TY - JOUR
T1 - Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet β cells
AU - Bernal-Mizrachi, Ernesto
AU - Fatrai, Szabolcs
AU - Johnson, James D.
AU - Ohsugi, Mitsuru
AU - Otani, Kenichi
AU - Han, Zhiqiang
AU - Polonsky, Kenneth S.
AU - Permutt, M. Alan
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=9644270397&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=9644270397&partnerID=8YFLogxK
U2 - 10.1172/JCI200420016
DO - 10.1172/JCI200420016
M3 - Article
C2 - 15467831
AN - SCOPUS:9644270397
VL - 114
SP - 928
EP - 936
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 7
ER -