期刊
DIABETES
卷 67, 期 7, 页码 1272-1284出版社
AMER DIABETES ASSOC
DOI: 10.2337/db17-1226
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-111175, R01-DK-33301]
- Nutrition Obesity Research Center [P30-DK056341]
- Diabetes Research Center [P30-DK020579]
- Longer Life Foundation [2017-007]
- Hope Center Alafi Neuroimaging Laboratory and National Institutes of Health Shared Instrumentation Grant [S10-RR-027552]
- pilot and feasibility awards
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR027552] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL045095] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020579, R01DK060022, R01DK033301, P30DK056341, R01DK111175] Funding Source: NIH RePORTER
During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.
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