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PMID: 11781359 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes.

The Journal of clinical investigation ·Vol. 109 ·No. 1 ·2002-01-00 ·Pages 141-9

Mauvais-Jarvis F, Ueki K, Fruman DA, Hirshman MF, Sakamoto K, Goodyear LJ, Iannacone M, Accili D, Cantley LC, Kahn CR

Abstract

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.

MeSH Terms
Alleles Animals Diabetes Mellitus, Experimental/enzymology,genetics,physiopathology Diabetes Mellitus, Type 2/enzymology,genetics,physiopathology Heterozygote Insulin/physiology Insulin Receptor Substrate Proteins Insulin Resistance/genetics,physiology Mice Mice, Inbred C57BL Mice, Knockout Mice, Mutant Strains Phosphatidylinositol 3-Kinases/chemistry,genetics,metabolism Phosphoproteins/genetics Protein Subunits Receptor, Insulin/genetics Signal Transduction
Chemicals
Insulin Insulin Receptor Substrate Proteins Irs1 protein, mouse Phosphoproteins Protein Subunits Phosphatidylinositol 3-Kinases Receptor, Insulin
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Mauvais-Jarvis Franck
Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ueki Kohjiro
Fruman David A
Hirshman Michael F
Sakamoto Kei
Goodyear Laurie J
Iannacone Matteo
Accili Domenico
Cantley Lewis C
Kahn C Ronald
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI13305
Published
2002-01-00
Pages
141-9
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC150818
Subset
IM
Grants
NIDDK NIH HHS · R01 DK055545 · United States
NIDDK NIH HHS · DK-55545 · United States
NIGMS NIH HHS · R37 GM041890 · United States
NIGMS NIH HHS · R01 GM041890 · United States
NIDDK NIH HHS · DK-33201 · United States
NIDDK NIH HHS · R01 DK033201 · United States
NIGMS NIH HHS · GM-41890 · United States
External Links
PubMed source DOI: 10.1172/JCI13305 PMC Full Text View journal details
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