Mol Cell Biol
University of Illinois at Chicago, Department of Biochemistry and Molecular Genetics, Chicago, IL 60607, USA.
Published: June 2009
Phenotypic analyses of mice null for the individual Akt isoforms suggested that they are functionally distinct and that only Akt2 plays a role in diabetes. We show here that Akt isoforms play compensatory and complementary roles in glucose homeostasis and diabetes. Insulin resistance in Akt2(-/-) mice was inhibited by haplodeficiency of Pten, suggesting that other Akt isoforms can compensate for Akt2 function. Haplodeficiency of Akt1 in Akt2(-/-) mice, however, converts prediabetes to overt type 2 diabetes, which is also reversed by haplodeficiency of Pten. Akt3 does not appear to contribute significantly to diabetes. Overt type 2 diabetes in Akt1(+/-) Akt2(-/-) mice is manifested by hyperglycemia due to beta-cell dysfunction combined with impaired glucose homeostasis due to markedly decreased leptin levels. Restoring leptin levels was sufficient to restore normal blood glucose and insulin levels in Akt1(+/-) Akt2(-/-) and Akt2(-/-) mice, suggesting that leptin-deficiency is the predominant cause of diabetes in these mice. These results uncover a new mechanism linking Akt to diabetes, provide a therapeutic strategy, and show that diabetes induced as a consequence of cancer therapy, via Akt inhibition, could be reversed by leptin therapy.
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http://dx.doi.org/10.1128/MCB.01792-08 | DOI Listing |
J Exp Med
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Institute of Cancer Research, Shenzhen Bay Laboratory , Shenzhen, China.
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National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali, Punjab, 140306, India.
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Department of Traditional Chinese Medicine, The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China. Electronic address:
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Department of Natural Compound, Nutrition, and Health, MIGAL Galilee Research Institute, Kiryat Shmona 1101600, Israel.
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Key Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia University, Yinchuan, Ningxia, China.
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