Cited by 207Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerAdipokines, Inflammation, and Metabolic Diseases

Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes

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Mauvais-Jarvis, Franck, Ueki, Kohjiro, Fruman, David A., Hirshman, Michael F., Sakamoto, Kei, Goodyear, Laurie J., Iannacone, Matteo, Accili, Domenico +2 more·2002·Journal of Clinical Investigation

Abstract

A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase.The major regulatory subunits of PI 3-kinase, p85α 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 p85α, 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 p85α levels may provide a novel therapeutic target for the treatment of type 2 diabetes.

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  1. Ueki, K., et al. 2001. Molecular balance between the regulatory and cat- alytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol. Cell. Biol. In press.

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Authors
Mauvais-Jarvis, F., Ueki, K., Fruman, D. A., Hirshman, M. F., Sakamoto, K., Goodyear, L. J., Iannacone, M., Accili, D., Cantley, L. C., & Kahn, C. R.
Affiliations
  • Joslin Diabetes Center (US)
  • Beth Israel Deaconess Medical Center (US)
  • Columbia University (US)
Corresponding author
Kahn, C. Ronald
Venue
Journal of Clinical Investigation
Published
2002-01-01
Volume
109
Issue
1
Pages
141-149
ISSN
0021-9738 (ISSN-L)
OpenAlex
W4243898144
Cited by
207
References
38
Citations by year
2026: 3 · 2025: 4 · 2024: 11 · 2023: 1 · 2022: 5 · 2021: 6 · 2020: 10 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 3 · 2015: 6 · 2014: 2 · 2013: 8 · 2012: 6
FWCI
6.16
Type
journal article
Language
en
Open access
Locations
Journal of Clinical Investigation (publishedVersion)
Funders
  • Damon Runyon Cancer Research Foundation
  • National Institutes of Health (GM41890)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK033201)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
phosphatidylinositol 3-kinase, PIK3R1, insulin signaling, insulin resistance, type 2 diabetes, insulin receptor, IRS-1, Akt, glucose homeostasis, glucose tolerance, heterozygous knockout mice, therapeutic target

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