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Review

The Effects of Vitamin D on Preventing Hyperglycemia and a Novel Approach to Its Treatment

by
Suchitra Monapati
1,*,
Pavani Kaki
2,
Mary Stella Gurajapu
2,
Prathibha Guttal Subhas
3 and
Harinadha Baba Kudipudi
4
1
Department of Pharmaceutical Chemistry, Narayana Pharmacy College, Nellore 524004, India
2
Department of Pharm.D Narayana Pharmacy College, Nellore 524004, India
3
Department of Pharmacognosy, Bapuji Pharmacy College, Davanagere 577004, India
4
Department of Pharmaceutical Analysis, Narayana Pharmacy College, Nellore 524004, India
*
Author to whom correspondence should be addressed.
Drugs Drug Candidates 2023, 2(4), 923-936; https://doi.org/10.3390/ddc2040046
Submission received: 30 August 2023 / Revised: 10 November 2023 / Accepted: 21 November 2023 / Published: 28 November 2023
(This article belongs to the Section Clinical Research)
Browse Figures
Review Reports Versions Notes

Abstract

:
The dietary reference levels for vitamin D were established with an emphasis on its role in bone health; however, with the identification of vitamin D receptors in all body tissues novel associations with other metabolic disorders, such as diabetes, are being researched. Aside from its standard function as the main regulator of calcium absorption, vitamin D also controls the calcium pool, mediates the activity of beta cell calcium-dependent endopeptidases, encourages the conversion of proinsulin to insulin, increases insulin output, and raises insulin activity in peripheral insulin target tissues. Both immune cells and pancreatic beta cells include vitamin D receptors. A deficiency of vitamin D causes glucose intolerance and affects insulin secretion. Different pathogenic characteristics of the disease are linked to a number of vitamin D-related genes. It has been proven that vitamin D supplementation lowers the risk of type 1 and type 2 diabetes and its associated problems. In this article, we discussed a few prospective clinical trials on vitamin D that are necessary to clearly demonstrate the role of vitamin D in the prevention and management of diabetes.

1. Introduction

Diabetes is a chronic metabolic disorder characterized by elevated levels of glucose in the blood. It occurs when the body either does not produce enough insulin or cannot effectively use the insulin it produces. Insulin is a hormone produced by the pancreas that regulates the absorption and utilization of glucose by cells for energy [1]. The word diabetes mellitus, however, was first used by the Greek doctor Aertaeus. Diabetes, which means “to pass through” in Greek, and mellitus, which denotes sweetness and is derived from the Latin word for honey, are two words that go together. Weight loss and polyuria are signs related to diabetes which were initially noted by the Egyptians. With roughly a single fatality every ten seconds, diabetes is a major contributor to long-term illness and early mortality. It also claims more lives each year than HIV/AIDS [2].
There are three main types of diabetes: type 1 which results from a lack of insulin due to an autoimmune attack, type 2 which is due to resistance to the effects of insulin, and the pancreas may not produce enough insulin to compensate, and Gestational diabetes which may develop during pregnancy [3]. According to the International Diabetes Federation (IDF), the number of people living with diabetes has been increasing significantly over the past few decades, primarily driven by the rise in type 2 diabetes. If current trends continue, it is expected that the number of individuals with diabetes will continue to grow in the coming years. Factors contributing to the increase in diabetes cases include aging populations, sedentary lifestyles, unhealthy diets, obesity, and urbanization. These factors, along with other demographic and socioeconomic changes, can influence the prevalence of diabetes in different regions.
Based on the IDF 2000, the United States (17.7 million) and China (20.8 million) had the largest global prevalence of diabetes mellitus, with India (31.7 million) having the highest rate. As of 2030, it is predicted that 79.4 million people in India, 42.3 million in China, and 30.3 million in the US will have diabetes mellitus. Diabetes is predicted to affect 2 billion people worldwide by 2030, up from 171 million in 2000 [4,5]. Given the potential cost that diabetes might have on the nation, India today faces an unclear future. It is anticipated that by 2045, there will be 783 million people affected. In low- and middle-income nations, 3 out of 4 adults with diabetes reside [6]. It is important to note that projections and estimates about future diabetes prevalence can vary based on numerous factors, including changes in population demographics, healthcare policies, and advancements in diabetes prevention and management. Symptoms and treatments are included in Figure 1. The objective of this review was to summarize the need for studying the role of vitamin D in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) and to examine the data from case studies that evaluated the effects of vitamin D supplementation in this setting. This was done in an effort to separate the currently available evidence that is either against or in favor of a role for vitamin D in the prevention and/or management of changes in glucose metabolism.
Vitamin D, also known as the “cholecalciferol” has recently gained new attention due to its connections to a variety of diseases, including diabetes, cancer, and heart disease. Vitamin D is a superstar when it comes to health, according to a plethora of research articles that keep appearing in the literature. This article’s goal is to provide a concise summary of the most recent findings about vitamin D and diabetes. Vitamin D is a fat-soluble vitamin that plays a crucial role in several physiological processes within the body. The primary functions of vitamin D are to regulate the absorption of calcium and phosphorus from the intestines, promote bone health, and support the proper functioning of the immune system.

1.1. Preface of Vitamin D

In 1923, Goldblatt and Soames became the first to recognize and define vitamin D (VD) [7]. The body naturally produces this crucial vitamin when exposed to sunlight. Ergocalciferol (VD2) (Figure 2) and cholecalciferol (VD3) (Figure 3) are secosterols that are included in the category of vitamin D. While VD3 is largely produced in the skin from 7-dehydro cholesterol by photochemical synthesis using UVB light from sunshine and can also be found in animal-based meals, plant sterols (ergosterol) are exposed to UVB radiation during the commercial manufacturing of VD2. [8].

1.2. Sources of Vitamin D

Vitamin D can be obtained through two main sources: an exposure to sunlight and dietary intake. When skin is exposed to sunlight, it synthesizes vitamin D3 (cholecalciferol) from a precursor molecule present in the skin. Sun exposure is related to seasonal positions, time of day, atmospheric components, clothing, sunscreen, and skin pigmentation. A substance called 7-dehydrocholesterol in the skin absorbs UVB rays from the sun and transforms them into pre-vitamin D3 when the skin is exposed to sunlight. By being isomerized by the body’s warmth, this pre-vitamin D3 eventually becomes vitamin D3. The name “cholecalciferol” is another name for vitamin D3 [9]. It is important to note that while sunlight exposure is a natural source of vitamin D, excessive sun exposure without proper protection can increase the risk of skin damage and potentially lead to skin cancer. Therefore, it is recommended to maintain a balance between safe sun exposure and obtaining vitamin D through dietary sources or supplements. With the exception of fatty fish and egg yolks, vitamin D levels in the human diet are typically low. Whereas vitamin D3 is largely derived from animal sources, vitamin D2 is produced by fungi and a limited quantity of plants and is found in nutrients that have been supplemented with vitamin D or dietary supplements. Fortified fish liver oils and fatty fish flesh are the finest sources. Smaller levels can be found in beef liver, cheese, and egg yolks. Vitamin D2 is present in some mushrooms, and some mushrooms used for commercial purposes have higher levels of D2 due to intentional exposure to strong ultraviolet radiation. Cereals and dairy products are just two examples of foods and supplements that include additional vitamin D.
For the daily intake of vitamin D across India in healthy persons, men and women should each obtain 600 IU (15 mcg) of vitamin D daily starting at the age of 19, while seniors should get 800 IU (20 mcg) daily. The daily intake level that is least likely to have a detrimental effect on health is known as the Tolerable Upper Intake Level, or UL. For adults and kids ages 9 and older, the UL for vitamin D is 4000 IU (100 mcg) [10]. Vitamin D levels and its corresponding health conditions are included in the following Table 1.
Other sources include red meat and fortified meals including various fat spreads and breakfast cereals [11].

2. Role of Vitamin D in Type 1 Diabetes Mellitus

A lack of insulin is caused by a complex autoimmune process that destroys pancreatic islet cells and causes type 1 diabetes, also known as insulin-dependent diabetes mellitus. The identification of auto-antibodies against islet β-cells and the invasion of these cells by T cells, B cells, and macrophages have shed light on the autoimmune character of type 1 diabetes [12]. Patients with type 1 diabetes were more likely to be vitamin D deficient by 15% to 90% [13]. Vitamin D is known to have immunomodulatory effects and plays a crucial role in regulating the immune system. It has been hypothesized that vitamin D deficiency or insufficiency may contribute to the development of autoimmune diseases including type 1 diabetes. Vitamin D may help regulate immune responses, reduce inflammation, and modulate the immune system’s attack on pancreatic beta cells, which produce insulin. There is proof that vitamin D is crucial for islet cell survival, may help with islet cell graft survival, and enhances insulin production. It also appears to be vital for the prevention of islet cell death. Vitamin D receptors have been found in pancreatic beta cells which are responsible for producing insulin. Research studies have suggested that vitamin D may support beta cell function, enhance insulin secretion, and promote beta cell survival. Maintaining adequate vitamin D levels could potentially preserve beta cell function and protect against the progression of type 1 diabetes. Beta cell function was found to be negatively impacted by low vitamin D levels. It has been demonstrated that taking vitamin D regularly in adolescence lowers the incidence of type 1 diabetes [14]. It has long been believed that pancreatic beta cells being assaulted by autoreactive T lymphocytes causes type 1 diabetes (T1D) [15]. It has been demonstrated that calcitriol and its analogues block IL-1-induced beta cell function inhibition and Interferon-gamma (IFN-y) stimulated beta cell expression of Major Histocompatibility Complex (MHC) class I and class II molecules [16] (Figure 4).
In individuals already diagnosed with type 1 diabetes, vitamin D supplementation may have beneficial effects on glycemic control. Some studies have suggested that vitamin D supplementation, along with standard diabetes management, could improve insulin sensitivity, reduce insulin requirements, and potentially lower the risk of diabetes-related complications. A few clinical studies are listed in the below Table 2.

3. Role of Vitamin D in Type 2 Diabetes Mellitus

Insulin resistance and irregular insulin secretion are two traits of type 2 diabetes. The seasonal variation in glycemic control in type 2 diabetes patients, which is claimed to be worse in the winter, may be caused by the prevalence of hypovitaminosis D as a result of less sunshine in winter and raises questions about the role of vitamin D in the disease. A number of studies have shown the relationship between vitamin D and the prevalence of type 2 diabetes. According to studies, the pancreas has receptors for the active vitamin D metabolite 1,25-dihydroxyvitamin D, which is necessary for the pancreatic beta cells to produce and secrete insulin [21]. A high rate of hypovitaminosis D was recorded among women with type 2 DM. Vitamin D shows its effects majorly in two ways: by directly increasing intracellular calcium concentration via non-selective voltage-dependent calcium channels, vitamin-D causes beta cell insulin secretion, and it involves the activation of beta cell calcium-dependent endopeptidases that results in the conversion of proinsulin to insulin [22] (Figure 4). Numerous studies have suggested that vitamin D has a significant role in the functional control of the endocrine pancreas, notably the beta cells. Beta cells contain 1,25(OH)2D3 receptors but they also include calbindin-D28k, a protein that is a vitamin D-dependent calcium-binding protein, which is an effector in the vitamin D pathway. Calbindin-D28K expression has been demonstrated to shield beta cells from cytokine-mediated cell death, lowering the risk of type 2 diabetes. A few clinical studies are reported in the following Table 3.

4. Role of Vitamin D in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is characterized by abnormal hyperglycemia brought on by pancreatic cell malfunction in pregnant women without known type 2 diabetes mellitus. Preeclampsia, a high chance of caesarean birth, and a lifelong elevated risk of developing metabolic syndrome and type 2 diabetes mellitus are just a few of the major negative effects this condition has on pregnant women [27]. An irregular glucose metabolism is linked to vitamin D insufficiency and epidemiological studies have revealed that women who acquire GDM are more likely to be vitamin D-deficient [28]. Gestational diabetes is significantly reduced when high-risk pregnant women take vitamin D supplements in the first and second trimesters [29]. The following are some potential mechanisms for the association between vitamin D and gestational diabetes: vitamin D directly influences the activity of pancreatic cells by the attachment of 1,25(OH)2D3 to the vitamin D receptors and it also regulates the blood’s glucose rate. [30]. A few clinical trials are included in the following Table 4.

5. Applications of Vitamin D

According to studies, having enough vitamin D levels lowers parathyroid hormone (PTH) levels, which over time may encourage weight loss and lower the likelihood of obesity, a significant risk factor for type 2 diabetes [35]. Getting enough vitamin D may help with weight loss, reduce body fat, and prevent weight gain [36]. Vitamin D has numerous effects outside of the skeletal system and is crucial for sustaining cardiovascular and bone health. The heart and blood vessels contain numerous vitamin D-related components and vitamin D insufficiency has been associated to a number of cardiovascular diseases (CVDs) [37]. In pregnant women with low vitamin D levels, vitamin D supplements may promote fetal growth and lower the risk of gestational diabetes, preeclampsia, preterm birth, and small-for-gestational-age birth. Children of mothers with adequate vitamin D levels have fewer enamel abnormalities, attention deficit and hyperactivity problems, and autism [38]. People also use vitamin D for weak and brittle bones, heart disease [39], asthma, hay fever, and many other conditions. Support from vitamin D lowers insulin resistance and improves blood pressure profiles [40]. Women with polycystic ovary syndrome (PCOS) may benefit from vitamin D and calcium supplements in addition to metformin therapy in terms of menstrual regularity and ovulation [41]. There is some proof that a vitamin D shortage might result in hair loss and other issues with the hair. Because vitamin D encourages the growth of hair follicles, the condition of the hair may be impacted if the body is deficient in it [42]. Dryness, acne, psoriasis, eczema, and vitiligo are just a few of the skin diseases that can be treated using vitamin D’s excellent anti-inflammatory qualities [43]. By increasing insulin receptors or the sensitivity of insulin receptors to insulin, as well as by having an impact on peroxisome proliferator-activated receptors (PPAR) and the regulation of extracellular calcium, vitamin D improves insulin sensitivity [44]. A few marketed supplements of vitamin D are included in the following Table 5.

6. An Overview of the Physiology of Vitamin D

Physiology of Vitamin D

Normal levels can be maintained with just the right amount of sun exposure, mostly on the hands and face. Overexposure to sunlight prevents vitamin D toxicity by converting pre-vitamin and vitamin D3 into inactive phytoproducts [45,46]. The vitamin D receptor (VDR), a nuclear receptor hormone, is expressed at a notably high level in the islets [47]. Although the precise mechanism of the VDR’s function as a transcription factor in pancreatic β-cells is not yet understood, it may be crucial for preserving the maturity of β-cells and preventing them from dedifferentiating [48,49]. Rather than being a genuine vitamin, vitamin D is a pre-hormone that is produced in the skin when exposed to sunshine. Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) are the two main forms that are generated by the skin [50,51]. Both types have the same metabolism: UVB light changes 7-dehydrocholesterol in the skin into pre-vitamin D3, which is then transformed into vitamin D3 by a non-enzymatic, heat-dependent mechanism [52].
Alternative sources of vitamin D are necessary to maintain a healthy lifestyle as many people worldwide suffer from vitamin D deficiency [53]. The ability of vitamin D to be absorbed in the colon, liver function, and fat accumulation all affect its bioavailability [54]. Adipose tissue has a high absorption capacity for vitamin D and some scientists propose that this buildup is necessary for the release of vitamin D during periods of decreased synthesis [55]. The vitamin D receptor (VDR), which was discovered and cloned for the first time in 1987, is the binding site for the active form of vitamin D. Since then, more vitamin D functions specific to tissues have been identified and the VDR is broadly dispersed across tissues [56].
The balance between the accessible tissue substrate circulating 25(OH)D concentration and 1,25(OH)2D3 (calcitriol), which is catabolized in islets by 24-hydroxylase, determines whether or not vitamin D is activated in pancreatic β-cells. This balance is independent of PTH. In addition, patients with low calcitriol show a marked decrease in 25(OH)D2, a fluctuation in blood insulin concentration, and poor glucose tolerance. Every ethnic race, including African Americans, Asians, and Europeans, is linked to a high incidence of diabetes in hypovitaminosis. Both the first and second phases of insulin secretion are replenished by supplementing with 1α,25(OH)2D3. 1α,25(OH)2D3 has an indirect function via increasing calcium flux and a direct effect by boosting insulin secretion, as shown in Figure 5.
(i)
Activation: vitamin D3 is first converted by the liver into calcidiol, 25(OH)D, or 25-hydroxyvitamin D. This is the primary form of vitamin D that circulates in the blood and is frequently used to determine one’s vitamin D level. The biologically active form of 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)2D], or calcitriol, is subsequently produced by the kidneys.
(ii)
Regulation: The synthesis and activation of vitamin D are tightly regulated by various factors, including the parathyroid hormone (PTH), calcium levels, and feedback mechanisms. When calcium levels are low in the blood, the parathyroid glands secrete PTH which stimulates the conversion of 25(OH)D into calcitriol in the kidneys. Calcitriol then enhances the absorption of calcium from the intestines and promotes the release of calcium from bones, thereby maintaining calcium homeostasis.
(iii)
Calcium and Phosphorus Absorption: One of the essential functions of vitamin D is to facilitate the absorption of calcium and phosphorus from the intestines. Calcitriol acts on the cells of the small intestine, promoting the synthesis of calcium-binding proteins that aid in the absorption of calcium. It also regulates the transport proteins responsible for the absorption of phosphorus. By enhancing the absorption of these minerals, vitamin D helps maintain optimal levels of calcium and phosphorus in the body, which are vital for bone health, muscle function, and nerve signaling.
(iv)
Bone Health: Vitamin D is crucial for proper bone development and maintenance. It works in conjunction with other hormones, such as the parathyroid hormone and calcitonin, to regulate bone remodeling, which involves the continuous process of bone formation and resorption. Vitamin D helps promote calcium deposition in bones, prevents calcium loss from bones, and ensures optimal mineralization, which contributes to bone strength and density.
(v)
Immune Function: Emerging research suggests that vitamin D plays a role in modulating the immune system. It has been found to regulate the expression of genes involved in immune response, inflammation, and cell growth. Adequate vitamin D levels are associated with a reduced risk of certain autoimmune diseases, such as multiple sclerosis and type 1 diabetes, and may also play a role in preventing respiratory infections and reducing the severity of certain inflammatory conditions.

7. Pharmacokinetics of Vitamin D

The small intestine effectively absorbs both vitamin D forms, D2 (ergocalciferol) and D3 (cholecalciferol). Simple, passive diffusion and an intestinal membrane carrier protein-based mechanism allow for absorption [57]. The main locations for vitamin D storage in humans are adipose tissue and voluntary muscle. In rare cases, the use of radioactively labelled cholecalciferol to trace the pattern of body distribution may be invalidated by pre-existing vitamin D tissue pools [58]. Vitamin D from the skin or oral consumption is metabolized by the liver and other organs into 25OHD, the main circulating form of vitamin D. There are other enzymes with 25-hydroxylase activity, but CYP2R1 is the most significant [59]. Vitamin D3 is primarily excreted into the feces through the bile. The amount of urine excretion seems to be little and no excretion products have been positively identified as of yet [60].

8. Future Perspectives of Vitamin D Related to Hyperglycemia

There was ongoing research into the potential role of vitamin D in the treatment of hyperglycemia. However, it is important to note that medical research is constantly evolving and new developments may have emerged since then. Here is an overview of the potential future perspectives of vitamin D in hyperglycemia treatment based on the research literature.
(i)
Diabetes Prevention: Research suggests adequate vitamin D intake may reduce type 2 diabetes risk. Future studies should investigate the mechanisms and potential use of vitamin D supplementation as a preventive measure for high-risk individuals.
(ii)
Inflammation and Beta Cell Function: Vitamin D is known to have anti-inflammatory properties and chronic inflammation is believed to play a role in the development and progression of type 2 diabetes. Vitamin D may help protect beta cells in the pancreas that produce insulin, and thus preserve their function.
(iii)
Cardiovascular Health: Diabetes and hyperglycemia are associated with an increased risk of cardiovascular complications. Vitamin D may have a beneficial impact on cardiovascular health, reducing the risk of heart disease and related complications in people with diabetes.
(iv)
Combination Therapy: Vitamin D supplementation could potentially be used as an adjunct therapy along with standard treatments for hyperglycemia. It may help enhance the effectiveness of traditional medications, improve overall metabolic control, and reduce the dosage requirements of other medications.
(v)
Individualized Treatment Plans: There is increasing recognition that different subgroups of people with diabetes may respond differently to various treatments. Vitamin D status might be considered as a factor in individualized treatment plans, tailoring interventions based on a person’s vitamin D levels and response to supplementation.
(vi)
Insulin Sensitivity and Glucose Regulation: Vitamin D has been implicated in improving insulin sensitivity, which is crucial for maintaining healthy blood glucose levels. Some studies have suggested that adequate vitamin D levels may help reduce insulin resistance and improve glucose regulation, potentially benefiting individuals with hyperglycemia or diabetes. It is essential to stress that while vitamin D shows promise in the context of hyperglycemia treatment, it should not be seen as a standalone treatment for diabetes or a replacement for established therapies. More research, including large-scale clinical trials, is necessary to fully understand the potential benefits.

9. Conclusions

In conclusion, the role of vitamin D in hyperglycemia appears to be significant as research suggests a link between vitamin D deficiency and impaired glucose metabolism. Diabetes is a serious, perhaps fatal, condition that needs to be closely monitored in order to be adequately controlled with medicine and lifestyle changes. Through the activation of calcium-dependent endopeptidases, vitamin D, the main regulator of calcium homeostasis, enhances insulin exocytosis directly or indirectly. Vitamin D plays a crucial role in regulating insulin secretion and sensitivity and its deficiency may contribute to insulin resistance, leading to elevated blood glucose levels. Studies have shown that maintaining adequate levels of vitamin D through supplementation or exposure to sunlight may help improve glycemic control in individuals with hyperglycemia or diabetes. However, while there is evidence supporting the association between vitamin D and hyperglycemia, more extensive and well-controlled clinical trials are needed to establish a definitive causal relationship. It is essential for healthcare professionals to consider monitoring and addressing vitamin D status in patients with hyperglycemia as part of comprehensive diabetes management strategies. Nonetheless, maintaining a balanced diet, regular physical activity, and appropriate medical interventions remain the cornerstones in the management of hyperglycemia and diabetes.

Author Contributions

Conceptualization and design S.M. and P.K.; data collection: P.K. and M.S.G.; analysis and interpretation of results: S.M., P.K. and M.S.G.; draft manuscript preparation: M.S.G., P.G.S. and H.B.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are thankful to the Principal of Narayana Pharmacy College, Nellore, Andhra Pradesh, and Bapuji Pharmacy College, Davanagere, Karnataka for their immense support during our work.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Marketed products for type 1 and type 2 diabetes mellitus.
Figure 1. Marketed products for type 1 and type 2 diabetes mellitus.
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Figure 2. Chemical structure of vitamin D2 (ergocalciferol).
Figure 2. Chemical structure of vitamin D2 (ergocalciferol).
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Figure 3. Chemical structure of vitamin D3 (cholecalciferol).
Figure 3. Chemical structure of vitamin D3 (cholecalciferol).
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Figure 4. Representation of the mechanism that is altered by vitamin D in both type 1 and type 2 diabetes mellitus.
Figure 4. Representation of the mechanism that is altered by vitamin D in both type 1 and type 2 diabetes mellitus.
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Figure 5. Representation of vitamin-D physiology.
Figure 5. Representation of vitamin-D physiology.
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Table 1. Vitamin D levels and associated health conditions.
Table 1. Vitamin D levels and associated health conditions.
Dose/Amount of the DrugCondition
<10 ng/mLSevere deficiency
10–24 ng/mLMild to moderate deficiency
25–80 ng/mLOptimal levels
>80 ng/mLToxicity possible
Table 2. Case study report related to type 1 diabetes mellitus.
Table 2. Case study report related to type 1 diabetes mellitus.
Study
(Year)		Study AreaStudy DesignFollow Up YearCharacteristic or AgeSample SizeResult
2006–2010Diabetes center of Soa Paulo Federal University, Sao Paulo, BrazilRandomized, double-blind, placebo-controlled trail18 monthsPatients with new onset of type 1 DM38In individuals with newly diagnosed type 1 diabetes, cholecalciferol used as adjuvant therapy in conjunction with insulin is safe, linked to a protective immunologic impact, and slows the decrease of remaining beta cell function. [17].
2017–2019Czech Republic, Netherlands, Spain, SwedenTwo-Arm, multicenter Randomized
Double-blinded
Placebo controlled trial 		15 monthsAge: ≥12 and <25 years, Diabetes Duration: <6 months109Intralymphatic administration of GAD-alum, with oral vitamin D, did not meet the primary endpoint in the full analysis set (treatment effect ratio 1.091 [CI 0.845–1.408]; p = 0.5009). However, in patients carrying HLA DR3-DQ2, there was greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126–2.153]; p = 0.0078) after 15 months compared to the placebo group with the same genotype. Positive trends were observed in several secondary endpoints, and a positive effect was seen in partial remission (insulin dose-adjusted HbA1c ≤9; p = 0.0310). Minor transient injection site reactions were reported [18].
2019–2020Moscow, RussiaProspective Controlled StudyMonthly
Follow up		Adults with T1DM (HbA1c < 8.0%) vs. Conditionally Healthy AdultsT1DM: 25, Control: 49Comparable elevation of 25(OH)D3 levels in both groups after 150,000 IU cholecalciferol; Diabetes group shows slightly higher 25(OH)D3 levels throughout the study since Day 1 (p < 0.05). Baseline differences in free 25(OH)D levels in diabetes group (p < 0.05). Lack of correlation in diabetes group between measured and calculated free 25(OH)D, possibly due to glycosylation of binding proteins affecting affinity constant (r = 0.41, p > 0.05) [19].
2020Rio-de Janeioro, BrazilProspective, Phase II, Open Trial, Pilot study3 monthsMean Age: 26.7 ± 6.1 years13Allogenic ASCs + cholecalciferol without immunosuppression showed stability of CP and mild transient adverse events in recent onset T1D. Lower insulin requirement (0.22 ± 0.17 vs. 0.61 ± 0.26 IU/Kg; p = 0.01) and HbA1c (6.47 ± 0.86 vs. 7.48 ± 0.52%; p = 0.03) in group 1 at T3. Two patients in group 1 became insulin-free for 4 and 8 weeks, and all were in honeymoon at T3 (vs. none in group 2; p = 0.01). CP variations did not differ between groups (−4.6 ± 29.1% vs. +2.3 ± 59.65%; p = 0.83) [20]
Table 3. Case study report related to type 2 diabetes mellitus.
Table 3. Case study report related to type 2 diabetes mellitus.
Study
(Year)		Study AreaStudy DesignFollow Up YearCharacteristic or AgeSample SizeResult
2013IranSingle-blind study8 weeksPatients with type 2 DM, 70 years old100 patientsNotable increases in HOMA-IR, insulin, and serum FPG following vitamin D treatment [23].
2013–2015Sri Guru Ram Das Institute of Medical sciences and Research, Punjab, IndiaOpen-labelled study12 weeksType-2 DM and Vitamin D deficiency50 patientsTreatment with vitamin D improves glycemic status, slows the disease’s course, and lessens its consequences in type 2 diabetes. For type 2 diabetic patients with low vitamin D levels, vitamin D supplements are a safe and effective adjuvant therapy [24].
2018Tertiary care hospital of Indian Armed ForcesRandomized, parallel group, placebo controlled trailMonthly follow upPatients with coexisting type 2 DM and hypovitaminosis D60 patientsIn individuals with type 2 diabetes and concomitant hypovitaminosis D, oral vitamin D treatment improves metabolic parameters and glycemic management [25].
2019CanadaSingle-centre RTC6 monthsParticipants at high risk of diabetes or newly diagnosed type 2 DM96 patientsIncreased peripheral insulin sensitivity and beta cell function [26].
Table 4. Case study report related to gestational diabetes mellitus.
Table 4. Case study report related to gestational diabetes mellitus.
Study (Year)Study AreaStudy DesignFollow Up YearCharacteristic or AgeSample SizeResult
2014IranRandomized Placebo-controlled TrailMonthly follow upPregnant women with GDM (24 weeks’ gestation, 18–40 years of age)56 patientsCalcium and vitamin D supplementation resulted in reduced fasting plasma glucose, serum insulin levels, HOMA-IR, and LDL- cholesterol. It also increased QUICKI, HDL-cholesterol levels, and antioxidant capacity (GSH) while preventing an increase in oxidative stress (MDA) compared to placebo [31].
2016Obstetrics and Gynecology Hospital of Fudan University, Shanghai, ChinaRandomized control trail2 weeksPregnant women with gestational diabetes mellitus (GDM) during weeks 24–28 of pregnancy133 patientsInsulin resistance was markedly reduced in GDM pregnant patients who used high-dose vitamin D supplements (50,000 IU every two weeks). From the 12th week of pregnancy until delivery, the study recommends high dose vitamin D treatment (50,000 IU every two weeks) for pregnant women with GDM [32].
2016Kosar clinic, Arak, IranRandomized Double-Blind Placebo-Controlled Clinical Trial6 weeksGDM patients140Vitamin D and omega-3 fatty acids co-supplementation for 6 weeks among GDM patients had beneficial effects on fasting plasma glucose, serum insulin levels, homeostatic model of assessment for insulin resistance, quantitative insulin sensitivity check index, serum triglycerides, and very low–density lipoprotein cholesterol levels. After 6 weeks of intervention, patients who received combined vitamin D and omega-3 fatty acids supplements compared with vitamin D, omega-3 fatty acids, and placebo had significantly decreased fasting plasma glucose, serum insulin levels, homeostatic model of assessment for insulin resistance, and increased quantitative insulin sensitivity check index. Changes in serum triglycerides and very low–density lipoprotein cholesterol in the vitamin D plus omega-3 fatty acids group were significantly different from the changes in these indicators in the vitamin D, omega-3 fatty acids, and placebo groups [33].
2022All India Institute of Medical Sciences, BhubaneswarRandomized control trail2 weeks (maximum 10 doses)Women with GDM and Vitamin D deficiency76High dose of vitamin D supplementation (60,000 IU every two weeks, up to a maximum of ten doses) in women with GDM and Vitamin D deficiency resulted in better glycemic control compared to the control group receiving the standard dose of vitamin D (500 IU/day). Mean differences of 1.06 mg/dL and 1.48 mg/dL were observed for fasting and post-prandial blood glucose levels, respectively. Mean insulin requirement increased by 5 units in the control group during pregnancy, while it was reduced by 1.1 unit in the intervention group. Poor perinatal outcome was observed in 65.2% of participants in the control group compared to 34.8% in the intervention group. High dose vitamin D supplementation showed effectiveness in preventing poor perinatal outcomes among GDM women with vitamin D deficiency. Routine Vitamin D testing and high dose supplementation in antenatal women with proven Vitamin D deficiency should be considered [34].
Table 5. Some of the marketed supplements of vitamin D.
Table 5. Some of the marketed supplements of vitamin D.
Marketed Drug (Brand Name)Generic Name of the DrugAvailable FormsDosageRoute of Administration
CALCIFEROLVitamin D3Oral solution Capsule Tablet8000 IU/mL 50,000 IU 400–2000 IUOral
DELTS D3Cholecalciferol (vitamin D3)Oral solution Capsule Tablet8000 IU/mL 50,000 IU 400–2000 IUOral
DHT INTENSOLDihydrotachysterolOral solution Tablet0.25 mg/mL 0.8–2.4 mg/mlOral
DRISDOLErgocalciferolOral solution Capsule0.05 mL once/day 50,000–2,00,000 IUOral
HECTOROLDoxercalciferol (or 1-hydroxy ergocalciferol)Capsule Injectable solution0.5–2.5 mcg 2 mL 5 mLOral and intravenous
RAYALDEECalcifediolCapsule30 mcgOral
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Monapati, S.; Kaki, P.; Gurajapu, M.S.; Subhas, P.G.; Kudipudi, H.B. The Effects of Vitamin D on Preventing Hyperglycemia and a Novel Approach to Its Treatment. Drugs Drug Candidates 2023, 2, 923-936. https://doi.org/10.3390/ddc2040046

AMA Style

Monapati S, Kaki P, Gurajapu MS, Subhas PG, Kudipudi HB. The Effects of Vitamin D on Preventing Hyperglycemia and a Novel Approach to Its Treatment. Drugs and Drug Candidates. 2023; 2(4):923-936. https://doi.org/10.3390/ddc2040046

Chicago/Turabian Style

Monapati, Suchitra, Pavani Kaki, Mary Stella Gurajapu, Prathibha Guttal Subhas, and Harinadha Baba Kudipudi. 2023. "The Effects of Vitamin D on Preventing Hyperglycemia and a Novel Approach to Its Treatment" Drugs and Drug Candidates 2, no. 4: 923-936. https://doi.org/10.3390/ddc2040046

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