Fasting proinsulin concentrations predict the development of type 2 diabetes

OBJECTIVE - The development of specific assays allows the different molecul es in the proinsulin processing pathway to be measured separately. 32,33 Sp lit proinsulin is the predominant form of proinsulin and accounts for the d isproportionate hyperproinsulinemia seen in individuals with prevalent type 2 diabetes. This study was established to examine whether the concentratio n of this molecule predicts diabetes. RESEARCH DESIGN AND METHODS - A population-based longitudinal cohort study was conducted in fly, Cambridgeshire. At baseline, 1,122 individuals comple ted a 75-g oral glucose tolerance test (OGTT). At the 4.5-year follow-up st udy repeat OGTTs were performed on 937 of the cohort of 1,071 individuals w ho had been nondiabetic at baseline. RESULTS - A total of 26 people progressed to diabetes as determined by the OGTTs. The risk of progression was strongly related to the fasting glucose concentration (relative risk [RR] comparing top with bottom quartile 17.6 [ 95% CI 2.4-130.4]) and fasting 32,33 split proinsulin (RR 16.4 [2.2-121.9]) , but less strongly to the fasting insulin (RR 4.41 [1.5-12.9]) or intact p roinsulin (RR 5.2 [1.5-17.3]). In multivariate analyses, these associations were independent of age, sex, BMI, and baseline glucose tolerance category . Subjects in the top quartile for fasting glucose and total proinsulin wit h a family history of diabetes were a high-risk subgroup (incidence 65.8 pe r 1,000 person-years of follow-up [pyfu]); 30% of them progressed to diabet es at follow-up. CONCLUSIONS - Fasting 32,33 split proinsulin independently predicts the dev elopment of diabetes. This prediction was better than that observed for eit her the insulin or intact proinsulin concentrations. The combination of fam ily history, fasting glucose, and total proinsulin identified a subgroup of individuals at high risk of progression who might benefit from targeted in terventions.