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

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 D-3(1,25(OH)(2)D-3) (25, 50 nM), the active form of vitamin D. 1,25(OH)(2)D-3 treatment caused significant up-regulation of GLUT4 total protein expression and its trans-location to cell surface, and an increase in glucose uptake as well as glucose utilization in HG-treated cells. 1,25(OH)(2)D-3 also caused cystathionine-gamma-lyase (CSE) activation and H2S formation in HG-treated adipocytes. The effect of 1,25(OH)(2)D-3 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)(2)D-3-supplemented CSE-siRNA-transfected adipocytes compared with controls. 1,25(OH)(2)D-3 treatment along with insulin enhanced GLUT4 translocation and glucose utilization compared with either insulin or 1,25(OH)(2)D-3 alone in HG-treated adipocytes. 1,25(OH)(2)D-3 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)(2)D-3 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)(2)D-3 can up-regulate the GLUT4 translocation essential for maintenance of glucose metabolism.