title: Activation of the ATP-sensitive K+ channel by long chain acyl-CoA. A role in modulation of pancreatic beta-cell glucose sensitivity.
abstract: 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 nM and 1 microM. These findings indicate that the ATP-regulated K/ channels 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.
authors.affiliation: Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Larsson
authors.forename: J T
authors.initials: JT
authors.lastname: Deeney
authors.forename: R
authors.initials: R
authors.lastname: Bränström
authors.forename: P O
authors.initials: PO
authors.lastname: Berggren
authors.forename: B E
authors.initials: BE
authors.lastname: Corkey
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D015221:Potassium Channels / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005947:Glucose