- Does metformin activate the vitamin D receptor? - asked Perplexity AI Deep Research March 2025
- Metformin improves VDR sensitivity and efficacy - 2024 (Vitamin D helped 14 million COVID patients)
- VitaminDWiki - Vitamin D Receptor activation can be increased in many ways
- Metformin fights COVID (Metformin $121, Vitamin D $10 per life saved)
Does metformin activate the vitamin D receptor? - asked Perplexity AI Deep Research March 2025
Does Metformin Activate the Vitamin D Receptor?
Metformin, a widely prescribed first-line medication for type 2 diabetes, has demonstrated numerous beneficial effects beyond glycemic control. Recent research has revealed intriguing interactions between metformin and the vitamin D receptor (VDR), suggesting potential synergistic therapeutic effects. This report examines the complex relationship between metformin and VDR, exploring how metformin influences VDR expression, function, and downstream signaling pathways across various physiological contexts.
Metformin's Impact on VDR Expression and Function
Current research demonstrates that metformin significantly affects VDR expression in several cell types. In studies examining diabetic kidney disease, metformin has been shown to upregulate VDR expression in renal tissues and human kidney cell lines. When kidney cells (HK2) were cultured in high-glucose environments that typically reduce VDR expression, metformin treatment successfully rescued VDR levels 4. This upregulation appears to be independent of metformin's glucose-lowering effects, suggesting a direct molecular mechanism through which metformin influences VDR expression 4 7.
The relationship between metformin and VDR extends beyond simple upregulation of receptor quantity. Molecular studies reveal that metformin may enhance VDR functionality by improving its binding characteristics with vitamin D and co-activator proteins. Detailed molecular dynamics simulations demonstrate that in the presence of metformin, there are significant conformational changes in the VDR structure that facilitate improved interactions [2]. Specifically, when metformin is present, the helix 12 region of the VDR approaches closer to the co-activator protein, strengthening this crucial molecular interaction [2]. This structural rearrangement potentially explains how metformin enhances vitamin D signaling even without directly binding to the receptor itself.
Molecular Mechanisms of Metformin's Effect on VDR
The molecular basis for metformin's effect on VDR involves several pathways. One proposed mechanism suggests metformin may improve VDR sensitivity through activation of AMP-activated protein kinase (AMPK) or through AMPK-independent mechanisms 6. Metformin has been recognized as a multi-acting drug that influences numerous cellular pathways, and its effects on VDR likely stem from this broad pharmacological profile 6. By affecting mitochondrial function, restoring redox homeostasis, and regulating several signaling pathways like mTOR and SIRT1, metformin creates a cellular environment that enhances VDR responsiveness to vitamin D 6.
Quantum mechanics and molecular mechanics (QM/MM) calculations provide further evidence of metformin's influence on VDR function. In the presence of metformin, the binding free energy between vitamin D and VDR decreases from 24.39 kcal/mol to -25.24 kcal/mol, indicating that the vitamin D-VDR complex becomes more stable when metformin is present 2. Additionally, metformin decreases the energy gap between HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital) of vitamin D in the VDR binding site from 0.170 eV to 0.162 eV, which increases the chemical reactivity of vitamin D within the receptor binding pocket 2. These molecular changes collectively enhance the functionality of the vitamin D-VDR signaling axis.
Pathophysiological Implications of Metformin-VDR Interaction
The interaction between metformin and VDR has significant implications for several pathological conditions, particularly diabetic kidney disease. Metformin's ability to upregulate VDR appears to protect against diabetic nephropathy by inhibiting epithelial-mesenchymal transition (EMT), a process implicated in the development of renal fibrosis 4 7. Research has demonstrated that metformin treatment significantly reduces renal pathological damage in diabetic mice compared to other anti-diabetic medications, despite similar glycemic control 4. This suggests that metformin's renoprotective effect is at least partly mediated through its impact on VDR expression and function.
The anti-inflammatory effects of combined metformin and vitamin D treatment further illustrate the significance of this interaction. Studies on adipose-derived stem cells (ADSCs) have shown that metformin and vitamin D together significantly reduce the expression and release of pro-inflammatory cytokines such as IL-6 and TNF-α 8. This combined treatment also modulates heat shock proteins and autophagy, with exposure to both metformin and vitamin D inhibiting autophagosome formation during adipogenic differentiation 8. These findings suggest a potential therapeutic application for this combination in addressing obesity-related inflammation and its complications.
Synergistic Effects in Chemopreventive Action
The combined use of metformin and vitamin D demonstrates synergistic effects against the development of early colon neoplasia. In animal models of chemically induced colon cancer, the combination of vitamin D and metformin showed more pronounced inhibitory effects on aberrant crypt foci (ACF) and tumor development compared to either agent alone 5. The most significant tumor-inhibiting effects were observed with medium doses of both compounds (vitamin D3 100 IU/kg/day plus metformin 120 mg/kg/day) 5. This synergistic action appears to involve complementary molecular mechanisms.
Metformin enhances vitamin D's chemopreventive effects by targeting the VDR/β-catenin pathway and subsequently down-regulating Cyclin D1 and c-Myc, key regulators of cell proliferation 5. Concurrently, vitamin D enhances metformin's chemopreventive effects by down-regulating S6P expression via the AMPK/mTOR pathway 5. The bidirectional enhancement of these complementary mechanisms explains the superior efficacy of combined treatment compared to monotherapy with either agent. This reciprocal amplification of beneficial effects provides a strong rationale for exploring combination therapy in various clinical contexts.
Therapeutic Implications in Diabetes and Beyond
The interaction between metformin and VDR offers promising therapeutic implications for diabetes management and its complications. Given that vitamin D deficiency is common in patients with diabetes and associated with adverse outcomes, metformin's ability to enhance VDR sensitivity could provide additional benefits beyond glucose control 6. This interaction may be particularly relevant for patients with diabetic complications such as nephropathy, where VDR activation has demonstrated protective effects 4.
Beyond diabetes, the metformin-VDR interaction has potential implications for inflammatory conditions, cancer prevention, and possibly even COVID-19. Some researchers have hypothesized that metformin's ability to improve VDR sensitivity could contribute to its observed benefits in COVID-19 patients 6. In several clinical trials, metformin has shown effectiveness in protecting against severe cases of COVID-19, with meta-analyses demonstrating associations between outpatient metformin treatment and reduced in-hospital mortality in COVID-19 patients 6. While further research is needed to establish a direct link to VDR modulation, these observations suggest broader applications for the metformin-VDR relationship.
Neurological Effects and Cognitive Protection
The interaction between metformin and vitamin D also appears to have neurological implications. In streptozotocin-induced type 1 diabetic rats, vitamin D treatment alone or in combination with metformin showed beneficial effects on behavioral performance, particularly in reversing anxiety and memory loss associated with the diabetic state 1. These neurological benefits appear to involve modulation of the purinergic system, which plays an important role in neuroinflammation, plasticity, and cell-cell communication 1.
Vitamin D treatment positively regulated ectonucleotidase activity and adenosine signaling in the cerebral cortex of diabetic rats, exhibiting neuroprotective effects through modulation of adenosine receptor proteins 1. When combined with metformin, these effects may be enhanced, suggesting potential applications for this combination in addressing diabetes-related cognitive dysfunction. The findings indicate that purinergic signaling modulation through vitamin D, potentially amplified by metformin, could represent a novel strategy for treating neurological complications of diabetes 1.
Conclusion
Current evidence strongly suggests that metformin influences VDR function through multiple mechanisms, rather than acting as a direct activator of the receptor. Metformin upregulates VDR expression, enhances the binding of vitamin D to VDR, improves VDR-coactivator interactions, and affects downstream signaling pathways associated with VDR activation. This complex relationship results in enhanced vitamin D signaling and synergistic therapeutic effects when metformin and vitamin D are used in combination.
The interaction between metformin and the vitamin D receptor represents a fascinating example of drug-nutrient interaction with significant clinical implications. The complementary mechanisms through which these agents enhance each other's effectiveness suggest that their combined use may offer superior benefits in various conditions including diabetes, kidney disease, inflammation, and possibly cancer prevention. As our understanding of this interaction continues to evolve, it may lead to improved therapeutic strategies that leverage the synergistic relationship between metformin and vitamin D signaling pathways.
Citations:
- https://pubmed.ncbi.nlm.nih.gov/36657632/
- https://jrespharm.com/uploads/pdf/pdf_MPJ_677.pdf
- https://pmc.ncbi.nlm.nih.gov/articles/PMC7444705/
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9792813/
- https://pmc.ncbi.nlm.nih.gov/articles/PMC4540484/
- https://www.springermedizin.de/pharmacological-evaluation-of-vitamin-d-in-covid-19-and-long-cov/26296818
- https://www.tandfonline.com/doi/full/10.2147/DMSO.S389918
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8269127/
- https://www.archivesofmedicalscience.com/A-novel-mechanism-of-vitamin-D-anti-inflammatory-antioxidative-potential-in-type,116414,0,2.html
- https://ascopubs.org/doi/10.14694/EdBook_AM.2014.34.e69
- https://pubmed.ncbi.nlm.nih.gov/29909574/
- https://cdnsciencepub.com/doi/abs/10.1139/cjpp-2020-0435
- https://www.tandfonline.com/doi/full/10.1080/15548627.2021.1962681
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9037529/
- https://pubmed.ncbi.nlm.nih.gov/36582506/
- https://aacrjournals.org/cancerpreventionresearch/article/8/2/139/50429/Combined-Use-of-Vitamin-D3-and-Metformin-Exhibits
- https://www.iomcworld.com/proceedings/investigation-of-synergistic-actions-of-vitamin-d-on-metformin-and-insulin-in-patients-with-diabetes-mellitus-type-2-a-c-41168.html
- https://pmc.ncbi.nlm.nih.gov/articles/PMC3205227/
- https://www.aging-us.com/article/100472/text
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Metformin improves VDR sensitivity and efficacy - 2024 (Vitamin D helped 14 million COVID patients)
Pharmacological evaluation of vitamin D in COVID-19 and long COVID-19: recent studies confirm clinical validation and highlight metformin to improve VDR sensitivity and efficacy
Inflammopharmacology Volume 32, pages 249–271, (2024)
Adel A. Gomaa, Yasmin A. Abdel-Wadood, Romany H. Thabet & Ghada A. Gomaa
Nearly four years after its first appearance, and having gone from pandemic to endemic, the SARS-CoV-2 remains out of control globally. The purpose of this study was to evaluate the clinical efficacy of vitamin D (VD) in COVID-19 and long COVID-19, explain the discrepancy in clinical outcomes and highlight the potential impact of metformin on VD efficacy in recent articles. Articles from January 2022 to August 2023 were selected for this review. The objective of this study was achieved by reviewing, analyzing, and discussing articles demonstrating (1) the mechanism of action of VD (2) observational or randomized clinical trials (RCTs) that support or not the beneficial clinical effects of VD in COVID-19 or long COVID. (3) genetic and non-genetic reasons for the variation in the effects of VD. Articles were collected from electronic databases such as PubMed, Scopus, MEDLINE, Google Scholar, Egyptian Knowledge Bank, Science Direct, and Cochrane Database of Systematic Reviews.
Twenty three studies conducted in vitro or in animal models indicated that VD may act in COVID-19 through protecting the respiratory system by
- antimicrobial peptide cathelicidins,
- reducing lung inflammation,
- regulating innate and adaptive immune functions and
- up regulation of autophagy gene activity.
Our review identified 58 clinical studies that met the criteria.
The number of publications supporting a beneficial clinical activity of VD in treating COVID-19 was 49 (86%), including 12 meta-analyses.
Although the total patients included in all articles was 14,071,273, patients included in publications supporting a beneficial role of VD in COVID-19 were 14,029,411 (99.7%).
Collectively, extensive observational studies indicated a decisive relationship between low VD levels and the severity of COVID-19 and mortality outcomes. Importantly, evidence from intervention studies has demonstrated the effectiveness of VD supplements in treating COVID-19. Furthermore, the results of 4 observational studies supported the beneficial role of VD in alleviating symptoms of long COVID-19 disease. However, eight RCTs and one meta-analysis of RCTs may contain low-grade evidence against a beneficial role of VD in COVID-19. Twenty-five articles have addressed the association between VDR and DBP genetic polymorphisms and treatment failure of VD in COVID-19.
Impaired VDR signaling may underlie the variability of VD effects as non-genetic mechanisms.
Interestingly, in recent studies, metformin has a beneficial therapeutic role in COVID-19 and long COVID-19, possibly by
- improving AMPK signaling of the VDR and
- enhancing the efficacy of the VD.
In conclusion, evidence has been significantly strengthened over the past 18 months, with several meta-analyses and RCTs reporting conclusive beneficial effects of VD supplementation against COVID-19 and highlighting metformin to improve VDR sensitivity and efficacy in treating COVID-19 and long COVID-19.
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VitaminDWiki - Vitamin D Receptor activation can be increased in many ways
Resveratrol, Omega-3, Magnesium, Zinc, Quercetin, non-daily Vit D, Curcumin, Berberine, intense exercise, Butyrate Sulforaphane Metflormin (Kidney) Ginger, Essential oils, etc Note: The founder of VitaminDWiki uses 10 of the many VDR activators
Metformin fights COVID (Metformin $121, Vitamin D $10 per life saved)
https://c19early.org/mfmeta.html
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