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Molecular and Cellular Biology, June 2009, p. 3151-3162, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01792-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Leptin Deficiency and Beta-Cell Dysfunction Underlie Type 2 Diabetes in Compound Akt Knockout Mice{triangledown} ,{dagger}

William S. Chen,1,{ddagger} Xiao-Ding Peng,1 Yong Wang,2 Pei-Zhang Xu,1 Mei-Ling Chen,1 Yongmei Luo,1 Sang-Min Jeon,1 Kevin Coleman,3 Wanda M. Haschek,4 Joseph Bass,5 Louis H. Philipson,6 and Nissim Hay1*

Department of Biochemistry and Molecular Genetics,1 Department of Surgery, University of Illinois at Chicago, Chicago, Illinois 60607,2 Pfizer Global Research and Development, Groton, Connecticut 06340,3 Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802,4 Evanston Northwestern Healthcare Research Institute and Department of Medicine Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60208,5 Department of Medicine-Endocrinology Section, University of Chicago, Chicago, Illinois 606376

Received 22 November 2008/ Returned for modification 11 February 2009/ Accepted 9 March 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.

* Corresponding author. Mailing address: University of Illinois at Chicago, Department of Biochemistry and Molecular Genetics (M/C 669), College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607. Phone: (312) 355-1684. Fax: (312) 355-2032. E-mail: nhay{at}uic.edu

{triangledown} Published ahead of print on 16 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Transgenic & Knockout Mouse Lab, University of Kansas, Lawrence, KS 66045.

Molecular and Cellular Biology, June 2009, p. 3151-3162, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01792-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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