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Metabolic Abnormalities Underlying the Different Prediabetic Phenotypes in Obese Adolescents

Department of Pediatrics (A.M.G.C., R.W., S.C.), Yale University School of Medicine, New Haven, Connecticut 06520; and the Department of Biomedical and Surgical Sciences (R.C.B., M.T.), Section of Endocrinology, Universita' di Verona and Azienda Ospedaliera di Verona, 37134 Verona, Italy

Address all correspondence and requests for reprints to: Sonia Caprio, M.D., Yale University School of Medicine, Department of Pediatrics, 330 Cedar Street, P.O. Box 208064, New Haven, Connecticut 06520. E-mail: Sonia.caprio{at}yale.edu.

Objective: The aim of this study was to define the metabolic abnormalities underlying the prediabetic status of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG/IGT in obese youth.

Research Design and Methods: We used state-of-the-art techniques (hyperinsulinemic-euglycemic and hyperglycemic clamps), applying a model of glucose-stimulated insulin secretion to the glucose and C-peptide concentration, in 40 normal glucose tolerance (NGT), 17 IFG, 23 IGT, and 11 IFG/IGT obese adolescents. Percent fat (by dual-energy x-ray absorptiometry), age, gender and ethnicity were comparable among groups.

Results: Peripheral insulin sensitivity was similar between the IFG and NGT groups. In contrast, the IGT and IFG/IGT groups showed marked reductions in peripheral insulin sensitivity (P < 0.002). Basal hepatic insulin resistance index (basal hepatic glucose production x fasting plasma insulin) was significantly increased in IFG, IGT, and IFG/IGT (P < 0.009) compared with NGT. Glucose sensitivity of first-phase insulin secretion was progressively lower in IFG, IGT, and IFG/IGT compared with NGT. Glucose sensitivity of second-phase secretion showed a statistically significant defect only in the IFG/IGT group. In a multivariate regression analysis, glucose sensitivity of first-phase secretion and basal insulin secretion rate were significant independent predictors of FPG (total r² = 25.9%).

Conclusions: IFG, in obese adolescents, is linked primarily to alterations in glucose sensitivity of first-phase insulin secretion and liver insulin sensitivity. The IGT group is affected by a more severe degree of peripheral insulin resistance and reduction in first-phase secretion. IFG/IGT is hallmarked by a profound insulin resistance and by a new additional defect in second-phase insulin secretion.