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Leptin Deficiency and Beta-Cell Dysfunction Underlie Type 2 Diabetes in Compound Akt Knockout Mice

Cited 45 time in Web of Science Cited 47 time in Scopus

Chen, William S.; Peng, Xiao-Ding; Wang, Yong; Xu, Pei-Zhang; Chen, Mei-Ling; Luo, Yongmei; Jeon, Sang-Min; Coleman, Kevin; Haschek, Wanda M.; Bass, Joseph; Philipson, Louis H.; Hay, Nissim

Issue Date
American Society for Microbiology
Molecular and Cellular Biology, Vol.29 No.11, pp.3151-3162
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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  • College of Pharmacy
  • Department of Pharmacy
Research Area Cancer Origin, Metabolism, Toxicology


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