Dietary Supplementation With High Doses of Regular Vitamin D3 Safely Reduces Diabetes Incidence in NOD Mice When Given Early and Long Term

Takiishi, Tatiana; Ding, Lei; Baeke, Femke; Spagnuolo, Isabella; Sebastiani, Guido; Laureys, Jos; Verstuyf, Annemieke; Carmeliet, Geert; Dotta, Francesco; Belle, Tom L. Van; Gysemans, Conny; Mathieu, Chantal

doi:10.2337/db13-1559

Cited by 67 publications

(53 citation statements)

References 41 publications

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“…Conversely, dietary vitamin D supplementation in HFD partially but significantly hampered the biogenesis of steatosis and MetS. This finding is consistent with a previous report showing improvement of diabetic outcomes in NOD background mice with a high dose of VD 3 supplementation (Takiishi et al, 2014). …”

Section: Discussionsupporting

confidence: 92%

Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models

et al. 2016

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Metabolic syndrome (MetS), characterized as obesity, insulin resistance, and non-alcoholic fatty liver diseases (NAFLD), is associated with vitamin D insufficiency/deficiency in epidemiological studies, while the underlying mechanism is poorly addressed. On the other hand, disorder of gut microbiota, namely dysbiosis, is known to cause MetS and NAFLD. It is also known that systemic inflammation blocks insulin signaling pathways, leading to insulin resistance and glucose intolerance, which are the driving force for hepatic steatosis. Vitamin D receptor (VDR) is highly expressed in the ileum of the small intestine, which prompted us to test a hypothesis that vitamin D signaling may determine the enterotype of gut microbiota through regulating the intestinal interface. Here, we demonstrate that high-fat-diet feeding (HFD) is necessary but not sufficient, while additional vitamin D deficiency (VDD) as a second hit is needed, to induce robust insulin resistance and fatty liver. Under the two hits (HFD+VDD), the Paneth cell-specific alpha-defensins including α-defensin 5 (DEFA5), MMP7 which activates the pro-defensins, as well as tight junction genes, and MUC2 are all suppressed in the ileum, resulting in mucosal collapse, increased gut permeability, dysbiosis, endotoxemia, systemic inflammation which underlie insulin resistance and hepatic steatosis. Moreover, under the vitamin D deficient high fat feeding (HFD+VDD), Helicobacter hepaticus, a known murine hepatic-pathogen, is substantially amplified in the ileum, while Akkermansia muciniphila, a beneficial symbiotic, is diminished. Likewise, the VD receptor (VDR) knockout mice exhibit similar phenotypes, showing down regulation of alpha-defensins and MMP7 in the ileum, increased Helicobacter hepaticus and suppressed Akkermansia muciniphila. Remarkably, oral administration of DEFA5 restored eubiosys, showing suppression of Helicobacter hepaticus and increase of Akkermansia muciniphila in association with resolving metabolic disorders and fatty liver in the HFD+VDD mice. An in vitro analysis showed that DEFA5 peptide could directly suppress Helicobacter hepaticus. Thus, the results of this study reveal critical roles of a vitamin D/VDR axis in optimal expression of defensins and tight junction genes in support of intestinal integrity and eubiosis to suppress NAFLD and metabolic disorders.

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Section: Discussionsupporting

confidence: 92%

Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models

et al. 2016

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“…In addition, vitamin D supplementation studies are often contradictory due to the lack of precise information on regimen and dosage protocols [14]. …”

Section: Introductionmentioning

confidence: 99%

Vitamin D Modulates Hematological Parameters and Cell Migration into Peritoneal and Pulmonary Cavities in Alloxan-Diabetic Mice

Bella

Fieri

Tessaro

et al. 2017

BioMed Research International

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Background/Aims. The effects of cholecalciferol supplementation on the course of diabetes in humans and animals need to be better understood. Therefore, this study investigated the effect of short-term cholecalciferol supplementation on biochemical and hematological parameters in mice. Methods. Male diabetic (alloxan, 60 mg/kg i.v., 10 days) and nondiabetic mice were supplemented with cholecalciferol for seven days. The following parameters were determined: serum levels of 25-hydroxyvitamin D, phosphorus, calcium, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, red blood cell count, white blood cell count (WBC), hematocrit, hemoglobin, differential cell counts of peritoneal lavage (PeL), and bronchoalveolar lavage (BAL) fluids and morphological analysis of lung, kidney, and liver tissues. Results. Relative to controls, cholecalciferol supplementation increased serum levels of 25-hydroxyvitamin D, calcium, hemoglobin, hematocrit, and red blood cell counts and decreased leukocyte cell counts of PeL and BAL fluids in diabetic mice. Diabetic mice that were not treated with cholecalciferol had lower serum calcium and albumin levels and hemoglobin, WBC, and mononuclear blood cell counts and higher serum creatinine and urea levels than controls. Conclusion. Our results suggest that cholecalciferol supplementation improves the hematological parameters and reduces leukocyte migration into the PeL and BAL lavage of diabetic mice.

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“…The finding of an association between inherited variations in vitamin D genes and predisposition to type 1 diabetes would support this hypothesis [15]. Recent experimental studies would support a protective role of vitamin D. Indeed, lifelong high doses of vitamin D prevented diabetes in NOD mice [26] and was able to promote the generation of tolerogenic mature dentritic cells with an impaired ability to activate autoreactive T cells [27]. Limitation of present study is the low number of cases and control children, so that statistical significant result in our migrant subgroup might be merely due to chance.…”

Section: Discussionmentioning

confidence: 82%

Vitamin D levels at birth and risk of type 1 diabetes in childhood: a case–control study

et al. 2015

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Dietary Supplementation With High Doses of Regular Vitamin D3 Safely Reduces Diabetes Incidence in NOD Mice When Given Early and Long Term

Cited by 67 publications

References 41 publications

Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models

Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models

Vitamin D Modulates Hematological Parameters and Cell Migration into Peritoneal and Pulmonary Cavities in Alloxan-Diabetic Mice

Vitamin D levels at birth and risk of type 1 diabetes in childhood: a case–control study

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