Vitamin D₃ improves glucose metabolism and attenuates inflammation in prediabetic human and mice

Prediabetes is a crucial stage for prevention and treatment of diabetes, and vitamin D (VD) has been found to be linked to the development of prediabetes and diabetes. Thus, we aimed to identify the effect of VD supplementation on glucose metabolism in prediabetic participants and mice. A 1:1 paired design of randomized, placebo-controlled trial with 1600 IU/day VD₃ or placebo was administered to individuals with prediabetes, two-way repeated-measures ANCOVA was used to analyze glycolipid and inflammatory factors. A high-fat diet induced prediabetic KKay mice were utilized to evaluate the effects of VD₃ with 16 weeks supplementation. Generalized estimation equation, one way ANOVA were used to analyze continuous monitoring indexes and terminal indexes, respectively. Exercise capacity, skeletal muscle pathological features and relevant proteins were examined. The clinical results showed that VD₃ could improve insulin secretion and decrease inflammation. Results of KKay mice exhibited that VD₃ not only ameliorate glycolipid metabolism and inflammatory indicators, but also regulated pathological changes of skeletal muscle and exercise capacity. Mechanistically, our results demonstrated that VD₃ could inhibit the TLR4/NFκB and activate PI3K/AKT signaling pathway. Collectively, the study indicated that VD₃ exerts its beneficial effects by inhibiting TLR4/NFκB to decrease inflammatory response, and activating PI3K/AKT signaling pathway to regulate glucose homeostasis.