Family History of Type 2 Diabetes Is Associated With Decreased Insulin Sensitivity and an Impaired Balance Between Insulin Sensitivity and Insulin Secretion in White Youth

Abstract

Family history of type 2 diabetes is a major risk factor for type 2 diabetes in youth, which is increasing. This investigation aimed to evaluate the impact of family history of type 2 diabetes on insulin secretion relative to insulin sensitivity in healthy children. beta-Cell compensation for insulin sensitivity was calculated as the product of insulin sensitivity x first-phase insulin secretion, termed glucose disposition index (GDI). A total of 28 healthy white children (12 boys and 16 girls; 12.1 +/- 0.5 years of age) with a positive family history of type 2 diabetes and 26 healthy white children (13 boys and 13 girls; 11.5 +/- 0.4 years of age) with a negative family history of type 2 diabetes underwent a 3-h 40 mU.m(-2).min(-1) hyperinsulinemic-euglycemic clamp to assess insulin sensitivity and clearance and a 2-h hyperglycemic clamp to assess insulin secretion. Body composition and visceral adiposity were evaluated with dual-energy X-ray absorptiometry and computed tomography at the L4-L5 intervertebral space. Insulin sensitivity was lower in children with a family history of type 2 diabetes versus children without a family history (8.8 +/- 0.9 vs. 12.2 +/- 1.1 micromol.kg(-1).min(-1) per pmol/l, P = 0.02). Similarly, insulin clearance was lower. First- and second-phase insulin levels were not different between groups with and without a positive family history. The GDI was lower in youth with versus youth without a positive family history (4.1 +/- 0.3 vs. 5.2 +/- 0.5 mmol.kg(-1).min(-1), P = 0.039). IGF binding protein-1 (IGFBP-1) was 60% lower in youth with versus youth without the positive family history. These results demonstrate that family history of type 2 diabetes in white children is associated with decreased insulin sensitivity and clearance, decreased IGFBP-1, and an impaired relationship between insulin action and beta-cell compensation. Detection of these alterations in hormonal and metabolic parameters in children with a positive family history suggests that at least some of the determinants of GDI are genetic/heritable.