Over the past 2 decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM) in children and adolescents has risen to epidemic proportions and disproportionately affects racial and ethnic minorities, who are at greater risk. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction, and visceral adiposity. Current treatments of T2DM are limited to lifestyle intervention, metformin, and insulin therapy; use of these strategies in combination is often most effective. The role of research is to uncover simple biomarkers for insulin sensitivity and optimal and innovative treatment of insulin resistance and T2DM.
Epidemiology of diabetes and insulin resistance
Before the 1990s, type 2 diabetes mellitus (T2DM) was rarely diagnosed in children. In 1994, however, T2DM represented nearly 16% of new cases of diabetes in children in urban areas. By 1999, the percent of new cases of diabetes that are T2DM ranged from 8% to 45% and was disproportionately represented in minority populations. Most overweight children have metabolic abnormalities associated with insulin resistance without T2DM. Metabolic syndrome represents a cluster of metabolic abnormalities associated with obesity and insulin resistance (ie, increased waist circumference, hypertension, low high-density lipoprotein, hypertriglyceridemia, and abnormal glucose tolerance). These metabolic abnormalities put children an increased risk for premature cardiovascular disease.
Recent population-based data from the SEARCH for Diabetes in Youth study indicate that approximately 3700 children and adolescents are diagnosed with type T2DM annually, with the highest prevalence in the 10-year-old to 19-year-old age group and in minority populations. Population-based studies differ by usage of diagnostic tests and classification scheme for diabetes and often do not account for undiagnosed or asymptomatic cases of T2DM, making comparisons between studies difficult.
Autoimmunity and diagnosis
The classification of diabetes is determined by the clinical presentation and course of the disease. Making the distinction between type 1 diabetes and T2DM is often difficult in overweight children and adolescents. Diabetes-associated autoantibodies are measured to aid in diagnosis (islet cell antibodies [ICAs], antibodies against insulin, glutamic acid decarboxylase [GAD], and insulinoma-associated protein 2 [IA-2] or islet cell antigen 512 [ICA512]). The SEARCH study is the first population-based study to present estimates on the incidence of different forms of diabetes mellitus in youth. This study measured GAD65 and IA2 antibodies. The SEARCH study reported 21% of children with T2DM aged 10 to 19 years had GAD65 positivity, whereas the treatment options for type 2 diabetes in adolescents and youth (TODAY) study reported a rate of 10% islet cell autoimmunity in children clinically diagnosed with T2DM —5.9% of subjects were positive for single antibody and 3.9% of subjects were positive for both antibodies. Diabetes autoimmunity was significantly associated with ethnicity and gender, and the higher rates of antibody positivity may have been due to the large non-Hispanic white population in the SEARCH study. Subjects both with and without diabetes autoimmunity were classified as overweight or obese, but the median body mass index (BMI) and BMI z scores were lower in the antibody-positive group. This is not surprising the antibody-positive group was less likely to have clinical and laboratory findings of T2DM and metabolic syndrome. As described previously, there are clinical characteristics that differ between those with and without diabetes autoimmunity; autoantibodies or phenotype methods cannot be used in isolation to distinguish between type 1 diabetes or T2DM.
Autoimmunity and diagnosis
The classification of diabetes is determined by the clinical presentation and course of the disease. Making the distinction between type 1 diabetes and T2DM is often difficult in overweight children and adolescents. Diabetes-associated autoantibodies are measured to aid in diagnosis (islet cell antibodies [ICAs], antibodies against insulin, glutamic acid decarboxylase [GAD], and insulinoma-associated protein 2 [IA-2] or islet cell antigen 512 [ICA512]). The SEARCH study is the first population-based study to present estimates on the incidence of different forms of diabetes mellitus in youth. This study measured GAD65 and IA2 antibodies. The SEARCH study reported 21% of children with T2DM aged 10 to 19 years had GAD65 positivity, whereas the treatment options for type 2 diabetes in adolescents and youth (TODAY) study reported a rate of 10% islet cell autoimmunity in children clinically diagnosed with T2DM —5.9% of subjects were positive for single antibody and 3.9% of subjects were positive for both antibodies. Diabetes autoimmunity was significantly associated with ethnicity and gender, and the higher rates of antibody positivity may have been due to the large non-Hispanic white population in the SEARCH study. Subjects both with and without diabetes autoimmunity were classified as overweight or obese, but the median body mass index (BMI) and BMI z scores were lower in the antibody-positive group. This is not surprising the antibody-positive group was less likely to have clinical and laboratory findings of T2DM and metabolic syndrome. As described previously, there are clinical characteristics that differ between those with and without diabetes autoimmunity; autoantibodies or phenotype methods cannot be used in isolation to distinguish between type 1 diabetes or T2DM.
Pathophysiology
Insulin Resistance and Insulin Secretion Defects
Glucose is the most important regulator of insulin release. Normally, there is a nonlinear dose-related effect of glucose on insulin secretion. The relationship between glucose and insulin secretion follows a sigmoidal curve. The threshold to secrete insulin corresponds to nonfasting glucose levels and the steepest portion corresponds to postprandial glucose levels. Data show that chronic exposure to hyperglycemia (glucotoxicity) reduces expression of genes important in β-cell function, specifically insulin gene. T2DM is a progressive disease involving insulin resistance and impaired insulin secretion. Insulin resistance is a state where peripheral tissues are insensitive to insulin action, resulting in increased insulin production by the β cells of the pancreas. Both prediabetes and diabetes develop when the β-cells are unable to compensate for the lack of insulin sensitivity in target tissues, resulting in hyperglycemia.
Because insulin resistance is a major factor in the development of T2DM, various strategies have been developed to identify high-risk children. The gold standard method for measuring insulin resistance is hyperglycemic-euglycemic clamp. This test requires an overnight fast followed by constant infusion of insulin and glucose with periodic sampling of insulin and glucose concentrations. It is cumbersome test, making it difficult to use in the outpatient setting. Another common assessment technique uses the frequently sampled intravenous glucose tolerance test (FSIVGTT). These tests are not recommended for mass population screening due to their labor-intensive nature and high cost. Alternatively, the homeostasis model assessment of insulin resistance (HOMA-IR), which estimates insulin resistance through fasting glucose and insulin levels, has been used in large epidemiologic studies. In studies of nondiabetic children, HOMA-IR was highly correlated with clamp and FSIVGTT, supporting its potential usefulness in diagnosing T2DM in a pediatric population.
The National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 examined the prevalence of insulin resistance, defined as HOMA-IR greater than 4.39 (upper 2.5 percentile) or greater than 2 SD above mean HOMA-IR, and determined that obesity was a major determinant of insulin resistance independent of age, gender, or ethnicity. Prevalence of insulin resistance in obese adolescents was 52.1%, and girls had higher HOMA-IR than boys. Furthermore, Mexican-American children had higher HOMA-IR than white children, whereas HOMA-IR in black and white children was not statistically different.
Ectopic Fat Deposition
Body fat distribution is an important component effecting the development of insulin resistance. Disruption of insulin signal transduction occurs due to presence of fatty acid derivatives of intramyocellular lipid deposition, which leads to decreased glucose uptake and is associated with insulin resistance. Despite similar adiposity, obese adolescents with impaired glucose tolerance (IGT) were more insulin resistant than those with normal glucose toleranace (NGT). Subjects with IGT had increased intramyocellular lipid content, increased visceral fat, and decreased subcutaneous fat deposition, which is not surprising because increased visceral fat has been related to increased insulin resistance in obese children.
It has been proposed that fat deposited into visceral fat and other nonadipose tissue is the result of overflow from subcutaneous fat. In adult data, increased fat cell size is a sign of impaired adipogenesis and was shown related to the development of T2DM. Another study reported that an increased proportion of small adipocytes and an impaired expression of adipogenesis markers were also related to insulin resistance. To explore this concept, obese adolescents were divided into two groups: high or low ratio of visceral adipose tissue to visceral plus subcutaneous adipose fat ratio (VAT/[VAT+SAT]). The high ratio group had smaller proportion of large adipocytes and less expression of adipogenesis markers. Large adipocytes down-regulate lipogenic genes to limit triglyceride storage and prevent metabolic dysfunction. Meanwhile, decreased gene expression involved in adipose cell differentiation was observed in insulin-resistant offspring of patients with T2DM compared with insulin-sensitive controls in a previous study. Thus, it can be concluded that reduced fraction of large subcutaneous adipocytes may play a part in abnormal abdominal fat partitioning and insulin resistance.
Progression to Type 2 Diabetes in Youth
In adults, the progression from NGT to overt T2DM involves an intermediate stage of hyperglycemia, characterized by impaired fasting glucose and/or IGT, now known as prediabetes. Reports have documented a high prevalence of prediabetes among obese children and adolescents. The authors’ cross-sectional study measured the prevalence of IGT in a multiethnic clinic-based population of 167 obese children and adolescents; IGT was detected in 25% of the obese children and 21% of the obese adolescents, and diabetes was identified in 4% of the obese adolescents, irrespective of ethnicity. In this study, the risk factors associated with IGT in order of importance were insulin resistance (HOMA-IR), fasting proinsulin, 2-hour insulin level, and fasting insulin. This study was the first to highlight the high prevalence of prediabetes in the midst of the childhood obesity epidemic. Meanwhile, high prevalence of IGT has been also reported in obese children from other parts of the world, including Thailand and the Philippines.
Similarly, Goran and colleagues found that 28% of obese Hispanic children with a positive family history for T2DM had IGT but found no cases of T2DM. Additionally, Weigand and colleagues reported that the prevalence of IGT was 36.3% among an obese multiethnic cohort of children and adolescents with a risk factor for T2DM. Finally, the authors’ longitudinal study was conducted in a multiethnic clinic-based population of 117 nondiabetic obese children and adolescents. IGT was initially detected in 25% of the obese youth. After almost 2 years’ follow-up, 10% of the NGT group converted to IGT and 45% reverted to NGT. In the baseline IGT group, 24% developed diabetes and 30% remained IGT. All subjects who developed diabetes had previously been IGT at baseline. Measures derived from oral glucose tolerance test (ie, disposition index) were helpful to predict changes in glucose metabolism but fasting measures (ie, fasting insulin and glucose) were not. Disposition index is calculated as the product of insulin secretion and insulin sensitivity. This study supports the need for sensitive and reliable diagnostic methods. The identification of children with abnormal glucose metabolism allows clinicians to intervene and prevent the progression to T2DM.
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