Shivaprakash Jagalur Mutt1,2,3, Ghulam Shere Raza1,2, Markus J Mäkinen3,4, Sirkka Keinänen-Kiukaanniemi5,6,7, Marjo-Riitta Järvelin2,5,7,6,8,9, Karl-Heinz Herzig1,2,3,10. 1. Institute of Biomedicine, Department of Physiology, University of Oulu, 90014, Oulu, Finland. 2. Biocenter of Oulu, University of Oulu, 90014, Oulu, Finland. 3. Medical Research Center, University of Oulu and Oulu University Hospital, 90014, Oulu, Finland. 4. Cancer and Translational Research Unit, Department of Pathology, University of Oulu, 90014, Oulu, Finland. 5. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90014, Oulu, Finland. 6. Unit of General Practice and Primary Care, Oulu University Hospital, 90220, Oulu, Finland. 7. Institute of Health Sciences, University of Oulu, 90014, Oulu, Finland. 8. Department of Children, Young People and Families, National Institute for Health and Welfare, 90101, Oulu, Finland. 9. Department of Epidemiology and Biostatistics, and MRC-PHE Center for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, UK. 10. Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, 61-701, Poznan, Poland.
Abstract
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.
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 WDmice 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.