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Mol Cell. 2017 May 4;66(3):332-344.e4. doi: 10.1016/j.molcel.2017.04.007.

Glucose Sensing by Skeletal Myocytes Couples Nutrient Signaling to Systemic Homeostasis.

Author information

1
Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Chronic Disease Research Institute of School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
2
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; College of Life Science and Technology and Collaborative Innovation Center for Brain Science, Key Laboratory of Molecular Biophysics of MOE, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
3
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
4
College of Life Science and Technology and Collaborative Innovation Center for Brain Science, Key Laboratory of Molecular Biophysics of MOE, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
5
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
6
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Electronic address: jdlin@umich.edu.

Abstract

Skeletal muscle is a major site of postprandial glucose disposal. Inadequate insulin action in skeletal myocytes contributes to hyperglycemia in diabetes. Although glucose is known to stimulate insulin secretion by β cells, whether it directly engages nutrient signaling pathways in skeletal muscle to maintain systemic glucose homeostasis remains largely unexplored. Here we identified the Baf60c-Deptor-AKT pathway as a target of muscle glucose sensing that augments insulin action in skeletal myocytes. Genetic activation of this pathway improved postprandial glucose disposal in mice, whereas its muscle-specific ablation impaired insulin action and led to postprandial glucose intolerance. Mechanistically, glucose triggers KATP channel-dependent calcium signaling, which promotes HDAC5 phosphorylation and nuclear exclusion, leading to Baf60c induction and insulin-independent AKT activation. This pathway is engaged by the anti-diabetic sulfonylurea drugs to exert their full glucose-lowering effects. These findings uncover an unexpected mechanism of glucose sensing in skeletal myocytes that contributes to homeostasis and therapeutic action.

KEYWORDS:

Baf60c; Deptor; SWI/SNF; chromatin remodeling; diabetes; epigenetic; glucose sensing; insulin resistance; skeletal muscle; sulfonylurea

PMID:
28475869
PMCID:
PMC5489118
DOI:
10.1016/j.molcel.2017.04.007
[Indexed for MEDLINE]
Free PMC Article

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