Vitamin D separately helps X or COVID, should help X with COVID (example: diabetes) – March 2022

An Overview of Systematic Reviews of the Role of Vitamin D on Inflammation in Patients with Diabetes and the Potentiality of Its Application on Diabetic Patients with COVID-19

Int. J. Mol. Sci. 2022, 23, 2873. https://doi.org/10.3390/ijms23052873
Christiano Argano , Raffaella Mallaci Bocchio 1, Marika Lo Monaco 1, Salvatore Scibetta 1, Giuseppe Natoli 1, Attilio Cavezzi , Emidio Troiani and Salvatore Corrao 1A*

• Department of Internal Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy; chargano at yahoo.it (C.A.); raffaellamallacibocchio at gmail.com
• (R.M.B.); marika.lomonaco at hotmail.it (M.L.M.); salvusxyz at gmail.com (S.S.); peppenatoli at gmail.com (G.N.)

Eurocenter Venalinfa, 63074 San Benedetto del Tronto, Italy; info at cavezzi.it

• Primary Care and Territorial Health Unit, Social Security Institute, 47893 Cailungo, San Marino; emidio.troiani at iss.sm
• Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties [PROMISE], University of Palermo, 90127 Palermo, Italy

Correspondence: s.corrao at tiscali.it or salvatore.corrao at unipa.it; Tel.: +39-091-655-2065;

Abstract:

Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.
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PDF - Vitamin D

Vitamin D, a secosteroid hormone, regulates calcium and phosphate homeostasis but also cell proliferation and differentiation. It plays a vital role in keeping the mineralized skeleton healthy, and it also plays a crucial function in the response of the immune system—[83,84]. Experimental and animal studies have shown, firstly, that vitamin D has important biological activities on the innate and adaptive immune system and, secondly, that the administration of vitamin D changes the onset and progression of various immune-factor diseases [85]. Humans get their vitamin D from sunlight, diet and supplements. The two main forms are: vitamin D2 or ergocalciferol and vitamin D3 or cholecalciferol. After entering the circulation, vitamin D (D expresses both vitamin D2 and D3) is metabolized by vitamin D-25-hydroxylase (CYP2R1) in the liver to 25-hydroxyvitamin D or calcifediol [25 (OH) D]. 25 (OH) D is further metabolized, mainly in the kidneys, by the enzyme 25-hydroxyvitamin D-1a-hydroxylase (CYP27B1) into the active form, 1,25-dihydroxy vitamin or calcitriol (CT) [1,25 (OH)2 D] [84,86]. Then, 1,25 (OH)2 D employs its physiological functions by binding to the vitamin D receptor (VDR) in the cytoplasm of cells, stimulating the heterodimerization of the VDR with the retinoid X receptor (RXR), forming a VDR-RXR-hormone complex [15]; in the nucleus, it leads to the up- or downregulation of a multitude of genes [84]. Kidneys are the primary site of the conversion of 25 (OH) D to systemically bioavailable 1,25 (OH)2 D. CYP27B1 is also expressed by many other tissues, including activated macrophages, parathyroid glands, microglia, breast, colon and keratinocytes, wherein 1,25 (OH)2 D is produced and exercises its autocrine and paracrine function [83,85,87].
During an infection, macrophages and monocytes are recruited to the inflammatory site; the exposure to inflammatory cytokines expresses CYP27B1, which converts 25 (OH) D to 1,25 (OH)2 D [88]. Then, 1,25 (OH)2 D develops the antimicrobial activities of macrophages and monocytes. Furthermore, 1,25 (OH)2 D suppresses the expression of toll-like receptors on monocytes and inhibits the production of some inflammatory cytokines such as IL-2, IL-6 and IL-17 [85,89,90]. Experimental studies have also shown that natural killer (NK) cell differentiation and function can be modulated by 1,25 (OH)2 D administration. At present, the data regarding the influence of 1,25 (OH)2 D on NK cells are still inconsistent [91-93].
Through multiple genomic and extragenomic pathways, numerous experimental studies have demonstrated that vitamin D and its metabolites modulate endothelial function and vascular permeability [94]. Other studies have indicated that 1,25 (OH)2 D3 is a transcriptional regulator of endothelial nitric oxide synthase (eNOS). This causes the upregulation of eNOS gene expression and consequently, an increase in endothelial nitric oxide production [93,95,96]. In local and systemic inflammation, vitamin D and its metabolites employ pleiotropic effects on vascular endothelium that are protective against vascular dysfunction and tissue damage [97,98]. Vitamin D may also activate hepcidin-antagonist pathways, regulating the hepcidin-ferroportin axis, which can be of help in COVID-19, for which hyperferritinemia is one of the major negative prognostic factors [20]. Vitamin D3 may also have an anticoagulant effect, in contrast to cholecalciferol insufficiency, which may be pro-thrombotic [99]. Recent studies showed that, in intensive care patients, 100,000 IU/day of cholecalciferol for five days resulted in higher and lower levels of hemoglobin and hepcidin, respectively. Cholecalciferol showed upregulatory epigenetic action on a few antioxidant systems too [100].
It was observed that a drastic shift from the proinflammatory state to a more regulated immune-inflammatory activity is achieved as a result of the local production of 1,25(OH)2D by monocytes/macrophages [101]. This is considered one of the reasons why vitamin D might exert protective effects against autoimmune diseases. Other studies have also demonstrated that a decreased CD4/CD8 ratio was associated with low 25(OH)D levels [102] and that the administration of 5000-10,000 IU of vitamin D3 was attributable to an increase in the CD4/CD8 ratio, reflecting immune regulation [103,104].
As regards B lymphocytes, inactive B lymphocytes do not have VDRs but only upregulate their VDR expression when they are activated to proliferate with mitogens [105]. Furthermore, 1,25(OH)2D inhibits immunoglobulin synthesis and therefore could potentially interfere with the immune system, and 1,25(OH)2D also regulates B-cell activity. The hyperactive state of 1,25(OH)2D appears to attenuate the immunoglobulin immune response through a variety of mechanisms [105-109].
By controlling B cell activity and the transformation of B cells into plasma cells, 1,25(OH)2D contributes to a reduction in autoantibody production, resulting in a reduced risk of antibody-mediated autoimmune disorders [99,104,105,110].

PDF - The Link among Diabetes, Vitamin D and COVID-19 Pandemic

It is well-known that people with diabetes are at higher risk of infections [111,112]. Diabetes is characterized by a hyperglycemic environment that promotes immune dysfunction through a variety of ways. In particular, in patients with DM, monocytes and mononuclear cells secrete less interleukin 1 (IL-1) and IL-6 when stimulated by lipopolysaccharide [113,114]. The low production of interleukins seems to be the result of inherent defects [113,115]. Hyperglycemia is also characterized by the reduced mobilization, chemotaxis and phagocytic activity of polymorphonuclear leukocytes [114,116,117]. A hyperglycemic environment blocks antibacterial function by inhibiting glucose 6-phosphate dehydrogenase (G6PD), increases the apoptosis of polymorphonuclear leukocytes and reduces the migration of polymorphonuclear leukocytes through the endothelium [114]. A reduction in C4 is associated with polymorphonuclear dysfunction and reduced cytokine production [111,113]. In addition, a hyperglycemic environment will increase intracellular glucose levels and then the utilization of NADPH as a cofactor for metabolism. The reduction of NADPH levels prevents the regeneration of molecules that play a key role in the cellular antioxidant mechanism, thus increasing sensitivity to oxidative stress. When glycosylated hemoglobin (HbAlc) is more than 8.0%, the proliferation function of CD4 T lymphocytes and their response to antigens by the altered expression of cellular adhesion molecules are affected [114]. Moreover, the virulence of different pathogens can be increased by hyperglycemia [116,117].
Concerning SARS-CoV-2 infection, clinical reports found DM to be one of the most-common comorbidities present in patients exhibiting a more severe course of the disease [118]. Generally, the susceptibility to the viral action seems to depend mainly on the typology/expression of the host cell receptors and on the affinity of the spike with these receptors. Interestingly, diabetic (and obese) patients show an overexpression of CD147 receptors [20], of ACE2 molecules [119] and, especially, the altered glycosylation of all membrane receptors [120,121]. Lastly, hepcidin axis upregulation has been detected in diabetic patients [122], which reinforces the likelihood of intracellular ferritin overconcentration in these individuals.
Overall, this altered profile of cell membrane receptors in DM may be one of the main factors explaining the higher susceptibility of these patients to COVID-19.
A link between hyperglycemia and ACE2r levels and the severity of COVID-19 disease has been documented, probably due to the changes in ACE2r glycosylation and viral spike protein glycosylation. Both may be caused by uncontrolled hyperglycemia, which may modify the binding of the viral spike protein to ACE2r and the degree of immune response to the virus [123].
Elevated blood glucose levels can directly increase the glucose concentration in airway secretions [124]. In uncontrolled hyperglycemia, high and abnormally glycosylated cell receptors in the lungs, nasal airways, tongue and oropharynx may also serve as increased SARS-CoV-2 virus binding sites, resulting in a higher trend of COVID-19 infection and more serious forms of the disease [123]. Glycemic control could reduce the levels of glycosylated ACE2r target in the lung, decreasing the number of glycosylated viral binding sites and possibly ameliorating inflammation and the symptoms of COVID-19 disease [123]. Hyperglycemia may also affect pulmonary function, and this effect could be linked to ACE2r overexpression in the lungs of diabetics
[19].
In patients with diabetes, higher circulating glucose levels will result in a higher percentage of glycated hemoglobin. SARS-CoV-2 surface proteins seem to bind to and potentially impair the heme molecule within red blood cells. In this way, a separation of iron from the molecule to form porphyrin occurs, determining in red blood cells an altered oxygen and carbon dioxide carriage, with consequent possible systemic alterations induced by free heme circulation [20,125].
Whereas diabetics and older subjects have more glycated hemoglobin, they may be preferentially affected by SARS-CoV-2 binding and dissociation of iron from heme to form porphyrins, and another receptor (CD147 or basigin) might be involved [49]. Affecting overall hemoglobin functionality, DM may alter oxygen transportation capacity, which may significantly impact the hypoxia patterns of these patients. Different studies reported that diabetic patients have low 25(OH)D levels, which may be due to impaired liver and kidney metabolism of vitamin D, reduced dietary vitamin D intake and decreased intestinal absorption of vitamin D caused by diabetic autonomic neuropathy [126-128]. In addition, it has been reported that low circulating 25(OH)D levels are associated with poor blood glucose control in diabetic patients. Prospective studies have shown that vitamin D deficiency may increase the risk of fasting blood glucose impaired and diabetes [129-131]. Furthermore, a clear association between hypovitaminosis D, obesity and diabetes mellitus, factors known to increase COVID-19 severity risks, have been widely recognized [126,127,132,133].
It worth to outline that vitamin D deficiency has been hypothesized to predispose individuals to SARS-CoV-2 infection and to increase COVID-19 severity. According to Di Filippo et al. [132], patients suffering from vitamin D deficiency and hyperglycemia were at a higher risk of severe COVID-19, higher inflammatory response and worse disease outcomes.
It was estimated that about 1 billion people worldwide have low vitamin D levels, and this is detected in all ethnicities and age groups [134]. Moreover, a significantly higher prevalence of vitamin D deficiency is reported in DM2 (83.5%) compared to normoglycemic controls in a north Indian community [126]. Tecilazich and colleagues found low 25(OH)D levels in diabetic patients with retinopathy [134], suggesting that hypovitaminosis D may worsen the predisposition of patients with diabetes to the microvascular damage typical of COVID-19. It was shown that supplementation with vitamin D may improve glucose metabolism control by reducing insulin resistance and stimulating p-cell function [135,136], especially in patients with poor baseline blood glucose control [137].
A recent cross-sectional study showed that there is a statistically negative correlation between 25(OH)D levels and the homeostasis model assessment of insulin resistance, but this association was only found in the female population and not in men [138]. Moreover, some studies have suggested that vitamin D treatment may slow the progression to diabetes in patients either at high risk of diabetes or with prediabetes, specifically in those with low baseline 25(OH)D levels [139].
Low 25(OH)D levels may be a predisposing factor in the bidirectional interrelation between diabetes and COVID-19, increasing from one side the susceptibility of diabetics to the infection, from the other side promoting the diabetogenic effect of COVID-19 in terms of endothelial dysfunction and microvascular complications.
Obesity and overweight may equally play a role in COVID-19. High BMI and altered body composition, with increased adiposity, are reported as independent risk factors for greater disease severity and poor prognosis in COVID-19 patients [139,140]. Interestingly, low levels of 25(OH)D were frequently reported in obese and overweight patients, being inversely related to BMI and adiposity [132,141], negatively influencing skeletal and muscle health, with a resulting increased predisposition to an obese osteosarcopenic phenotype [142,143]. In fact, BMI has also been reported to predict resistance to vitamin D [144]. A possible direct relationship between vitamin D status, adiposity, age and COVID-19 severity has been previously hypothesized. In fact, aging and fat accumulation may decrease vitamin D bioavailability and efficacy [29]. A low vitamin D status is present in obese patients and patients with metabolic syndrome, and these conditions are associated with reduced hepatic 25-hydroxylation of vitamin D. Experimental studies showed that CYP2R1 (the major vitamin D-25 hydroxylase) is lower in the livers of obese mice in comparison with normal mice [145]. According to Ekwaru and colleagues obese and overweight subjects had serum 25(OH)D significantly lower than normal weight people and vitamin D supplementation would be 2 to 3 times higher and 1.5 times higher for obese and overweight subjects respectively, in comparison with normal weight subjects [146].
A recent study showed that a strong relationship exists among vitamin D, glycemia and BMI in COVID-19 subjects [147]. Vitamin D deficiency could be identified as a common pathophysiological mechanism involved in the detrimental effect of hyperglycemia and adiposity on disease severity.
Overall, a clear-cut effect of vitamin D serum level on COVID-19 incidence and prognosis was demonstrated [30], which may be explained through the several beneficial effects of this pre-hormone on several biochemical pathways that may putatively contrast the viral invasiveness.
This umbrella review demonstrated that vitamin D supplementation in subjects with diabetes leads to improved circulating inflammatory biomarkers, representing an adjuvant therapy for COVID-19 patients with diabetes and a vitamin D status deficiency. It can therefore be affirmed that, based upon this umbrella review, a strong rationale exists for the therapeutic administration of supplemental vitamin D in order to reduce COVID-19 respiratory complications or prevent, in case of infection, a severe form of COVID-19.
The major strength of this analysis is represented by the resolution of the clinical heterogeneity problem. The presence of clinical heterogeneity across studies is related to the different characteristics and health conditions of the participants included. In this sense, we considered only patients affected by diabetes and according to the different types of diabetes. In addition, our analysis also highlights the heterogeneity of treatments [29-34]. In fact, heterogeneity exists in doses of the vitamin administerd to the target population. This study has a limitation. The umbrella review makes a qualitative assessment and compiles all the evidence from existing reviews on a topic through to a specified date. Through extensive searching, an additional thirteen randomized clinical trials [RCTs] are available at this time and, obviously, had not been considered in this umbrella review. For this reason, further studies are necessary for the evaluation of these RCTs. In this sense, it must be outlined that, according to Sabico et al. [148], oral supplementation with vitamin D3 reduces the time to recovery for cough and ageusia among patients with COVID-19, highlighting the beneficial effects of vitamin D supplementation against COVID-19. On the contrary, it is worth it to outline that recent studies showed that long-term supplementation with vitamin D(3) did not reduce IL-6, hsCRP or NT-proBNP in patients with type 2 diabetes [149]; additionally, high-dose vitamin D supplementation did not improve biomarkers of glycemia, inflammation, neurohormonal activation or lipids [150].

PDF - Conclusions

Our overview of systematic reviews concerning vitamin D's role in the inflammatory processes, highlighted a series of documented interactions among this molecule and a large series of cell metabolic pathways involved in DM and the potential application in patients with diabetes and COVID-19. Current evidence supports the benefits of vitamin D supplementation for managing or treating both of these pathological conditions. Most of the literature reports showed that vitamin D supplementation significantly reduce CRP in diabetic patients, while contrasting data are available about IL-6. Further studies should highlight the optimal treatment doses for the maximum benefit to patients. Meanwhile, vitamin D deficiency should be corrected, since vitamin D supplementation is safe, and it results in potential benefits on the cytokine storm by reducing the severity of several respiratory complications of COVID-19.

CDC identified increased COVID risk for 26 health conditions, ALL of which are associated with low Vitamin D

26 health factors increase the risk of COVID-19 – all are proxies for low vitamin D includes

• Mental disorders such as Schizophrenia was added by CDC Oct 2021

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Vitamin D Life - VIRUS and Diabetes

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Vitamin D Life - Overview Diabetes and vitamin D contains

• Diabetes is 5X more frequent far from the equator
• Children getting 2,000 IU of vitamin D are 8X less likely to get Type 1 diabetes
• Obese people get less sun / Vitamin D - and also vitamin D gets lost in fat
• Sedentary people get less sun / Vitamin D
• Worldwide Diabetes increase has been concurrent with vitamin D decrease and air conditioning
• Elderly get 4X less vitamin D from the same amount of sun
      Elderly also spend less time outdoors and have more clothes on
• All items in category Diabetes and Vitamin D 537 items: both Type 1 and Type 2

Vitamin D appears to both prevent and treat diabetes

• Appears that >2,000 IU will Prevent
• Appears that >4,000 IU will Treat , but not cure
• 90% less T2 Diabetes in the group having lots of Vitamin D
• Appears that Magnesium helps both Prevention and Treatment
• Many diabetics would be better treated if Gut-Friendly Vitamin D were used

Number of articles in both categories of Diabetes and:
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• Dark Skin 24;   Intervention 56;   Meta-analysis 38;   Obesity 35;  Pregnancy 44;   T1 (child) 39;  Omega-3 11;  Vitamin D Receptor 24;  Genetics 12;  Magnesium 27    Click here to see details

Some Diabetes studies

• Type 2 Diabetes treated by Vitamin D (often 50,000 IU weekly) – meta-analysis July 2023
• Diabetic inflammation synergistically decreased by Vitamin D and exercise – RCT June 2022
• Incidence of Type-2 Diabetes increased 3X in 30 years (by the way, Vitamin D helps) – July 2022
• Vitamin d treats Type II Diabetes in many ways (14 article review) - Sept 2021
• T2 Diabetes 30 percent more likely if poor Vitamin D Receptor – meta-analysis of 47 studies – July 2021
• Diabetes helped somewhat by weekly 50,000 IU of vitamin D (5 ways to improve) – RCT Aug 2021

50 ng of Vitamin D fights Diabetes

• Saudi study defines normal Vitamin D level to be 50 to 70 ng (diabetes, etc.) - June 2020
• Diabetes 5X less likely if more than 50 ng of Vitamin D – April 2018

T1 Diabetes

• T1 Diabetes 3X lower risk if high vitamin D (over 40 ng) – Meta-analysis Nov 2020
• Type 1 Diabetes is prevented and treated by Vitamin D – review of 16 studies – Sept 2019
• Type 1 Diabetes prevention with Vitamin D and Omega-3 – Symposium April 2019

Pre-Diabetes

• 4X reduction in prediabetes progressing to T2D if more than 50 ng of vitamin D – RCT March 2023
• Prediabetes reduced by weekly 60,000 IU of Vitamin D – RCT Jan 2021
• Prediabetes 1.5 X more likely to go away if take Vitamin D – meta-analysis July 2020

Diabetes, Metabolic Syndrome and Magnesium - many studies

Vitamin D Life Example: Obesity and Virus

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Vitamin D Life Example: Cardiology and Virus

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Vitamin D Life – COVID-19 treated by Vitamin D - studies, reports, videos

As of March 31, 2024, the Vitamin D Life COVID page had:  trial results,   meta-analyses and reviews,   Mortality studies   see related:   Governments,   HealthProblems,   Hospitals,  Dark Skins,   All 26 COVID risk factors are associated with low Vit D,   Fight COVID-19 with 50K Vit D weekly   Vaccines   Take lots of Vitamin D at first signs of COVID   166 COVID Clinical Trials using Vitamin D (Aug 2023)   Prevent a COVID death: 9 dollars of Vitamin D or 900,000 dollars of vaccine - Aug 2023
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