Glucose Sensing by Skeletal Myocytes Couples Nutrient Signaling to Systemic Homeostasis

• Published in: Molecular cell Vol. 66; no. 3; pp. 332 - 344.e4
• Main Authors: Meng, Zhuo-Xian, Gong, Jianke, Chen, Zhimin, Sun, Jingxia, Xiao, Yuanyuan, Wang, Lin, Li, Yaqiang, Liu, Jianfeng, Xu, X. Z. Shawn, Lin, Jiandie D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.05.2017
• Subjects: Animals; Baf60c; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell Line; chromatin remodeling; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Deptor; diabetes; Energy Metabolism - drug effects; Enzyme Activation; epigenetic; glucose sensing; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Homeostasis; Humans; Hypoglycemic Agents - pharmacology; Insulin - blood; insulin resistance; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; KATP Channels - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle Proteins - genetics; Muscle Proteins - metabolism; Postprandial Period; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; skeletal muscle; sulfonylurea; Sulfonylurea Compounds - pharmacology; SWI/SNF; Time Factors; Tissue Culture Techniques; sulfonylurea; Deptor; epigenetic; Baf60c; SWI/SNF; chromatin remodeling; skeletal muscle; glucose sensing; diabetes; insulin resistance
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.04.007

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. [Display omitted] •Skeletal myocytes engage in physiological glucose sensing via the KATP channel•Glucose stimulates insulin-independent AKT activation through HDAC5/Baf60c•Muscle glucose sensing is required for postprandial glucose homeostasis•Sulfonylureas lower blood glucose in part through the Baf60c-Deptor-AKT axis Skeletal myocytes directly sense extracellular glucose concentrations and activate a signaling pathway to drive hormone-independent AKT activation. This glucose-sensing pathway acts in concert with insulin to promote muscle glucose utilization and maintain systemic glucose homeostasis.