The relation of proinsulin and insulin to insulin sensitivity and acute insulin response in subjects with newly diagnosed Type II diabetes: the Insulin Resistance Atherosclerosis Study

Aims/hypothesis. Proinsulin concentrations are increased relative to insuli n concentrations in subjects with Type II (non-insulin-dependent) diabetes mellitus. This could be secondary to hyperglycaemia or insulin resistance o r due to a defect in insulin secretion. Methods. We investigated the association between fasting insulin, intact pr oinsulin and the intact proinsulin: insulin ratio with insulin sensitivity, estimated by a frequently sampled intravenous glucose tolerance test and t he minimal model and with acute insulin response (AIR) in 182 newly diagnos ed Type II diabetic subjects aged 40 to 69 years. None of the subjects was receiving hypoglycaemic medication. Results. Insulin sensitivity correlated inversely with fasting insulin (r(s ) = -0.42) and intact proinsulin (r(s) = -0.32) (p < 0.001). The intact pro insulin:insulin ratio was not correlated with insulin sensitivity. AIR corr elated positively with intact proinsulin (r(s) = 0.23) and inversely with t he intact proinsulin:insulin ratio (r(s) = -0.29, p < 8.001). Fasting gluco se correlated positively with intact proinsulin (r(s) = 0.34) and the intac t proinsulin:insulin ratio (r(s) = 0.24, p < 0.001). The intact proinsulin: insulin ratio increased by decreasing AIR (quartiles of AIR from high to lo w: 7.8, 8.2, 9.7 and 12.1%, p < 0.001). This association was independent of age, sex, ethnicity, body mass index, fasting glucose, and insulin sensiti vity. Conclusion/interpretation. Insulin resistance (low insulin sensitivity) was not related to the intact proinsulin:insulin ratio in subjects with Type I I diabetes. In contrast, both low AIR and high fasting glucose concentratio ns were associated with a disproportionate increase in proinsulin concentra tion. These results suggest that increased intact proinsulin:insulin ratio is a marker of a defect in insulin secretion in Type II diabetic subjects.