Elevation in Intracellular Long Chain Acyl-CoAs Leads to Reduced {beta}-cell Excitability via Activa
March 29th, 2008 | by admin |Elevation in Intracellular Long Chain Acyl-CoAs Leads to Reduced {beta}-cell Excitability via Activation of KATP Channels.
Closure of pancreatic beta-cell ATP-sensitive potassium (KATP) channels links glucose metabolism to electrical activity and insulin secretion. It is now known that saturated, but not polyunsaturated, long chain acyl-CoA esters (acyl-CoAs) can potently activate KATP channels when superfused directly across excised membrane patches, suggesting a plausible mechanism to account for reduced beta-cell excitability and insulin secretion observed in obesity and type 2 diabetes (T2D). However, reduced beta-cell excitability due to elevation of endogenous saturated acyl-CoAs has not been confirmed in intact pancreatic beta-cells. To test this notion directly, endogenous acyl-CoA levels were elevated within primary mouse beta-cells using virally-delivered over-expression of long chain acyl-CoA synthetase-1 (AdACSL-1), and the effects on beta-cell KATP channel activity and cell excitability assessed using the perforated whole-cell and cell-attached patch-clamp technique. Data indicated a significant increase in KATP channel activity in AdACSL-1-infected beta-cells cultured in media 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 beta-cells (+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 KATP channel activation, which may contribute to beta-cell dysfunction in type 2 diabetes.
Webster NJ, Searle GJ, Lam PP, Huang YC, Riedel MJ, Harb G, Gaisano HY, Holt A, Light PE.
Department of Pharmacology, University of Alberta, Edmonton, AB, Canada, T6G 2H7; Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada, M5S 1A8; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada, V6T 1Z3; Surgical Medical Research Institute, 1074 B Dentistry/Pharmacy Building, University of Alberta, Edmonton, AB, Canada, T6G 2N8.