Inhibition of Ca2+-independent phospholipase A2 results in insufficient insulin secretion and impaired glucose tolerance

Mol Endocrinol. 2005 Feb;19(2):504-15. doi: 10.1210/me.2004-0169. Epub 2004 Oct 7.

Abstract

Islet Ca2+-independent phospholipase A2 (iPLA2) is postulated to mediate insulin secretion by releasing arachidonic acid in response to insulin secretagogues. However, the significance of iPLA2 signaling in insulin secretion in vivo remains unexplored. Here we investigated the physiological role of iPLA2 in beta-cell lines, isolated islets, and mice. We showed that small interfering RNA-specific silencing of iPLA2 expression in INS-1 cells significantly reduced insulin-secretory responses of INS-1 cells to glucose. Immunohistochemical analysis revealed that mouse islet cells expressed significantly higher levels of iPLA2 than pancreatic exocrine acinar cells. Bromoenol lactone (BEL), a selective inhibitor of iPLA2, inhibited glucose-stimulated insulin secretion from isolated mouse islets; this inhibition was overcome by exogenous arachidonic acid. We also showed that iv BEL administration to mice resulted in sustained hyperglycemia and reduced insulin levels during glucose tolerance tests. Clamp experiments demonstrated that the impaired glucose tolerance was due to insufficient insulin secretion rather than decreased insulin sensitivity. Short-term administration of BEL to mice had no effect on fasting glucose levels and caused no apparent pathological changes of islets in pancreas sections. These results unambiguously demonstrate that iPLA2 signaling plays an important role in glucose-stimulated insulin secretion under physiological conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Gene Silencing
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Group VI Phospholipases A2
  • Immunohistochemistry
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Naphthalenes / pharmacology
  • Patch-Clamp Techniques
  • Phospholipases A / antagonists & inhibitors*
  • Phospholipases A / metabolism*
  • Phospholipases A2
  • Pyrones / pharmacology
  • RNA / metabolism
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Time Factors
  • Transfection

Substances

  • Insulin
  • Naphthalenes
  • Pyrones
  • RNA, Small Interfering
  • RNA
  • 6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one
  • Phospholipases A
  • Group VI Phospholipases A2
  • Phospholipases A2
  • Pla2g6 protein, mouse
  • Glucose