Membrane Phosphoinositides Control Insulin Secretion Through Their Effects on ATP-Sensitive K+ Channel Activity

Research output: Contribution to journalArticle

Abstract

ATP-sensitive K(+) channels (K(ATP) channels) of pancreatic beta-cells play key roles in glucose-stimulated insulin secretion by linking metabolic signals to cell excitability. Membrane phosphoinositides, in particular phosphatidylinositol 4,5-bisphosphates (PIP(2)), stimulate K(ATP) channels and decrease channel sensitivity to ATP inhibition; as such, they have been postulated as critical regulators of K(ATP) channels and hence of insulin secretion in beta-cells. Here, we tested this hypothesis by manipulating the interactions between K(ATP) channels and membrane phospholipids in a beta-cell line, INS-1, and assessing how the manipulations affect membrane excitability and insulin secretion. We demonstrate that disruption of channel interactions with PIP(2) by overexpressing PIP(2)-insensitive channel subunits leads to membrane depolarization and elevated basal level insulin secretion at low glucose concentrations. By contrast, facilitation of channel interactions with PIP(2) by upregulating PIP(2) levels via overexpression of a lipid kinase, phosphatidylinositol 4-phosphate 5 kinase, decreases the ATP sensitivity of endogenous K(ATP) channels by approximately 26-fold and renders INS-1 cells hyperpolarized, unable to secrete insulin properly in the face of high glucose. Our results establish an important role of the interaction between membrane phosphoinositides and K(ATP) channels in regulating insulin secretion.

Details

Authors
  • Chia-Wei Lin
  • Feifei Yan
  • Satoko Shimamura
  • Sebastian Barg
  • Show-Ling Shyng
External organisations
  • External Organization - Unknown
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • Kir6.2, insulin secretion, KATP, PIP2, INS-1 cells
Original languageEnglish
Pages (from-to)2852-2858
JournalDiabetes
Volume54
Issue number10
Publication statusPublished - 2005
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes