Proinsulin and acute insulin response independently predict type 2 diabetes mellitus in men - report from 27 years of follow-up study

Aims/hypothesis. Defects in insulin secretion and insulin action, resulting in compensatory hyperinsulinaemia, are the major abnormalities in the development of Type 2 diabetes mellitus (Type 2 diabetes). The most frequently used conventional immunoreactive assays for insulin cross-react with proinsulin. In short-term studies (<5 years), proinsulin predicts the development of Type 2 diabetes. We studied, with a 27-year follow-up, the longitudinal relationships between intact proinsulin, 32-33 split proinsulin, specific and immunoreactive insulin (IRI), acute insulin response (AIR) after an intravenous glucose load and the development of Type 2 diabetes in a population-based cohort of 50-year-old men. Methods. Fasting peptide concentrations were measured in plasma samples, stored since 1970-73 using specific two-site immunometric assays. IRI was measured at baseline using radioimmunoassay. Associations between development of Type 2 diabetes and predictor variables, were analysed with logistic regression. Results are shown as odds ratios (ORs) with their 95% confidence intervals (CIs) for a one standard deviation increase in a predictor variable. Results. Cumulative incidence of Type 2 diabetes was 33% over 27 years of follow-up. Intact proinsulin (OR, 1.57, CI, 1.16-2.14), and 32-33 split proinsulin (OR, 1.70, CI, 1.20-2.39) were associated with development of Type 2 diabetes, independent of AIR, adjusted for BMI and fasting glucose, whereas specific insulin was not (OR, 1.31, CI, 0.98-1.77), nor was IRI (OR, 1.25, CI, 0.96-1.63). Proinsulin and AIR interacted in the development of Type 2 diabetes (p < 0.05). Conclusion/interpretation. Proinsulin predicts the development of Type 2 diabetes mellitus over a 27-year period.