Abstract |
The insulin/ insulin-like growth factor-1 signalling (IIS) pathway regulates cellular and organismal metabolism and controls the rate of aging. Gain-of-function mutations in p110α, the principal mammalian IIS-responsive isoform of PI 3-kinase (PI3K), promote cancer. In contrast, loss-of-function mutations in p110α impair insulin signalling and cause insulin resistance, inducing a pre-diabetic state. It remains unknown if long-term p110α inactivation induces further metabolic deterioration over time, leading to overt unsustainable pathology. Surprisingly, we find that chronic p110α partial inactivation in mice protects from age-related reduction in insulin sensitivity, glucose tolerance and fat accumulation, and extends the lifespan of male mice. This beneficial effect of p110α inactivation derives in part from a suppressed down-regulation of insulin receptor substrate (IRS) protein levels induced by age-related hyperinsulinemia, and correlates with enhanced insulin-induced Akt signalling in aged p110α-deficient mice. This temporal metabolic plasticity upon p110α inactivation indicates that prolonged PI3K inhibition, as intended in human cancer treatment, might not negatively impact on organismal metabolism.
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Authors | Lazaros C Foukas, Benoit Bilanges, Lucia Bettedi, Wayne Pearce, Khaled Ali, Sara Sancho, Dominic J Withers, Bart Vanhaesebroeck |
Journal | EMBO molecular medicine
(EMBO Mol Med)
Vol. 5
Issue 4
Pg. 563-71
(Apr 2013)
ISSN: 1757-4684 [Electronic] England |
PMID | 23483710
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. |
Chemical References |
- Fats
- Insulin
- Insulin Receptor Substrate Proteins
- 1-phosphatidylinositol 3-kinase p110 subunit, mouse
- Class I Phosphatidylinositol 3-Kinases
- Glucose
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Topics |
- Animals
- Class I Phosphatidylinositol 3-Kinases
(genetics, metabolism)
- Fats
(metabolism)
- Female
- Gene Silencing
- Glucose
(metabolism)
- Humans
- Insulin
(metabolism)
- Insulin Receptor Substrate Proteins
(genetics, metabolism)
- Male
- Metabolic Diseases
(enzymology, genetics, metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Time Factors
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