Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling.

Samovski D, Dhule P, Pietka T, Jacome-Sosa M, Penrose E, Son NH, Flynn CR, Shoghi KI, Hyrc KL, Goldberg IJ, Gamazon ER, Abumrad NA
Diabetes. 2018 67 (7): 1272-1284

PMID: 29748289 · PMCID: PMC6014550 · DOI:10.2337/db17-1226

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.

© 2018 by the American Diabetes Association.

MeSH Terms (20)

Animals Carbohydrate Metabolism CD36 Antigens Cells, Cultured CHO Cells Cricetinae Cricetulus Diabetes Mellitus, Type 2 Female Glucose Humans Insulin Insulin Resistance Male Mice Mice, Inbred C57BL Mice, Knockout Muscle, Skeletal Receptor, Insulin Signal Transduction

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