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Diabetes 50:1791-1798, 2001
© 2001 by the American Diabetes Association, Inc.

Glycerol-Stimulated Proinsulin Biosynthesis in Isolated Pancreatic Rat Islets via Adenoviral-Induced Expression of Glycerol Kinase Is Mediated via Mitochondrial Metabolism

Robert H. Skelly, Barton Wicksteed, Peter A. Antinozzi, and Christopher J. Rhodes

Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, WA 98112.

In this study, we examined whether adenoviral-mediated glycerol kinase (AdV-CMV-GlyK) expression in isolated rat pancreatic islets could introduce glycerol-induced proinsulin biosynthesis. In AdV-CMV-GlyK–infected islets, specific glycerol-induced proinsulin biosynthesis translation and insulin secretion were observed in parallel from the same islets. The threshold concentration of glycerol required to stimulate proinsulin biosynthesis was lower (0.25–0.5 mmol/l) than that for insulin secretion (1.0–1.5 mmol/l), reminiscent of threshold differences for glucose-stimulated proinsulin biosynthesis versus insulin secretion. The dose-dependent glycerol-induced proinsulin biosynthesis correlated with the rate of glycerol oxidation in AdV-CMV-GlyK–infected islets, indicating that glycerol metabolism was required for the response. However, glycerol did not significantly increase lactate output from AdV-CMV-GlyK–infected islets, but the dihydroxyacetone phosphate (DHAP) to {alpha}-glycerophosphate ({alpha}-GP) ratio significantly increased in AdV-CMV-GlyK–infected islets incubated at 2 mmol/l glycerol compared with that at a basal level of 2.8 mmol/l glucose (P <= 0.05). The DHAP:{alpha}-GP ratio was unaffected in AdV-CMV-GlyK–infected islets incubated at 2 mmol/l glycerol in the added presence of {alpha}-cyanohydroxycinnaminic acid ({alpha}-CHC), an inhibitor of the plasma membrane and mitochondrial lactate/pyruvate transporter. However, {alpha}-CHC inhibited glycerol-induced proinsulin biosynthesis and insulin secretion in AdV-CMV-GlyK–infected islets (>75%; P = 0.05), similarly to glucose-induced proinsulin biosynthesis and insulin secretion in AdV-CMV-GlyK–infected and control islets. These data indicated that in AdV-CMV-GlyK–infected islets, the importance of mitochondrial metabolism of glycerol was required to generate stimulus–response coupling signals to induce proinsulin biosynthesis and insulin secretion.


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