Activation of the ATP-sensitive K+ channel by long chain acyl-CoA - A role in modulation of pancreatic beta-cell glucose sensitivity

Long term exposure to elevated levels of long chain free fatty acids decreases glucose-induced insulin secretion from pancreatic islets and clonal pancreatic beta-cells. The mechanism for this loss of glucose sensitivity is at present not known, In this study, we evaluated the possibility that increases in long chain acyl-CoA esters (LC-CoA), the metabolically active form of free fatty acids, might mediate the loss of glucose sensitivity, We observed that cellular levels of LC-CoA increased more than 100% in response to overnight incubation with 0.5 mM palmitic acid complexed to albumin, In the same studies, the total CoA pool increased by about 40%. Patch-clamp studies demonstrated that saturated and unsaturated LC-CoA, but not malonyl-CoA or free CoASH, induced a rapid and slowly reversible opening of ATP-sensitive K+ channels, The effect was concentration-dependent between 10 nn and 1 mu M. These findings indicate that the ATP-regulated K+ channel is a sensitive target for LC-CoA and suggest that high levels of LC-CoA, which accumulate in response to hyperglycemia or prolonged exposure to free fatty acids, may prevent channel closure and contribute to the development of beta-cell glucose insensitivity.