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

Abstract

Objective: Impaired Glucose Tolerance (IGT) is a prediabetic state of increasing prevalence among obese adolescents. The natural history of progression from normal glucose tolerance to IGT in obese adolescents is unknown.

Research Design and Methods: We determined the evolution of beta-cell function, insulin sensitivity (S_I) and glucose tolerance in a multiethnic group of 60 obese youngsters over ∼30 months. Each subject underwent three serial 3hr- OGTT. Beta-cell function (dynamic, Φ-dynamic, static, Φ-static, and total Beta-cell responsivity, Φ) and S_I were assessed by C-peptide and Glucose Oral Minimal Model. The Disposition Index (DI), which adjusts insulin secretion for insulin sensitivity, was calculated.

Results: At baseline all 60 subjects were NGT. Seventy seven % (46 subjects), remained NGT over the 3 testing periods (Non-Progressors), whereas 23% (14 subjects) developed IGT overtime (Progressors). At baseline % fat and BMI z-score were comparable between the groups. Plasma fasting and 2h-glucose, AUC-glucose180 and Φ-dynamic were significantly different between the 2 groups at baseline; whereas, S_I was comparable between the 2 groups. Over time, while S_I remained unchanged in the Non-Progressors, it steadily worsened by ∼45% (p>0.04) in the Progressors. Beta-cell responsivity decreased by 20% in the Progressors, while it remained stable in the Non-Progressors. The DI showed a progressive decline in the Progressors compared to a modest improvement in the Non-Progressors (p=0.02).

Conclusions: Obese adolescents who progress to IGT may manifest primary defects in beta-cell function. In addition, progressive decline in insulin sensitivity further aggravates beta-cell function contributing to the worsening of glucose intolerance.