Leptin deficiency and beta-cell dysfunction underlie type 2 diabetes in compound Akt knockout mice

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3151-3162
Number of pages12
JournalMolecular and cellular biology
Volume29
Issue number11
DOIs
StatePublished - Jun 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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