Calmodulin overexpression causes Ca(2+)-dependent apoptosis of pancreatic beta cells, which can be prevented by inhibition of nitric oxide synthase.

Published

Journal Article

We investigated the mechanism of beta-cell loss in transgenic mice with elevated levels of beta cell calmodulin. The transgenic mice experienced a sudden rise in blood glucose levels between 21 and 28 days of age. This change was associated with development of severe hypoinsulinemia and loss of beta cells from the islets. Ultrastructural analysis revealed that compromised granule formation and apoptotic changes in the transgenic beta cells preceded the onset of hyperglycemia. Intraperitoneal injection of tolbutamide, an antidiabetic sulfonylurea, decreased blood glucose levels but increased the number of apoptotic beta cells. Finally, injection of transgenic mice with N(omega)-nitro-L-arginine methyl ester, which inhibits nitric oxide synthase activity, prevented hyperglycemia and lessened the changes in number and size of beta cells. Because immunofluorescent staining revealed preferential distribution of neural nitric oxide synthase in pancreatic beta cells, we speculate that overexpression of calmodulin sensitizes the beta cells to Ca(2+)-dependent activation of neural nitric oxide synthase, which mediates apoptosis.

Full Text

Duke Authors

Cited Authors

  • Yu, W; Niwa, T; Miura, Y; Horio, F; Teradaira, S; Ribar, TJ; Means, AR; Hasegawa, Y; Senda, T; Niki, I

Published Date

  • September 2002

Published In

Volume / Issue

  • 82 / 9

Start / End Page

  • 1229 - 1239

PubMed ID

  • 12218084

Pubmed Central ID

  • 12218084

International Standard Serial Number (ISSN)

  • 0023-6837

Digital Object Identifier (DOI)

  • 10.1097/01.lab.0000027921.01548.c5

Language

  • eng

Conference Location

  • United States