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

• Published in: Endocrinology (Philadelphia) Vol. 149; no. 7; pp. 3679 - 3687
• Main Authors: Webster, Nicola J, Searle, Gavin J, Lam, Patrick P. L, Huang, Ya-Chi, Riedel, Michael J, Harb, George, Gaisano, Herbert Y, Holt, Andrew, Light, Peter E
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.07.2008
• Subjects: Acyl Coenzyme A - metabolism; Acyl Coenzyme A - physiology; Adenosine Diphosphate - metabolism; Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Blotting, Western; Cells, Cultured; Chromatography, High Pressure Liquid; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Fundamental and applied biological sciences. Psychology; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; KATP Channels - physiology; Membrane Potentials - drug effects; Mice; Mice, Inbred BALB C; Patch-Clamp Techniques; Tolbutamide - pharmacology; Vertebrates: endocrinology; Purine nucleoside; Adenosine; Langerhans islet; Excitability; Activation; Ionic channel; Triphosphates; Inorganic element; Coenzyme; β Cell; Intracellular; Potassium; Endocrine pancreas
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-1138

Closure of pancreatic β-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-coenyzme A esters (acyl-CoAs) can potently activate KATP 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 KATP channel activity and cell excitability was 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 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 KATP channel activation, which may contribute to β-cell dysfunction in type 2 diabetes.