the physiologic 30% increase in insulin resistance observed in children as they go through Tanner stages II to IV [120–124]. This physiologic increase in insulin resistance is thought to be related to increased growth hormone production during puberty [121,122] but not related to the increase of sex hormones [121]. In the presence of increased insulin resistance produced by overweight and physical inactivity the reduction in insulin resistance around puberty may precipitate T2DM in these children especially if they have inadequate compensatory insulin secretion (see Figure 3.11).










Prenatal and early childhood events may also increase the risk of developing T2DM in children. Among siblings from the same nuclear family, the child of a mother who had diabetes during pregnancy has a threefold greater risk of developing early onset diabetes than their sibling who was born before the mother became diabetic [125]. This increased risk is mainly due to exposure to diabetes in utero since these siblings share the same environment and a similar probability of inheriting the same genetic composition.

Low birth weight and disproportionate growth in utero have been shown to be associated with both T2DM and insulin resistance [126,127]. Breastfeeding is also protective against obesity and T2DM [128–130] especially when sustained for a long durations.

Complications and comorbid conditions

The development of T2DM in children is alarming. In adults, T2DM is associated with the development of complications such as retinopathy, renal disease, and CVD. Recent reports of T2DM in children suggest that diabetes carries a similar risk for the development of complications in early adulthood. In a study on the development of complications in Pima Indian children with T2DM, the rate of development of nephropathy was as severe in children as in adults over 30 years of follow-up [131]. The rate of development of retinopathy was, however, lower in cases that developed diabetes in childhood. A small series of young adults from the First Nation in Canada who had been diagnosed with T2DM before their 17th birthday were traced and followed up for the prevalence of diabetic complications and adverse outcomes by their 36th birthday. In this small series 9% had died, and 6.3% were already on dialysis and their blood glucose control was poor [132].

At diagnosis, a number of children have comorbid conditions such as dyslipidemia and hypertension both of which are risk factors for CVD [133]. Cardiovascular risk is strongly related to duration of diabetes [134] and T2DM in children will increase their risk to develop CVD later on in life.

The apparent rise in the prevalence of T2DM in childhood is presenting new challenges in the management and classification of diabetes in children. Adolescents are more likely to be noncompliant and may find it more difficult to follow the lifestyle modifications and treatment regimen that would be necessary to control blood glucose [108,135]. Furthermore, very few medications have been approved for use in treating type 2 diabetic children. Insulin and metformin are the only medications currently licensed for treatment of T2DM in children in the United States.
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