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 leptindeficiency 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.

Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation

“…It was reported that Akt2 gene deletion causes hyperinsulinemia and diabetes mellitus-like syndrome, since it is highly expressed in insulin-responsive tissues (47). Interestingly, diabetes induced by deletion of Akt2 could be reversed by leptin therapy, whereby leptin was restored in Akt2 KO mice (48). Although we did not see any change in blood glucose and serum insulin levels after a one-time injection of AKTi XII at a dose of 10 to 30 μg/g BW (data not shown), future studies, such as those involving longterm treatment with high concentrations of AKTi XII, are required to assess the potential side effects of targeting AKT2.…”

“…Six-to 8-week-old WT (C57BL/6), αM (Itgam) KO, αL (Itgal) KO, and Berkeley mice were purchased from The Jackson Laboratory. Akt1, Akt2, Akt3, and GPIbα (Gp1ba) KO mice on a C57BL/6 background were described previously (48,(50)(51)(52). Age-matched (6-to 10-week-old) male mice were used in our studies.…”

Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization

“…Previous studies had shown that 6-mo-old Akt2 −/− mice have reduced levels of circulating leptin (17). Because of this finding, we measured the levels of leptin and adiponectin in the serum of WT, Akt1 −/− , and Akt2 −/− mice at the age of 6-8 wk, the age of the mice used in our experiments, and found that they do not vary between mice of these genotypes ( Fig.…”

“…C/EBPβ expression is regulated posttranscriptionally by the microRNA miR-155, which targets its 3′ UTR (4,17). Earlier work from our group had shown that Akt1 ablation promotes miR-155 expression in LPS-stimulated macrophages (11).…”

Disassociation of insulin action and Akt/FOXO signaling in skeletal muscle of older Akt-deficient mice

“…We demonstrate that Akt2 Ϫ/Ϫ mice are severely insulin resistant. Similar to other investigations, the insulin resistance observed in Akt2 null mice is a unique phenotype that is not associated with obesity (7,8,13). Since muscle is the primary site for insulin-stimulated glucose disposal, it is reasonable to hypothesize that Akt2 Ϫ/Ϫ mice have a defect in insulin signal transduction in this important metabolically active tissue.…”