Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes.
A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. The major regulatory subunits of PI 3-kinase, p85alpha and its splice variants, are encoded by the Pik3r1 gene. Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice and mice made insulin-resistant by heterozygous deletion of the Insulin receptor and/or insulin receptor substrate-1 (IRS1) genes. Reduced expression of p85 modulates the molecular balance between this protein, the p110 catalytic subunit of PI 3-kinase, and the IRS proteins. Thus, despite the decrease in p85alpha, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved. Furthermore, Pik3r1 heterozygosity protects mice with genetic insulin resistance from developing diabetes. These data suggest that regulation of p85alpha levels may provide a novel therapeutic target for the treatment of type 2 diabetes.
Mauvais-Jarvis
Franck
F
Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ueki
Kohjiro
K
Fruman
David A
DA
Hirshman
Michael F
MF
Sakamoto
Kei
K
Goodyear
Laurie J
LJ
Iannacone
Matteo
M
Accili
Domenico
D
Cantley
Lewis C
LC
Kahn
C Ronald
CR
D000483:Alleles; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D006579:Heterozygote; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics; D021122:Protein Subunits; D011972:Receptor, Insulin / Q000235:genetics; D015398:Signal Transduction
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin