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Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward Island, Canada C1A 4P3

(Requests for offprints should be addressed to C B Chan; Email: cbchan{at}ualberta.ca)

Hyperproinsulinemia is observed in type 2 diabetic patients. We hypothesized that the induction of uncoupling protein-2 (UCP2) would impair processing of proinsulin to mature insulin and potentially contribute to hyperproinsulinemia, based on the evidence that hormone processing is an ATP-dependent process and UCP2 up-regulation can suppress cellular ATP production. UCP2 was overexpressed (UCP2-OE) by twofold in INS-1 cells by means of plasmid transfection. Although UCP2-OE reduced glucose-stimulated insulin secretion and cellular ATP content, no effects on proinsulin processing, as measured by western blotting, were observed. To increase the demand for insulin, we then cultured UCP2-OE and control INS-1 cells in medium containing 20 mM KCl for 24 h. High K⁺ markedly reduced glucose-stimulated insulin secretion from control cells, indicating inability of cells to meet secretory demand. Independent of UCP2 expression, high K⁺ reduced preproinsulin mRNA expression but had no effect on ATP content despite increasing ATP synthase expression. In UCP2-OE cells, high K⁺decreased total cellular insulin species content and increased the ratio of proinsulin to insulin, indicating an impairment of processing. We conclude that UCP2-OE can negatively impact proinsulin processing, possibly by ATP-dependent alteration of the granule environment or reduction of Ca²⁺availability, particularly when cells are chronically stimulated to secrete insulin.