Protein kinase B (PKB)/Akt is considered to be a key target downstream of insulin receptor substrate 2 (IRS2) in the regulation of ß-cell mass. However, while deficiency of IRS2 in mice results in diabetes with insulin resistance and severe failure of ß-cell mass and function, only loss of the PKBß 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 Pkba, Pkbß, and Pkb¿-deficient mice. Our study uncovered a novel role for PKBa in the regulation of glucose homeostasis, whereas it confirmed that Pkbß-/- mice are insulin resistant with compensatory increase of islet mass. Pkba-/- mice displayed an opposite phenotype with improved insulin sensitivity, lower blood glucose, and higher serum glucagon concentrations. Pkb¿-/- mice did not show metabolic abnormalities. Additionally, our signaling analyses revealed that PKBa, but not PKBß or PKB¿, is specifically activated by overexpression of IRS2 in ß-cells and is required for IRS2 action in the islets.

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