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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

From the Divisions of Pediatric Endocrinology, Metabolism, and Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Silva A. Arslanian, MD, Division of Endocrinology, Children’s Hospital of Pittsburgh, 3705 Fifth Ave. at DeSoto St., Pittsburgh, PA 15213. E-mail: silva.arslanian{at}chp.edu

OBJECTIVE—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. ß-Cell compensation for insulin sensitivity was calculated as the product of insulin sensitivity x first-phase insulin secretion, termed glucose disposition index (GDI).

RESEARCH DESIGN AND METHODS—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.

RESULTS—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 µmol · 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.

CONCLUSIONS—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 ß-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.

Abbreviations: GDI, glucose disposition index • IGFBP-1 • IGF binding protein-1

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