Differential Effects of Protein Kinase B/Akt Isoforms on Glucose Homeostasis and Islet Mass

Protein kinase B (PKB)/Akt is considered to be a key target downstream of insulin receptor substrate 2 (IRS2) in the regulation of beta-cell mass. However, while deficiency of IRS2 in mice results in diabetes with insulin resistance and severe failure of beta-cell mass and function, only loss of the PKB beta isoform leads to a mild metabolic phenotype with insulin resistance. Other isoforms were reported not to be required for metabolic regulation. To clarify the roles of the three PKB isoforms in the regulation of islet mass and glucose homeostasis, we assessed the metabolic and pancreatic phenotypes of Pkb alpha, Pkb beta, and Pkb gamma-deficient mice. Our study uncovered a novel role for PKB alpha in the regulation of glucose homeostasis, whereas it confirmed that Pkb beta(-/-) mice are insulin resistant with compensatory increase of islet mass. Pkb alpha(-/-) mice displayed an opposite phenotype with improved insulin sensitivity, lower blood glucose, and higher serum glucagon concentrations. Pkb gamma(-/-) mice did not show metabolic abnormalities. Additionally, our signaling analyses revealed that PKB alpha, but not PKB beta or PKB gamma, is specifically activated by overexpression of IRS2 in beta-cells and is required for IRS2 action in the islets.