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 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.
Buzzi
Francesca
F
University Hospital of Zurich,Zurich, Switzerland.
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
D000818:Animals; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose