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


Buzzi, F; Xu, L; Zuellig, R A; Boller, S B; Spinas, G A; Hynx, D; Chang, Z; Yang, Z; Hemmings, B A; Tschopp, O; Niessen, M (2010). Differential effects of protein kinase B/Akt isoforms on glucose homeostasis and islet mass. Molecular and Cellular Biology, 30(3):601-612.

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 role of the three PKB isoforms in the regulation of islet mass and glucose homeostasis, we assessed the metabolic and pancreatic phenotypes of Pkbalpha, Pkbbeta or Pkbgamma -deficient mice. Our study uncovers a novel role for PKBalpha in the regulation of glucose homeostasis, whereas it confirms 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 signalling analyses reveal that PKBalpha, but not PKBbeta or gamma, is specifically activated by overexpression of IRS2 in beta-cells and is required for IRS2 action in the islets.

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 role of the three PKB isoforms in the regulation of islet mass and glucose homeostasis, we assessed the metabolic and pancreatic phenotypes of Pkbalpha, Pkbbeta or Pkbgamma -deficient mice. Our study uncovers a novel role for PKBalpha in the regulation of glucose homeostasis, whereas it confirms 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 signalling analyses reveal that PKBalpha, but not PKBbeta or gamma, is specifically activated by overexpression of IRS2 in beta-cells and is required for IRS2 action in the islets.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2010
Deposited On:26 Jan 2010 10:23
Last Modified:05 Apr 2016 13:45
Publisher:American Society for Microbiology
ISSN:0270-7306
Publisher DOI:https://doi.org/10.1128/MCB.00719-09
PubMed ID:19933838
Permanent URL: https://doi.org/10.5167/uzh-27450

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