b-Cell Function, Incretin Effect, and Incretin Hormones in Obese Youth Along the Span of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired b-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)–modeled b-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. b-Cell function parameters were derived from established mathematical models yielding b-cell glucose sensitivity (bCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT bCGS to the 2-h hyperglycemic clamp bCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, bCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia. A core defect in the pathogenesis of type 2 diabetes (T2D) is impaired b-cell function (1,2). In adults, longitudinal (2,3) and cross-sectional (4,5) investigations have demonstrated that b-cell function declines with increasing hyperglycemia already within the normal glucose tolerance (NGT) range, and is further impaired with the onset of impaired glucose tolerance (IGT) and progression to T2D. Similarly, crosssectional and longitudinal studies in pediatrics, using a variety of methodologies, have established that b-cell function is impaired in prediabetes, and to a worse extent in T2D (6– 12), with evidence of rapid deterioration (13–15). Using the hyperglycemic clamp together with the hyperinsulinemiceuglycemic clamp, we demonstrated that b-cell function relative to insulin sensitivity was diminished in obese youth with IGT by ;40% and in T2D by ;80% compared with their NGT peers (6). Because of the important physiological role of incretin hormones (GLP-1 and glucose-dependent insulinotropic polypeptide [GIP]) in augmenting insulin secretion, a frequent view is that GLP-1 secretion is deficient in T2D patients and, in a lesser degree, in people with prediabetes (16). However, studies in adults have yielded conflicting results showing decreased (16,17), normal (16,18,19), or increased (20) GLP-1 concentrations in