Vitamin D Up-regulates Glucose Transporter 4 (GLUT4) Translocation and Glucose Utilization Mediated by Cystathionine-γ-lyase (CSE) Activation and H2S Formation in 3T3L1 Adipocytes*
December 7, 2012 The Journal of Biological Chemistry, 287, 42324-42332.
Prasenjit Manna and Sushil K. Jain
From the Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103
↵1 To whom correspondence should be addressed: Dept. of Pediatrics, LSU Health Sciences Center, 1501 Kings Hwy., Shreveport, LA 71103. Tel.: 1-318-675-6086; Fax: 1-318-675-6059; E-mail: sjain@lsuhsc.edu.
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Background: Circulating vitamin D relationship with insulin resistance is not resolved.
Results: 1,25(OH)2D3 (active form of vitamin D) up-regulates GLUT4 translocation and glucose utilization and is inhibited by chemical inhibition or silencing of cystathionine-γ-lyase in high glucose-treated adipocytes.
Conclusion: 1,25(OH)2D3-induced GLUT4 translocation and glucose utilization are mediated by cystathionine-γ-lyase activation and H2S formation.
Significance: 1,25(OH)2D3 up-regulates the insulin signaling for maintenance of glucose homeostasis in diabetes.
Abstract
A scientific explanation for the beneficial role of vitamin D supplementation in the lowering of glycemia in diabetes remains to be determined. This study examined the biochemical mechanism by which vitamin D supplementation regulates glucose metabolism in diabetes. 3T3L1 adipocytes were treated with high glucose (HG, 25 mM) in the presence or absence of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (25, 50 nM), the active form of vitamin D. 1,25(OH)2D3 treatment caused significant up-regulation of GLUT4 total protein expression and its translocation to cell surface, and an increase in glucose uptake as well as glucose utilization in HG-treated cells. 1,25(OH)2D3 also caused cystathionine-γ-lyase (CSE) activation and H2S formation in HG-treated adipocytes. The effect of 1,25(OH)2D3 on GLUT4 translocation, glucose utilization, and H2S formation was prevented by propargylglycine, an inhibitor of CSE that catalyzes H2S formation. Studies using antisense CSE also demonstrated the inhibition of GLUT4 translocation as well as glucose uptake and utilization in 1,25(OH)2D3-supplemented CSE-siRNA-transfected adipocytes compared with controls. 1,25(OH)2D3 treatment along with insulin enhanced GLUT4 translocation and glucose utilization compared with either insulin or 1,25(OH)2D3 alone in HG-treated adipocytes. 1,25(OH)2D3 supplementation also inhibited monocyte chemoattractant protein-1 and stimulated adiponectin secretion in HG-treated adipocytes, and this positive effect was prevented in propargylglycine-treated or CSE-knockdown adipocytes. This is the first report to demonstrate that 1,25(OH)2D3 up-regulates GLUT4 translocation and glucose utilization and decreases inflammatory markers, which is mediated by CSE activation and H2S formation in adipocytes. This study provides evidence for a novel molecular mechanism by which 1,25(OH)2D3 can up-regulate the GLUT4 translocation essential for maintenance of glucose metabolism.
↵* This work was supported by National Institutes of Health Grant R01 DK072433 through the NIDDK and the Office of Dietary Supplements. This work was also supported by the Malcolm Feist Chair in Diabetes and the Malcolm Feist Cardiovascular research fellowship.
Received August 3, 2012. Revision received October 12, 2012.
© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.