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

Mol Nutr Food Res. 2020 Jan;64(1):e1900728. doi: 10.1002/mnfr.201900728.


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.

Keywords: 25OHD; AKT-FOXO1 pathway; AKT-GSK3β pathway; insulin resistance; lean and obese mice; type 2 diabetes; vitamin D supplementation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Diet, High-Fat / adverse effects
  • Forkhead Box Protein O1 / metabolism
  • Gluconeogenesis / drug effects
  • Glucose / metabolism*
  • Glycogen / metabolism
  • Hepatitis / etiology
  • Insulin Resistance*
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Obesity / etiology
  • Obesity / metabolism
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Vitamin D / blood
  • Vitamin D / pharmacology*
  • Vitamin D Deficiency / complications*
  • Vitamin D Deficiency / metabolism


  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Vitamin D
  • Glycogen
  • Proto-Oncogene Proteins c-akt
  • Glucose