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Differential effects of protein kinase B/Akt isoforms on glucose homeostasis and islet mass.

ABSTRACT: 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 PKBbeta 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 Pkbalpha, Pkbbeta, and Pkbgamma-deficient mice. Our study uncovered a novel role for PKBalpha in the regulation of glucose homeostasis, whereas it confirmed that Pkbbeta(-/)(-) mice are insulin resistant with compensatory increase of islet mass. Pkbalpha(-/)(-) mice displayed an opposite phenotype with improved insulin sensitivity, lower blood glucose, and higher serum glucagon concentrations. Pkbgamma(-/)(-) mice did not show metabolic abnormalities. Additionally, our signaling analyses revealed that PKBalpha, but not PKBbeta or PKBgamma, is specifically activated by overexpression of IRS2 in beta-cells and is required for IRS2 action in the islets.

SUBMITTER: Buzzi F

PROVIDER: S-EPMC2812230 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Differential effects of protein kinase B/Akt isoforms on glucose homeostasis and islet mass.

Buzzi Francesca F Xu Linhua L Zuellig Richard A RA Boller Simone B SB Spinas Giatgen A GA Hynx Debby D Chang Zai Z Yang Zhongzhou Z Hemmings Brian A BA Tschopp Oliver O Niessen Markus M

Molecular and cellular biology 20091123 3

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 PKBbeta 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 i ...[more]

PMID: 19933838

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Project description:ObjectiveSkeletal muscle insulin signaling is a major determinant of muscle growth and glucose homeostasis. Protein kinase B/Akt plays a prominent role in mediating many of the metabolic effects of insulin. Mice and humans harboring systemic loss-of-function mutations in Akt2, the most abundant Akt isoform in metabolic tissues, are glucose intolerant and insulin resistant. Since the skeletal muscle accounts for a significant amount of postprandial glucose disposal, a popular hypothesis in the diabetes field suggests that a reduction in Akt, specifically in skeletal muscle, leads to systemic glucose intolerance and insulin resistance. Despite this common belief, the specific role of skeletal muscle Akt in muscle growth and insulin sensitivity remains undefined.MethodsWe generated multiple mouse models of skeletal muscle Akt deficiency to evaluate the role of muscle Akt signaling in vivo. The effects of these genetic perturbations on muscle mass, glucose homeostasis and insulin sensitivity were assessed using both in vivo and ex vivo assays.ResultsSurprisingly, mice lacking Akt2 alone in skeletal muscle displayed normal skeletal muscle insulin signaling, glucose tolerance, and insulin sensitivity despite a dramatic reduction in phosphorylated Akt. In contrast, deletion of both Akt isoforms (M-AktDKO) prevented downstream signaling and resulted in muscle atrophy. Despite the absence of Akt signaling, in vivo and ex vivo insulin-stimulated glucose uptake were normal in M-AktDKO mice. Similar effects on insulin sensitivity were observed in mice with prolonged deletion (4 weeks) of both skeletal muscle Akt isoforms selectively in adulthood. Conversely, short term deletion (2 weeks) of skeletal muscle specific Akt in adult muscles impaired insulin tolerance paralleling the effect observed by acute pharmacological inhibition of Akt in vitro. Mechanistically, chronic ablation of Akt induced mitochondrial dysfunction and activation of AMPK, which was required for insulin-stimulated glucose uptake in the absence of Akt.ConclusionsTogether, these data indicate that chronic reduction in Akt activity alone in skeletal muscle is not sufficient to induce insulin resistance or prevent glucose uptake in all conditions. Therefore, since insulin-stimulated glucose disposal in skeletal muscle is markedly impaired in insulin-resistant states, we hypothesize that alterations in signaling molecules in addition to skeletal muscle Akt are necessary to perturb glucose tolerance and insulin sensitivity in vivo.

Dataset Information

Differential effects of protein kinase B/Akt isoforms on glucose homeostasis and islet mass.

Publications

Differential effects of protein kinase B/Akt isoforms on glucose homeostasis and islet mass.

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