Vitamin D Deficiency Induces Insulin Resistance and Re‐Supplementation Attenuates Hepatic Glucose Output via the PI3K‐AKT‐FOXO1 Mediated Pathway

Background Pandemic vitamin D deficiency is associated with insulin resistance and type 2 diabetes. Vitamin D supplementation has been reported to have improved glucose homeostasis. However, its mechanism to improve insulin sensitivity remains unclear. Methods and results Male C57BL/6J mice are fed with/without vitamin D control (CD) or Western (WD) diets for 15 weeks. The vitamin‐D‐deficient lean (CDVDD) and obese (WDVDD) mice are further subdivided into two groups. One group is re‐supplemented with vitamin D for 6 weeks and hepatic insulin signaling is examined. Both CD and WD mice with vitamin D deficiency developed insulin resistance. Vitamin D supplementation in CDVDD mice significantly improved insulin sensitivity, hepatic inflammation, and antioxidative capacity. The hepatic insulin signals like pAKT, pFOXO1, and pGSK3β are increased and the downstream Pepck , G6pase , and Pgc1α are reduced. Furthermore, the lipogenic genes Srebp1c , Acc , and Fasn are decreased, indicating that hepatic lipid accumulation is inhibited. Conclusion The results demonstrate that vitamin D deficiency induces insulin resistance. Its supplementation has significant beneficial effects on pathophysiological mechanisms in type 2 diabetes but only in lean and not in the obese phenotype. The increased subacute inflammation and insulin resistance in obesity cannot be significantly alleviated by vitamin D supplementation. This needs to be taken into consideration in the design of new clinical trials.