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Biochem Biophys Res Commun. 2014 Jan 10;443(2):689-93. doi: 10.1016/j.bbrc.2013.12.023. Epub 2013 Dec 11.

IRS1Ser³⁰⁷ phosphorylation does not mediate mTORC1-induced insulin resistance.

Author information

1
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: umut.ozcan@childrens.harvard.edu.

Abstract

Increased mammalian target of rapamycin complex 1 (mTORC1) activity has been suggested to play important roles in development of insulin resistance in obesity. mTORC1 hyperactivity also increases endoplasmic reticulum (ER) stress, which in turn contributes to development of insulin resistance and glucose intolerance. Increased IRS1 phosphorylation at Ser307 in vitro is correlated with mTORC1- and ER stress-induced insulin resistance. This phosphorylation site correlates strongly with impaired insulin receptor signaling in diabetic mice and humans. In contrast, evidence from knock-in mice suggests that phosphorylation of IRS1 at Ser307 is actually required to maintain insulin sensitivity. To study the involvement of IRS1(Ser307) phosphorylation in mTORC1-mediated glucose intolerance and insulin sensitivity in vivo, we investigated the effects of liver specific TSC1 depletion in IRS1(Ser307Ala) mice and controls. Our results demonstrate that blockade of IRS1(Ser307) phosphorylation in vivo does not prevent mTORC1-mediated glucose intolerance and insulin resistance.

KEYWORDS:

Diabetes; ER stress; IRS1; mTORC1

PMID:
24333417
PMCID:
PMC3926104
DOI:
10.1016/j.bbrc.2013.12.023
[Indexed for MEDLINE]
Free PMC Article

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