title: Leptin deficiency and beta-cell dysfunction underlie type 2 diabetes in compound Akt knockout mice.
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.
authors.affiliation: University of Illinois at Chicago, Department of Biochemistry and Molecular Genetics, Chicago, IL 60607, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Chen
authors.forename: Xiao-Ding
authors.initials: XD
authors.lastname: Peng
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Pei-Zhang
authors.initials: PZ
authors.lastname: Xu
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Chen
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Luo
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Jeon
authors.forename: Kevin
authors.initials: K
authors.lastname: Coleman
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Haschek
authors.forename: Joseph
authors.initials: J
authors.lastname: Bass
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology*; D005247:Feeding Behavior; D006706:Homeostasis; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000172:deficiency / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency* / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D007527:Isoenzymes; D020738:Leptin; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt