Role of calcium-independent phospholipase A(2)β in human pancreatic islet β-cell apoptosis.

Journal Article (Journal Article)

Death of β-cells due to apoptosis is an important contributor to β-cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)β) in apoptosis of insulinoma cells due to ER stress. To examine whether islet β-cells are similarly susceptible to ER stress and undergo iPLA(2)β-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA(2)β protein is expressed predominantly in the β-cells of human islets and that thapsigargin-induced ER stress promotes β-cell apoptosis, as reflected by increases in activated caspase-3 in the β-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet iPLA(2)β message, protein, and activity, iPLA(2)β-dependent induction of neutral sphingomyelinase and ceramide accumulation, and subsequent loss of mitochondrial membrane potential. We also observe that basal activated caspase-3 increases with age, raising the possibility that β-cells in older human subjects have a greater susceptibility to undergo apoptotic cell death. These findings reveal for the first time expression of iPLA(2)β protein in human islet β-cells and that induction of iPLA(2)β during ER stress contributes to human islet β-cell apoptosis. We hypothesize that modulation of iPLA(2)β activity might reduce β-cell apoptosis and this would be beneficial in delaying or preventing β-cell dysfunction associated with diabetes.

Full Text

Duke Authors

Cited Authors

  • Lei, X; Zhang, S; Bohrer, A; Barbour, SE; Ramanadham, S

Published Date

  • December 1, 2012

Published In

Volume / Issue

  • 303 / 11

Start / End Page

  • E1386 - E1395

PubMed ID

  • 23074238

Pubmed Central ID

  • PMC3774083

Electronic International Standard Serial Number (EISSN)

  • 1522-1555

Digital Object Identifier (DOI)

  • 10.1152/ajpendo.00234.2012

Language

  • eng

Conference Location

  • United States