Insulin Resistance, Impaired Early Insulin Response, and Insulin Propeptides as Predictors of the Development of Type 2 Diabetes

Abstract

OBJECTIVE—Defects in insulin secretion and insulin action are the major abnormalities in the development of type 2 diabetes. In middle-aged subjects, elevated plasma proinsulin has been found to predict type 2 diabetes. Therefore, our aim was to study the longitudinal relationships between baseline determinations of insulin sensitivity index (Si) assessed by euglycemic insulin clamp, the early insulin response (EIR) at an oral glucose tolerance test (OGTT), fasting intact proinsulin, 32–33 split proinsulin and specific insulin, and the development of type 2 diabetes in a population-based cohort of 70-year-old nondiabetic men (n = 667) with 7-year follow-up. RESEARCH DESIGN AND METHODS—A euglycemic insulin clamp study and a 75-g OGTT were performed at baseline, and fasting peptide concentrations were measured using specific two-site immunometric assays. Results from logistic regression models are presented as odds ratios (ORs) with 95% CIs for a 1-SD increase in the predictor variable. RESULTS—In separate multivariate analyses adjusted for EIR (OR 0.72, 95% CI 0.59–0.89) and Si (0.68, 0.58–0.88), 32–33 split proinsulin (1.49, 1.18–1.88) or intact proinsulin (1.30, 1.04–1.63) were significantly associated with the development of type 2 diabetes, whereas specific insulin (1.24, 0.91–1.66) was not. The significant associations between 32–33 split or intact proinsulin and the development of type 2 diabetes were unaltered after adjustment for BMI and glucose tolerance. CONCLUSIONS—Insulin propeptides predicted type 2 diabetes over a 7-year period in elderly men, independent of the EIR and Si.