Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet β cells

Ernesto Bernal-Mizrachi, Szabolcs Fatrai, James D. Johnson, Mitsuru Ohsugi, Kenichi Otani, Zhiqiang Han, Kenneth S. Polonsky, M. Alan Permutt

Research output: Contribution to journalArticle

168 Scopus citations

Abstract

The insulin and IGF signaling pathways are critical for development and maintenance of pancreatic β cell mass and function. The serine-threonine kinase Akt is one of several mediators regulated by these pathways. We have studied the role of Akt in pancreatic β cell physiology by generating transgenic mice expressing a kinase-dead mutant of this enzyme in β cells. Reduction of Akt activity in transgenic animals resulted in impaired glucose tolerance due to defective insulin secretion. The mechanisms involved in dysregulation of secretion in these mice lie at the level of insulin exocytosis and are not the result of abnormalities in glucose signaling or function of voltage-gated Ca2+ channels. Therefore, transgenic mice showed increased susceptibility to developing glucose intolerance and diabetes following fat feeding. These observations suggest that Akt plays a novel and important role in the regulation of distal components of the secretory pathway and that this enzyme represents a therapeutic target for improvement of β cell function in diabetes.

Original languageEnglish (US)
Pages (from-to)928-936
Number of pages9
JournalJournal of Clinical Investigation
Volume114
Issue number7
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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