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Calcium-activated calpain-2 is a mediator of beta cell dysfunction and apoptosis in type 2 diabetes

Chang-jiang Huang1, Tatyana Gurlo, Leena Haataja

  • 1Larry Hillblom Islet Research Center, David Geffen School of Medicine, California Nano Systems Institute, UCLA, Los Angeles, California 90024-2852, USA.

The Journal of Biological Chemistry
|October 29, 2009
PubMed

Insights

Type 2 diabetes involves islet amyloid polypeptide (IAPP) toxicity. This study shows IAPP triggers cell death via calcium and calpain-2 overactivation, contributing to beta cell loss in T2DM.

Area of Science:

  • Endocrinology
  • Cell Biology
  • Neuroscience

Background:

  • Type 2 diabetes (T2DM) and neurodegenerative diseases share cell dysfunction and amyloid protein accumulation.
  • Islet amyloid polypeptide (IAPP) is implicated in T2DM, while calpain-2 protease activation is linked to cell death in neurodegeneration.

Purpose of the Study:

  • To investigate if human IAPP toxicity in T2DM is mediated by calpain-2 activation, similar to neurodegenerative diseases.
  • To elucidate the role of Ca(2+)-calpain pathways in beta cell dysfunction and apoptosis in T2DM.

Main Methods:

  • Overexpression of human IAPP in rat insulinoma cells and human islets.
  • Analysis of pancreatic tissue from T2DM and control individuals.
  • Assessment of beta cell apoptosis, cytosolic Ca(2+) levels, and calpain-2 activity.

Main Results:

  • Human IAPP overexpression induced toxic oligomer formation and beta cell apoptosis.
  • This process was mediated by increased cytosolic Ca(2+) and hyperactivation of calpain-2.
  • Increased alpha-spectrin cleavage, a marker of calpain activation, was observed in beta cells from T2DM patients.

Conclusions:

  • Overactivation of Ca(2+)-calpain pathways contributes significantly to beta cell dysfunction and apoptosis in T2DM.
  • Targeting these pathways may offer therapeutic strategies for T2DM.

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