Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ

Abstract

The serine/threonine kinase Akt/PKB plays key roles in the regulation of cell growth, survival, and metabolism. It remains unclear, however, whether the functions of individual Akt/PKB isoforms are distinct. To investigate the function of Akt2/PKBβ, mice lacking this isoform were generated. Both male and female Akt2/PKBβ-null mice exhibit mild growth deficiency and an age-dependent loss of adipose tissue or lipoatrophy, with all observed adipose depots dramatically reduced by 22 weeks of age. Akt2/PKBβ-deficient mice are insulin resistant with elevated plasma triglycerides. In addition, Akt2/PKBβ-deficient mice exhibit fed and fasting hyperglycemia, hyperinsulinemia, glucose intolerance, and impaired muscle glucose uptake. In males, insulin resistance progresses to a severe form of diabetes accompanied by pancreatic β cell failure. In contrast, female Akt2/PKBβ-deficient mice remain mildly hyperglycemic and hyperinsulinemic until at least one year of age. Thus, Akt2/PKBβ-deficient mice exhibit growth deficiency similar to that reported previously for mice lacking Akt1/PKBα, indicating that both Akt2/PKBβ and Akt1/PKBα participate in the regulation of growth. The marked hyperglycemia and loss of pancreatic β cells and adipose tissue in Akt2/PKBβ-deficient mice suggest that Akt2/PKBβ plays critical roles in glucose metabolism and the development or maintenance of proper adipose tissue and islet mass for which other Akt/PKB isoforms are unable to fully compensate.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

An inflammatory micro-environment promotes human adipocyte apoptosis

“…Most interestingly, Akt2 has already been linked to loss of adipose tissue, most likely by apoptosis of fat cells in mice and in humans. Along with insulin resistance, Akt2 knockout mice display an age-dependent loss of adipose tissue (Garofalo et al, 2003). Likewise, a family with a mutation in the Akt2-gene shows an autosomal dominant inheritance of severe insulin resistance and lipodystrophy (George et al, 2004).…”

Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells

“…Nonetheless, it is unclear whether PKBβ plays a role in the modulation of betacell proliferation and/or apoptosis. Indeed, studies on PKBβ null mice have yielded conflicting results with respect to their islet cell response to the development of insulin resistance, with 129SV/C57BL/6 mice showing impaired ability to increase islet mass in response to insulin resistance, and male DBA/1lacJ mice developing overt diabetes with complete loss of beta cells [38,39]. Taken with the results of the present study, the available data suggest that PKBα is more important in the regulation of beta-cell mass than PKBβ.…”

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

“…By contrast, the expression of AKT3 appears more restricted and is found mainly in the brain, the testis, adipose tissue and pancreatic islets (Refs 48, 49). As in the case of humans, mice lacking AKT2 are insulin resistant, hyperglycaemic and hyperinsulineamic (Refs 8,48,50). Deficiency in AKT3 does not result in metabolic aberrations.…”