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Elevation in Intracellular Long-Chain Acyl-Coenzyme A Esters Lead to Reduced β-Cell Excitability via Activation of Adenosine 5'-Triphosphate-Sensitive Potassium Channels

Department of Pharmacology (N.J.W., G.J.S., A.H., P.E.L.), University of Alberta, Edmonton, Alberta, Canada T6G 2H7; Departments of Medicine and Physiology (P.P.L.L., Y.-C.H., H.Y.G.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; Department of Cellular and Physiological Sciences (M.J.R.), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3; and Surgical Medical Research Institute (G.H.), University of Alberta, Edmonton, Alberta, Canada T6G 2N8

Address all correspondence and requests for reprints to: Dr. Peter E. Light, Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. E-mail: peter.light{at}ualberta.ca.

Closure of pancreatic β-cell ATP-sensitive potassium (K_ATP) channels links glucose metabolism to electrical activity and insulin secretion. It is now known that saturated, but not polyunsaturated, long-chain acyl-coenyzme A esters (acyl-CoAs) can potently activate K_ATP channels when superfused directly across excised membrane patches, suggesting a plausible mechanism to account for reduced β-cell excitability and insulin secretion observed in obesity and type 2 diabetes. However, reduced β-cell excitability due to elevation of endogenous saturated acyl-CoAs has not been confirmed in intact pancreatic β-cells. To test this notion directly, endogenous acyl-CoA levels were elevated within primary mouse β-cells using virally delivered overexpression of long-chain acyl-CoA synthetase-1 (AdACSL-1), and the effects on β-cell K_ATP channel activity and cell excitability was assessed using the perforated whole-cell and cell-attached patch-clamp technique. Data indicated a significant increase in K_ATP channel activity in AdACSL-1-infected β-cells cultured in medium supplemented with palmitate/oleate but not with the polyunsaturated fat linoleate. No changes in the ATP/ADP ratio were observed in any of the groups. Furthermore, AdACSL-1-infected β-cells (with palmitate/oleate) showed a significant decrease in electrical responsiveness to glucose and tolbutamide and a hyperpolarized resting membrane potential at 5 mM glucose. These results suggest a direct link between intracellular fatty ester accumulation and K_ATP channel activation, which may contribute to β-cell dysfunction in type 2 diabetes.