HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

Abstract
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(2protein 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(2protein 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.
AuthorsXiaoyong Lei, Sheng Zhang, Alan Bohrer, Suzanne E Barbour, Sasanka Ramanadham
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 303 Issue 11 Pg. E1386-95 (Dec 01 2012) ISSN: 1522-1555 [Electronic] United States
PMID23074238 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Enzyme Inhibitors
  • Thapsigargin
  • Phospholipases A2, Calcium-Independent
Topics
  • Adult
  • Apoptosis (physiology)
  • Cells, Cultured
  • Endoplasmic Reticulum (drug effects, metabolism, pathology)
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Humans
  • In Vitro Techniques
  • Insulin-Secreting Cells (drug effects, enzymology)
  • Islets of Langerhans (cytology, enzymology)
  • Male
  • Phospholipases A2, Calcium-Independent (drug effects, metabolism)
  • Thapsigargin (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: