OBJECTIVE -This study evaluates insulin sensitivity, pancreatic -cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA 1c to insulin sensitivity and BCF.RESEARCH DESIGN AND METHODS -The subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU ⅐ m -2 ⅐ min -1 ) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-2 H 2 ]glucose.RESULTS -Fasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 Ϯ 1.1 vs. 12.3 Ϯ 0.5 mol ⅐ kg -1 ⅐ min -1 ; P ϭ 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 Ϯ 0.1 vs. 2.0 Ϯ 0.2 mol ⅐ kg -1 ⅐ min -1 per pmol/l; P ϭ 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 Ϯ 24.6 vs. 220.2 Ϯ 18.0 pmol/l; P ϭ 0.007), and FPIS and SPIS were lower (FPIS: 357.6 Ϯ 42.0 vs. 1,365.0 Ϯ 111.0 pmol/l; SPIS: 652.2 Ϯ 88.8 vs. 1,376.4 Ϯ 88.8 pmol/l; P Ͻ 0.001 for both). The glucose disposition index (GDI ϭ insulin sensitivity ϫ FPIS) was ϳ86% lower in type 2 diabetic patients than in obese control subjects. HbA 1c correlated with FPIS (r ϭ Ϫ0.61, P ϭ 0.025) with no relationship to insulin sensitivity.CONCLUSIONS -Despite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA 1c may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of -cell failure and means of retarding and/or preventing it.
Diabetes Care 28:638 -644, 2005D espite the increasing rate of type 2 diabetes in youth, the information on its pathophysiology is mostly derived from adult studies (1). Decreased insulin sensitivity and impaired -cell function (BCF) are the two key components in type 2 diabetes pathogenesis (2-4). The development sequence of these abnormalities has been long debated. Several studies in adults proposed that insulin resistance with compensatory hyperinsulinemia is the initial step in type 2 diabetes pathogenesis (2,4). This is an implication of the hyperbolic relationship between insulin sensitivity and BCF, which calls for an increase in insulin secretion when insulin sensitivity decreases (4). The subsequent step in type 2 diabetes pathogenesis is impaired early insulin secretion, leading to postprandial and, later, fasting hyperglycemia (at which time clinical diabetes becomes evident). This sequence has also been do...