Calpains Play a Role in Insulin Secretion and Action

Seamus K. Sreenan, Yun Ping Zhou, Kenichi Otani, Polly A. Hansen, Kevin P.M. Currie, Chien Yuan Pan, Jean Pyo Lee, Diane M. Ostrega, William Pugh, Yukio Horikawa, Nancy J. Cox, Craig L. Hanis, Charles F. Burant, Aaron P. Fox, Graeme I. Bell, Kenneth S. Polonsky

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.

Original languageEnglish (US)
Pages (from-to)2013-2020
Number of pages8
JournalDiabetes
Volume50
Issue number9
DOIs
StatePublished - Sep 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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