Long-Chain CoA esters activate human pancreatic beta-cell KATP channels: Potential role in Type 2 diabetes

R. Bränström, C. A. Aspinwall, S. Välimäki, C. G. Östensson, A. Tibell, M. Eckhard, H. Brandhorst, B. E. Corkey, P. O. Berggren, O. Larsson

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Aims/hypothesis. The ATP-regulated potassium (KATP) channel in the pancreatic beta cell couples the metabolic state to electrical activity. The primary regulator of the KATP channel is generally accepted to be changes in ATP/ADP ratio, where ATP inhibits and ADP activates channel activity. Recently, we showed that long-chain CoA (LC-CoA) esters form a new class of potent KATP channel activators in rodents, as studied in inside-out patches. Methods. In this study we have investigated the effects of LC-CoA esters in human pancreatic beta cells using the inside-out and whole-cell configurations of the patch clamp technique. Results. Human K ATP channels were potently activated by acyl-CoA esters with a chain length exceeding 12 carbons. Activation by LC-CoA esters did not require the presence of Mg2+ or adenine nucleotides. A detailed characterization of the concentration-dependent relationship showed an EC50 of 0.7±0.1 μmol/l. Furthermore, in the presence of an ATP/ADP ratio of 10 (1.1 mmol/l total adenine nucleotides), whole-cell KATP channel currents increased approximately six-fold following addition of 1 μmol/l LC-CoA ester. The presence of 1 μmol/l LC-CoA in the recording pipette solution increased beta-cell input conductance, from 0.5±0.2 nS to 2.5±1.3 nS. Conclusion/interpretation. Taken together, these results show that LC-CoA esters are potent activators of the KATP channel in human pancreatic beta cells. The fact that LC-CoA esters also stimulate K ATP channel activity recorded in the whole-cell configuration, points to the ability of these compounds to have an important modulatory role of human beta-cell electrical activity under both physiological and pathophysiological conditions.

Original languageEnglish (US)
Pages (from-to)277-283
Number of pages7
JournalDiabetologia
Volume47
Issue number2
DOIs
StatePublished - Feb 1 2004
Externally publishedYes

Keywords

  • Diabetes
  • Fatty acids
  • Human
  • Ion channel
  • Pancreas

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Bränström, R., Aspinwall, C. A., Välimäki, S., Östensson, C. G., Tibell, A., Eckhard, M., Brandhorst, H., Corkey, B. E., Berggren, P. O., & Larsson, O. (2004). Long-Chain CoA esters activate human pancreatic beta-cell KATP channels: Potential role in Type 2 diabetes. Diabetologia, 47(2), 277-283. https://doi.org/10.1007/s00125-003-1299-x