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Liver Insulin Sensitizing Effects of Vitamin D Mediated through Reduced Adipose Tissue Inflammation and Fibrosis
Eric Lontchi Yimagou1, Sona Kang2, Kehao Zhang1, Akankasha Goyal3, Jee Young You1, Preeti Kishore1, Evan Rosen4, Meredith Hawkins1. 1Albert Einstein College of Medicine, Bronx, New York, United States, 2Berkeley University, Berkeley, California, United States, 3NYU Langone, NYC, New York, United States, 4Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Purpose of Study Since vitamin D (25(OH)D) has anti-inflammatory and anti-fibrotic effects, expression of its receptor in adipocytes and macrophages suggests that 25(OH)D signaling could mediate paracrine effects within adipose tissue and improve insulin resistance. We assessed the effects of vitamin D on adipose tissue inflammation and fibrosis, and on systemic insulin resistance.
Methods Used We performed a randomized, double-blinded placebo-controlled trial to examine the effects of repleting vitamin D levels to >30ng/ml in 25(OH)D-deficient (<20ng/ml), insulin resistant, obese humans (n=19). Insulin sensitivity was assessed with stepped euglycemic hyperinsulinemic clamps before (1st visit) and after administration of vitamin D or placebo (2ndvisit). Adipose tissue fibrosis and inflammation were quantified in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we performed hyperinsulinemic clamps and adipose tissue analysis in an adipocyte-specific vitamin D receptor knockout (VDR KO) mouse model.
Summary of Results 25(OH)D repletion was associated with reductions in adipose tissue gene expression of inflammatory (0.6-0.7-fold decreased expression of TNF-α, IL-6, iNOS, PAI-1) and pro-fibrotic (0.4-0.8-fold decreased expression of TGF-β1, HiF1α, Collagen I, V, VI and MMP7) factors, decreased collagen VI immunofluorescence (p=0.02) and improved hepatic insulin sensitivity in humans, with suppression of endogenous glucose production(EGP)(p=0.03)(Fig.1a). Compared to wild type (WT), adipose-specific VDR KO mice exhibited increased adipose tissue expression of several pro-inflammatory (Tnf-α, iNos, Pai-1, Mcp-1, F4/80; 4-10 fold) and pro-fibrotic genes (Tgf-β1, Collagen VI, Tsp1; 2-4 fold) in concert with hepatic insulin resistance (p=0.021)(Fig.1b). There were no changes in glucose uptake in either humans or mice.
Conclusions These complementary human and rodent studies establish a beneficial role of vitamin D to improve hepatic insulin resistance, likely by restraining adipose tissue inflammation and fibrosis. Thus, normalizing 25(OH)Dlevels could have metabolic benefits in targeted individuals.


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