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

Olof Larsson, Jude T. Deeney, Robert Bränström, Per Olof Berggren, Barbara E. Corkey

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

Long term exposure to elevated levels of long chain free fatty acids decreases glucose-induced insulin secretion from pancreatic islets and clonal pancreatic β-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 μM. 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 β-cell glucose insensitivity.

Original languageEnglish (US)
Pages (from-to)10623-10626
Number of pages4
JournalJournal of Biological Chemistry
Volume271
Issue number18
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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