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SIRT1 dependent IRS1 phosphorylation mediates the effect of vitamin D on GLUT4 translocation and glucose utilization via PI3K/PTEN/PTP1B/ PIP3/AKT/PKCζ/λ signaling cascade in high glucose treated 3T3L1 adipocytes (260.5)
Author(s) -
Manna Prasenjit,
Jain Sushil
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.260.5
Subject(s) - glut4 , pten , protein kinase b , pi3k/akt/mtor pathway , phosphorylation , insulin receptor , irs1 , chemistry , glucose transporter , medicine , endocrinology , glucose uptake , downregulation and upregulation , signal transduction , protein kinase c , cancer research , insulin , insulin resistance , biology , biochemistry , gene
This study examined the biochemical mechanism by which VD regulates glucose homeostasis in diabetes. 3T3L1 adipocytes were treated with VD (1,25(OH)2D3, 0‐50 nM, 2 h) and high glucose (HG, 25mM, 20 h). Results (n=4) showed that VD upregulated SIRT1 protein expression and IR phosphorylation, stimulated IRS1/PI3K/PTEN/PTP1B/PIP3/AKT/PKCζ/λ signaling cascade, and increased GLUT4 translocation (44%), and glucose utilization in HG treated cells. VD also upregulated its receptor (VDR) protein expression (45%) and decreased ROS (31%), NOX4 protein expression (71%), and NF‐κB phosphorylation (47%) in HG treated cells. VD treatment along with insulin enhanced GLUT4 translocation (29%) and glucose utilization (32%) compared to either insulin or VD alone in HG treated cells. Signal silencing studies showed that in IR siRNA transfected cells, VD can increase the IRS1 phosphorylation, GLUT4 translocation, and glucose utilization; however the effect of VD was significantly inhibited in the SIRT1 siRNA transfected cells. Studies with VDR siRNA demonstrated that the effect of VD on glucose metabolism in HG treated cells is mediated via its receptor. This study demonstrates a novel molecular mechanism by which VD upregulates SIRT1 protein expression and IRS1 phosphorylation which mediate the GLUT4 translocation and glucose utilization via PI3K/PTEN/PTP1B/PIP3/AKT/PKCζ/λ signaling cascade in adipocytes. Grant Funding Source : Supported by NIH RO1 AT007442 and Malcolm Feist Chair in Diabetes