Primary Defects in β-Cell Function Further Exacerbated by Worsening of Insulin Resistance Mark the Development of Impaired Glucose Tolerance in Obese Adolescents

OBJECTIVE—Impaired glucose tolerance (IGT) is a pre-diabetic state of increasing prevalence among obese adolescents. The purpose of this study was to determine the natural history of progression from normal glucose tolerance (NGT) to IGT in obese adolescents. RESEARCH DESIGN AND METHODS—We determined the evolution of β-cell function, insulin sensitivity (S(I)), and glucose tolerance in a multiethnic group of 60 obese adolescents over the course of approximately 30 months. Each subject underwent three serial 3-h oral glucose tolerance tests. Dynamic, static, and total β-cell responsivity (Φ(d), Φ(s), and Φ(tot), respectively) and S(i) were assessed by oral C-peptide and glucose minimal models. The disposition index (DI), which adjusts insulin secretion for S(i), was calculated. RESULTS—At baseline, all 60 subjects had NGT. Seventy-seven percent (46 subjects) maintained NGT over the three testing periods (nonprogressors), whereas 23% (14 subjects) developed IGT over time (progressors). At baseline, percent fat and BMI Z score were comparable between the groups. Fasting plasma glucose, 2-h glucose, glucose area under the curve at 180 min, and Φ(d) were significantly different between the two groups at baseline, whereas S(i) was comparable between the two groups. Over time, although S(i) remained unchanged in nonprogressors, it steadily worsened by ∼45% (P > 0.04) in progressors. β-Cell responsivity decreased by 20% in progressors, whereas it remained stable in nonprogressors. The DI showed a progressive decline in progressors compared with a modest improvement in nonprogressors (P = 0.02). CONCLUSIONS—Obese adolescents who progress to IGT may manifest primary defects in β-cell function. In addition, progressive decline in S(i) further aggravates β-cell function, contributing to the worsening of glucose intolerance.