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

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

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.

Authors

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

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Assessment of islet apoptosis in RIP-kdAkt and WT mice. (A) Frequency of...
Assessment of islet apoptosis in RIP-kdAkt and WT mice. (A) Frequency of activated caspase-positive cells in islets from RIP-kdAkt and WT mice (n = 3). (B) DNA laddering in RIP-kdAkt and WT islets after 48 hours of incubation in RPMI containing 10 mM glucose, 10% serum (control medium), and 1 μM thapsigargin. (C) Apoptosis assessment by DNA laddering in RIP-kdAkt and WT islets cultured for 7 days in control medium and in serum-free RPMI with 10 mM glucose. Data are representative of at least 3 experiments in duplicate.