University of Oulu

Mutt, S. J., Raza, G. S., Mäkinen, M. J., Keinänen‐Kiukaanniemi, S., Järvelin, M., Herzig, K., Vitamin D Deficiency Induces Insulin Resistance and Re‐Supplementation Attenuates Hepatic Glucose Output via the PI3K‐AKT‐FOXO1 Mediated Pathway. Mol. Nutr. Food Res. 2019, 64, 1900728. https://doi.org/10.1002/mnfr.201900728

Vitamin D deficiency induces insulin resistance and re‐supplementation attenuates hepatic glucose output via the PI3K‐AKT‐FOXO1 mediated pathway

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Author: Mutt, Shivaprakash Jagalur1,2,3; Raza, Ghulam Shere1,2; Mäkinen, Markus J3,4;
Organizations: 1Institute of Biomedicine, Department of Physiology, University of Oulu, 90014 Oulu, Finland
2Biocenter of Oulu, University of Oulu, 90014 Oulu, Finland
3Medical Research Center, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
4Cancer and Translational Research Unit, Department of Pathology, University of Oulu, 90014 Oulu, Finland
5Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90014 Oulu, Finland
6Unit of General Practice and Primary Care, Oulu University Hospital, 90220 Oulu, Finland
7Institute of Health Sciences, University of Oulu, 90014 Oulu, Finland
8Department of Children, Young People and Families, National Institute for Health and Welfare, 90101 Oulu, Finland
9Department of Epidemiology and Biostatistics, and MRC‐PHE Center for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG UK
10Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, 61–701 Poznan, Poland
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2020052038560
Language: English
Published: John Wiley & Sons, 2020
Publish Date: 2020-12-04
Description:

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.

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Series: Molecular nutrition & food research
ISSN: 1613-4125
ISSN-E: 1613-4133
ISSN-L: 1613-4125
Volume: 64
Issue: 1
Article number: 1900728
DOI: 10.1002/mnfr.201900728
OADOI: https://oadoi.org/10.1002/mnfr.201900728
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: University of Oulu Hospital Fund; Finnish Cultural Foundation.
Copyright information: © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This is the peer reviewed version of the following article: Mutt, S. J., Raza, G. S., Mäkinen, M. J., Keinänen‐Kiukaanniemi, S., Järvelin, M., Herzig, K., Vitamin D Deficiency Induces Insulin Resistance and Re‐Supplementation Attenuates Hepatic Glucose Output via the PI3K‐AKT‐FOXO1 Mediated Pathway. Mol. Nutr. Food Res. 2019, 64, 1900728., which has been published in final form at https://doi.org/10.1002/mnfr.201900728. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.