Physiological increase in plasma insulin concentration suppresses proinsulin secretion in normal controls but not in subjects with glucose intolerance.

Since insulin negatively controls its own secretion, we examined if insulin also inhibits the secretion of its precursor, proinsulin, in subjects with varying degrees of glucose tolerance. Under comparable hyperinsulinemia (50-70 microU/ml) achieved by the euglycemic insulin clamp technique, plasma C-peptide concentrations were equally suppressed to approximately 40-50% in nonobese subjects with normal glucose tolerance (NGT) (n = 13, 35.5 +/- 3.7%, M +/- SEM), borderline glucose intolerance (BGI) (n = 12, 46.7 +/- 5.6%), and non-insulin-dependent diabetes mellitus (NIDDM) (n = 12, 48.9 +/- 5.4%). In contrast, plasma proinsulin concentrations were slightly but significantly suppressed in NGT (4.1 +/- 0.2 to 3.7 +/- 0.2 pmol/L, P < 0.05), but not in patients with BGI (4.6 +/- 0.3 to 4.8 +/- 0.5 pmol/L, NS) and NIDDM (5.5 +/- 0.5 to 4.9 +/- 0.4 pmol/L, NS). The basal concentrations of proinsulin increased as glucose tolerance declined (P < 0.05 between NGT and NIDDM). These results suggest that the basal secretion of proinsulin by beta-cells seems relatively insensitive to insulin compared with C-peptide, and that the insulin-proinsulin feedback loop is disturbed in glucose-intolerant subjects. Therefore, a defective feedback inhibition of proinsulin secretion by insulin may be partly involved in the disproportionate increase of plasma proinsulin concentrations in patients with NIDDM.