Evidence for inhibitory autocrine effects of proinsulin C-peptide on pancreatic β-cell function and insulin secretion

Aims Autocrine and paracrine regulatory mechanisms ensure integrated secretion of islet hormones that respond efficiently to changes in metabolic need. As proinsulin C‐peptide exerts various biological effects and binds to cell membranes including insulin‐secreting β cells, its physiological role in insulin release was examined. Methods Insulin releasing activity of human and rat C‐peptides were studied in the clonal pancreatic cell line, BRIN‐BD11, with findings substantiated using isolated islets and in vivo studies employing SWISS TO mice. Results Acute exposure of clonal β cells to human C‐peptide resulted in concentration‐dependent inhibitory effects on insulin secretion at 5.6 mM (p < 0.05–p < 0.001) and 16.7 mM (p < 0.01–p < 0.001) glucose. At physiologically relevant intra‐islet concentrations (10−9–10−6 M), C‐peptide suppressed the insulin‐secretory responses to a range of secretagogues acting at different points in the β cell stimulus‐secretion coupling pathway including alanine (p < 0.05), Ca2+ (p < 0.001), arginine (p < 0.05), tolbutamide (p < 0.001), glucagon‐like peptide 1 (GLP‐1) (p < 0.001), isobutylmethylxanthine (IBMX) (p < 0.01) and KCl (p < 0.05). Similar results were obtained using isolated mouse pancreatic islets. Human C‐peptide (3 × 10−7 M, p < 0.001), somatostatin‐14 (3 × 10−7 M, p < 0.01) and diazoxide (300 µM, p < 0.001) reduced both alanine and glucose‐stimulated insulin release by 43, 25 and 48%, respectively. The effects of human C‐peptide were reproduced using rat C‐peptide I and II. C‐peptide also inhibited in vivo glucose‐stimulated insulin release and impaired glucose tolerance in mice. Conclusions C‐peptide is a biologically active endogenous peptide hormone that exerts inhibitory autocrine effects on pancreatic β‐cell function. Mechanisms involving the activation of K+ channels and a distal effect downstream of increased cytoplasmic Ca2+ appear to be implicated in the inhibition of insulin secretion.