Type 2 Diabetes in Children and Adolescents - The Next Epidemic?

Eva M. Vivian


Curr Med Res Opin. 2006;22(2):297-306. 

In This Article

Pathogenesis of Type 2 Diabetes in the Young

The hallmark of type 2 diabetes in the young, as in most adults, is insulin resistance. Defects in insulin receptor function, insulin receptor-signal transduction pathway, glucose transport and phosphorylation, glycogen synthesis, and glucose oxidation contribute to muscle insulin resistance. The pancreas compensates for this deficiency by secreting larger amounts of insulin. Patients remain euglycemic until the pancreatic beta-cells are no longer able to compensate for the insulin resistance. Hence, insulin is unable to suppress hepatic glucose production and hyperglycemia results. By the time diabetes is diagnosed, insulin resistance and decreased secretion are already present.[9,10,11,12]

Type 2 diabetes is probably caused by the same genetic factors in children and adults. Several genes have been identified on chromosomes 1q, 12q, 20q, and 17q that predispose a person to the development of type 2 diabetes. Hepatic nuclear factor (HNF)-1α mutations also place children at higher risk for the development of type 2 diabetes.[13,14] However, the recent increase in the prevalence of diabetes has occurred too rapidly to be solely attributable to genetic factors, indicating that environmental effects may play a significant role in the development of type 2 diabetes in children.[15]

It has been proposed that nutritional and genetic factors interact in the etiology of type 2 diabetes. Poor nutrition in fetal and infant life may impair the normal development and function of beta-cells, thus increasing the risk of diabetes later in life. The sensitivity of skeletal muscle may also be impaired, contributing to insulin resistance.[15]

The 'thrifty genotype' hypothesis states that there are diabetogenic genes that confer a survival advantage accrued from generations of exposure to malnutrition. This genotype may have served as a survival advantage in times of famine. However, these thrifty genes promote obesity and insulin resistance in contemporary children who have adequate nutrition throughout the year. To date no genetic markers have been shown to be consistently associated with type 2 diabetes in humans, making it impossible to test this hypothesis.[16]

The 'thrifty phenotype' hypothesis states that type 2 diabetes is the result of the fetus being thrifty during exposure to malnutrition. The undernourished fetus alters its metabolic pathway and becomes nutritionally thrifty or insulin resistant. This thrift results in underdeveloped beta-cells and islets of Langerhans. The resultant insulin deficiency is sufficient for survival if the person is under-nourished throughout life. However, good or over nutrition can result in type 2 diabetes due to this lack of insulin secretion.[16,17,18]

Persons with a low birth weight may be at a higher risk of developing insulin resistance and diabetes. Li et al..[19] examined the effects of low birth weight on the development of insulin resistance syndrome in 139 children (86 Caucasians and 53 African-American) aged 4-14 years (mean age 8.1). Ethnicity was determined by self-report, based on parents and grandparents being of the same ethnicity. The investigators reported that low birth weight was associated with increased risk of insulin resistance, and that African-American children with low birth weight were at the highest risk of developing insulin resistance during childhood. Low birth weight, defined as less than 2500 g, was also associated with increases in visceral fat mass and decreased beta-cell function in the African-American children. There were significant differences in fasting insulin, insulin sensitivity, acute insulin response, and high density lipoprotein (HDL) cholesterol between Caucasians and African-Americans with low birth weights (p < 0.05).[19]

The Early Bird Study,[20], a non-intervention prospective cohort study, monitored 300 healthy British children from 5-16 years of age to determine if insulin resistance could be accounted for by current weight rather than by birth weight. There was no correlation between birth weight and insulin resistance at 5 years of age (boys r = -0.11, p = 0.18; girls r = -0.11, p = 0.23). Insulin resistance at 5 years of age correlated with current weight and weight catch-up in both sexes; more so in girls (r = 0.33, p < 0.001), who were inherently more insulin-resistant than boys ( r = 0.18, p = 0.03). The authors concluded that insulin resistance in contemporary children was a function of excess current weight rather than low birth weight.[20]

Obese children from ethnic groups with a high prevalence of diabetes have a higher risk of developing diabetes themselves.[6] A study conducted in 710 obese children in Italy found that only 0.2% of participants developed diabetes.[21] In contrast, a study conducted in the United States, with 167 obese children of Caucasian, African-American, and Hispanic descent, showed a 4% prevalence of type 2 diabetes among Hispanic and African-American adolescents. Pre-diabetes was seen in 16, 27 and 26% of the obese Caucasian, African-American, and Hispanic adolescents, respectively.[22] The results of these studies suggest that environmental and genetic differences may contribute to the development of diabetes in obese children and adolescents.

Insulin resistance in the young has been reported among persons from high-risk ethnic groups and is strongly associated with obesity and high fat consumption.[1,2,3] Several studies have reported that African-American children have higher fat and cholesterol consumption compared to Caucasian children.[23,24,25] Arslanian et al.[23] compared insulin sensitivity in 22 African-American and 22 Caucasian non-obese children, using a 3-hour hyperinsulinemic euglycemic clamp to calculate insulin sensitivity and insulin clearance. Insulin clearance and sensitivity were found to correlate inversely with dietary fat and carbohydrate consumption. The investigators reported dietary differences between the two groups, with African-American children consuming more dietary fat. The African-American children had lower insulin clearance and insulin sensitivity than white children, placing them at greater risk for the development of type 2 diabetes. The investigators postulated that short-term exposure of islet cells to fatty acids may lower insulin clearance and sensitivity, and increase insulin secretion.[23]

The onset of puberty also contributes to insulin resistance, with insulin sensitivity decreasing by approximately 30% and compensatory increases in insulin secretion.[26,27] Growth hormone has been considered a contributing factor in the development of insulin resistance during puberty, with an inverse correlation between growth hormone levels and insulin action. Sex steroids have also been implicated in causing insulin resistance during puberty. However, insulin sensitivity often improves after puberty while sex steroids levels remain constant. In addition, testosterone administration to non-hormone deficient adolescents is not associated with a decrease in insulin sensitivity, thus making the role of sex steroids in the development of insulin resistance questionable.[27]


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