Beyond bones, vitamin D as a sunshine hormone in type 2 diabetes mellitus and its complications

Summary

The aim of this review is to thoroughly examine the intricate connection between vitamin D and type 2 diabetes mellitus. A detailed investigation of the potential role of vitamin D in the onset, prevention, and management of type 2 diabetes mellitus was conducted through an extensive review of the available literature and relevant research findings. Numerous studies have indicated that vitamin D contributes significantly to maintaining the metabolic balance of calcium and phosphorus and supporting bone health while potentially affecting the development and incidence of diabetes via various mechanisms. Nevertheless, many ambiguities persist regarding the association between vitamin D and diabetes, and further studies are needed to clarify its exact mechanism of action and clinical application value.

Graphical abstract

Health sciences

Introduction

Type 2 diabetes mellitus (T2DM) has rapidly become a major threat to global public health, significantly increasing the risk of long-term complications such as cardiovascular disease and chronic kidney disease.¹ Moreover, it has a negative effect on individuals’ overall quality of life and mental health. The development of T2DM results from the interaction between genetic and environmental factors. Its primary pathogenesis is attributable to insufficient insulin secretion or to insulin resistance (IR).² According to data released in the Diabetes Atlas 2025 (11th Edition) from the International Diabetes Federation (IDF), the number of people aged 20 to 79 years with diabetes worldwide reached 589 million in 2024, with 148 million of these individuals living in China. China’s total diabetes-related healthcare expenditure has reached $168.9 billion, accounting for 16.6% of global diabetes-related spending and ranking second worldwide.³ These findings indicate that China’s future economic burden related to diabetes will increase significantly. In recent years, the relationship between vitamin D and T2DM has garnered significant attention. Vitamin D helps maintain the calcium and phosphorus balance and is thus essential for maintaining bone health. In addition to its classic functions, vitamin D also serves as an indispensable regulator of immunity and inflammation. More importantly, vitamin D can regulate insulin secretion and improve IR through multiple mechanisms. Therefore, a comprehensive study of the relationship between vitamin D and T2DM has important theoretical and clinical value.

Vitamin D

Sources of vitamin D

Vitamin D is a fat-soluble vitamin. To date, more than 50 metabolites of vitamin D with different biological activities have been discovered, and its main forms include vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol).⁴ Vitamin D plays a vital role in the human body, and its metabolic process is complex and involves the synergistic actions of multiple enzymes in various organs. Very few foods (e.g., milk, veal, beef, and pork) naturally contain vitamin D. Generally, the amount of vitamin D in food depends on the fat content, and vitamin D synthesis occurs mainly in the skin after exposure to ultraviolet B (UVB).⁵ However, the contribution rate of sun exposure to vitamin D synthesis varies significantly depending on factors such as geographic latitude, climate, sunlight exposure, and the season of blood collection.⁶

As shown in Figure 1, 7-dehydrocholesterol (7-DHC) in skin epidermal cells can be converted to vitamin D precursors, namely, vitamin D₂ and vitamin D₃, after UVB irradiation. Both of these precursors are biologically inactive and need to be further converted into active forms. They are hydroxylated to form 25-hydroxyvitamin D (25(OH)D) in the liver by at least five enzymes (CYP2DII, CYP2D25, CYP3A4, CYP2R1, and CYP27A1).⁷ 25(OH)D is subsequently converted into 1,25-dihydroxyvitamin D (1,25VD) by 1-α-hydroxylase (CYP27B1) in the kidneys, and its synthesis in the kidneys is regulated by parathyroid hormone (PTH), growth hormone (GH), blood phosphorus and other substances.⁸

Figure 1.

The process of vitamin D production

Vitamin D is synthesized primarily through exposure to UVB radiation, with dietary intake serving as a secondary source. The 7-dehydrocholesterol (7-DHC) present in epidermal skin cells is converted to vitamin D₂ and vitamin D₃ upon UVB irradiation. These precursors then undergo sequential metabolism in the liver and kidneys to generate the biologically active compound 1,25-dihydroxyvitamin D (1,25VD). Notably, the production of 1,25VD is tightly regulated by parathyroid hormone (PTH) and growth hormone (GH).

Vitamin D deficiency (VDD) may lead to rickets and osteomalacia.⁹ GH and insulin-like growth factor 1 (IGF-1) are crucial hormones that play key regulatory roles during human growth and development. IGF-1 is a downstream effector of GH. Studies have shown that vitamin D supplementation can increase IGF-1 levels; moreover, IGF-1 increases the activity of 1-alpha-hydroxylase, thus regulating the production of active vitamin D.^10,11 Furthermore, GH directly stimulates the production of 1,25VD.¹² The relationships among these hormones provide researchers with a new perspective for exploring the mysteries of the human body. In the future, as research on vitamin D deepens, its role in human health will be more clearly understood, and new methods for the prevention and treatment of vitamin D-related diseases will be developed. Vitamin D receptors (VDRs) belong to the nuclear receptor transcription factor superfamily. They bind to DNA in target cells as either VDR/VDR homodimers or VDR/retinoid X receptor (RXR) heterodimers, influencing the transcription of certain genes (Figure 2).¹³ They also participate in the regulation of skeletal and calcium balance, inflammatory responses, cell-mediated immune responses, the cell cycle, apoptosis, and other signaling pathways.¹⁴ This fine regulatory mechanism provides a solid foundation for maintaining human health. 25(OH)D and 1,25VD are broken down by the same 24-hydroxylase (CYP24A1).⁷ Under the catalytic action of CYP24A1, 25(OH)D is converted to 24,25-dihydroxyvitamin D, while 1,25VD is converted to 1,24,25-trihydroxyvitamin D. Upon further catalysis, these compounds are transformed into inactive water-soluble products.¹⁵ Following inactivation, vitamin D metabolites undergo modifications such as glucuronidation in the liver, during which they are converted to water-soluble conjugates that are subsequently excreted via the kidneys into the urine or through the bile into the feces. Some vitamin D can be stored in fat tissue, and the serum 25(OH)D concentration and vitamin D concentration in adipose tissue are positively correlated in both obese and nonobese individuals.¹⁶ The half-life of 25(OH)D is longer than that of other vitamin D metabolites and is approximately 3 weeks. Therefore, among vitamin D metabolites, 25(OH)D is relatively stable. Because of these characteristics, in clinical practice, vitamin D status is typically assessed by measuring serum 25(OH)D levels as the primary indicator. In previous studies, we gained a relatively clear understanding of the fundamental synthesis and metabolic pathways of vitamin D. However, with respect to the various regulatory mechanisms of vitamin D, the discoveries made to date are just the tip of the iceberg. To explore the intrinsic mechanisms of vitamin D regulation, researchers must further focus on its diverse signaling pathways. This foundational research will aid the development of more effective therapeutic approaches for vitamin D-related disorders. Moreover, the regulatory mechanisms of action of various hormones in vitamin D metabolism require systematic elucidation.

Figure 2.

The functions of vitamin D

The biologically active form of vitamin D is 1,25VD. Its mechanism of action begins with binding to the vitamin D receptor (VDR). Once attached to the VDR, 1,25VD forms a dimeric complex with the retinoid X receptor (RXR). This complex then binds to vitamin D response elements (VDREs) in the DNA of target cells, as either a VDR/VDR homodimer or a VDR/RXR heterodimer. The functions of vitamin D include regulating calcium and phosphorus homeostasis, regulating immune function, playing an anti-inflammatory role, participating in cell differentiation and apoptosis, promoting insulin secretion, and improving insulin resistance.

The classical roles of vitamin D

Regulating calcium and phosphorus metabolism

The most important function of vitamin D is to maintain stable levels of calcium and phosphorus in the blood (Figure 2). It ensures normal bone growth and development. The primary organs through which vitamin D regulates calcium and phosphorus metabolism are the intestines, bones, and kidneys.¹⁷ The human body can absorb calcium from the intestinal lumen through both transcellular and intercellular pathways. Among these, the transcellular pathway predominates and is regulated by 1,25VD. It elevates calcium absorption by increasing the mRNA levels of transient receptor potential vanilloid 6 (TRPV6) in the intestine.^18,19 Phosphorus absorption occurs mainly in the jejunum. Coincidentally, 1,25VD can promote phosphorus absorption through small intestinal mucosal cells by regulating sodium‒phosphorus transporters. For this reason, 1,25VD can increase calcium and phosphorus levels in the blood. More importantly, 1,25VD affects both bone resorption and bone formation. On the one hand, 1,25VD promotes the differentiation of preosteoclasts, increasing the number of osteoclasts. This effect facilitates bone resorption and promotes the release of calcium and phosphorus from bone into the bloodstream, thereby increasing blood calcium and phosphorus concentrations.²⁰ On the other hand, bone resorption leads to elevated levels of calcium and phosphorus in the blood, which accelerates calcium deposition and bone mineralization.²¹ Compared with bone formation, bone resorption is affected more significantly by 1,25VD, so its overall effect is an increase in blood calcium and phosphorus levels. When the level or activity of 1,25VD in the blood is reduced, the bones exhibit signs of rickets or osteomalacia. In the kidney, 1,25VD can cooperate with PTH to promote the reabsorption of calcium in renal tubules, reducing the excretion of calcium in the urine.²² Moreover, PTH can stimulate the expression of 1-α-hydroxylase in the kidney, thus promoting 1,25VD synthesis and affecting the absorption of calcium and phosphorus in the intestine. Vitamin D is crucial for maintaining the balance of calcium and phosphorus. When this balance is disrupted, a variety of diseases, such as osteomalacia, osteoporosis, and kidney stones, can develop. Moreover, vitamin D functions in regulating calcium and phosphorus metabolism in the intestines, bones, and kidneys. In the future, clinicians will be able to classify diseases related to imbalances in calcium and phosphorus metabolism and identify the core affected organs. Targeted intervention plans can be designed, reducing the generalized use of traditional supplements and their side effects (such as hypercalcemia).

Modulating immune function

Vitamin D is a regulator of the immune system (Figure 2). VDR is widely present in nucleated cells, including immune cells.²³ T lymphocytes express high levels of VDR, and the highest levels are present in CD8⁺ lymphocytes, whereas the levels of VDR in B lymphocytes and monocytes/macrophages are low. These findings indicate that CD8 lymphocytes might be the main target of 1,25VD.²⁴ The immunomodulatory effects of vitamin D are partly mediated by its effect on regulatory T cells (Tregs). Low levels of vitamin D reduce the number of circulating Tregs, disrupt immune homeostasis in patients with psoriasis, and promote inflammatory activity.²⁵ Merriman et al. reported that injecting 25(OH)D into the mammary glands of dairy cows could regulate the innate immune response to endotoxin-induced mastitis, upregulate the expression of the CYP24A1 gene in mammary cells, and downregulate the expression of CCL5 in macrophages.²⁶ Vitamin D promotes the synthesis of antimicrobial peptides by increasing the expression and secretion of cathelicidin and β-defensin, stimulates autophagy by initiating autophagosome formation, and increases the production of lysosomal degradation enzymes in macrophages.²⁷

Other roles

Vitamin D affects gene transcription and participates in cell differentiation and apoptosis. The vitamin D signaling pathway involves the active forms of 1,25VD, VDR, RXR, vitamin D-binding protein (DBP), target genes and their downstream effector molecules, as well as multiple metabolic enzymes and transporters. Studies have revealed more than 20,000 genomic VDR binding sites in the human genome.²⁸ After binding to the VDR, 1,25VD forms a dimeric structure with RXR and binds to the vitamin D response element (VDRE) in the DNA of target cells in the form of a VDR/VDR homodimer or a VDR/RXR heterodimer (Figure 2).²⁹ Protein disulfide isomerase A3 (PDIA3) is known for its role in calcium absorption during intestinal and bone development. It is the most commonly researched candidate binding protein associated with 1,25VD. PDIA3 mediates the 1,25VD-dependent activation of phospholipase A₂-activating protein (PLAA), phospholipase A₂ (PLA2), and phospholipase C (PLC) and opens Ca²⁺ channels and Pi channels, leading to a swift increase in the levels of second messengers such as DAG, IP3, cAMP, and Ca²⁺. This process is followed by PKA, PKC, or CAMK2G activation and changes in several downstream targets, including components of the mitogen-activated protein kinase (MAPK) pathway.³⁰ Vitamin D modulates the differentiation, growth, and apoptosis of monocytes, dendritic cells (DCs), and various T cell types (Figure 2).³¹ VDR knockout mice have been shown to exhibit abnormal epidermal cell differentiation, and the addition of vitamin D to normal mouse hematopoietic cells in vitro can lead to the differentiation of these cells into macrophages; however, no effect has been observed on cells from VDR knockout mice.³² Extracellular signal-regulated kinase (ERK) is a MAPK, and 1,25VD can inhibit the mRNA expression and phosphorylation of ERK, thus inhibiting adipocyte differentiation.³³ In summary, vitamin D plays important roles in gene transcription, cell differentiation, and apoptosis.

Vitamin D can regulate cell proliferation and apoptosis, suggesting its potential for antitumor effects. Rapidly proliferating cells in the immune system and tumor cells share similar signaling pathways, some of which are regulated by vitamin D. Vitamin D exerts anticancer effects. On the one hand, it acts directly by regulating tumor cell differentiation, proliferation, and apoptosis; for example, 1,25VD regulates the expression of proto-oncogenes (such as c-myc) and tumor suppressor genes (such as p21 and p27) through VDR, thereby inhibiting abnormal proliferation of tumor cells and inducing tumor cell apoptosis. On the other hand, it also exerts indirect effects by modulating the function of immune cells within the tumor microenvironment.³⁴ Insufficient vitamin D levels are associated with the occurrence of various cancers, such as breast cancer, prostate cancer, and colon cancer.³⁵ The survival rate of patients with follicular lymphoma and VDD is low, and these patients respond poorly to rituximab treatment.³⁶ Researchers have reported that vitamin D supplementation can enhance immune system function in patients with cancer and improve the effectiveness of anticancer treatment regimens. Therefore, it can improve patient outcomes and reduce mortality rates among patients with cancer. Vitamin D supplementation can serve as an adjunct therapy for patients with cancer.

Additionally, vitamin D provides cardiovascular protection and reduces the risk of atherosclerosis. It regulates vascular endothelial function, increases nitric oxide (NO) release, and reduces the incidence of hypertension.³⁷ Moreover, research has shown that vitamin D may improve muscle strength and endurance.³⁸ However, other studies have shown that vitamin D supplementation does not significantly improve muscle strength in adults.³⁹ The role of vitamin D in muscle function requires further validation. All in all, vitamin D has even more potential benefits waiting to be discovered.

Current research status on the relationship between vitamin D and type 2 diabetes mellitus

T2DM is a chronic endocrine and metabolic disorder characterized by insulin deficiency, insulin insensitivity, or both, along with high blood glucose levels and vascular complications.⁴⁰ T2DM contributes to numerous diseases, and patients may also suffer from many complications, including cardiovascular disease, kidney disease, neuropathy, and diabetic foot. Poor blood glucose control can increase the severity of complications. Vitamin D has direct or indirect effects on various pathophysiological processes of T2DM, such as pancreatic β-cell dysfunction, impaired insulin activity, and systemic inflammation states. Vitamin D protects β cell function by regulating calcium metabolism and the immune system, thereby promoting insulin secretion. VDD can exacerbate IR by disrupting fat cell metabolism and promoting the release of inflammatory factors.

The epidemiology of vitamin D deficiency and type 2 diabetes mellitus

The serum 25(OH)D concentration is widely regarded as the most reliable and practical biomarker for assessing vitamin D status and can reflect vitamin D levels in the human body. In accordance with the expert consensus on evaluating and improving vitamin D nutritional status in China, a serum 25(OH)D concentration of ≥20 ng/mL or ≥50 nmol/L is considered a normal vitamin D concentration, a concentration of ≥12 to <20 ng/mL or ≥30 to <50 nmol/L is considered an insufficient vitamin D concentration, and a concentration of <12 ng/mL or <30 nmol/L is considered VDD.⁴¹ VDD is widespread worldwide. Data from the NHANES 2007–2010 survey indicated that approximately 5.9% of the population in the United States had 25(OH)D concentrations less than 30 nmol/L, and 24% had concentrations less than 50 nmol/L.⁴² Notably, 13.0% of 55,844 European individuals had serum 25(OH)D concentrations less than 30 nmol/L. The percentages of samples with low 25(OH)D levels collected during the extended winter period (from October to March) and summer period (from April to November) were 17.7% and 8.3%, respectively. The prevalence of VDD among darker-skinned ethnic subgroups is much higher than that among the white population.⁴³ A study conducted in Henan Province, China, revealed that VDD is correlated with prediabetes. Compared with men without VDD, men with VDD are more likely to develop impaired glucose tolerance (IGT). There is a sex difference in the correlation between VDD and prediabetes.⁴⁴ In the UK population, nonlinear associations were observed between higher 25(OH)D levels and a reduced risk of adverse cardiovascular outcomes and mortality in patients with prediabetes or diabetes.⁴⁵ Several studies conducted in multiple countries and regions have identified a potential link between vitamin D and diabetes. VDD may increase the risk of developing diabetes and is associated with negative outcomes in patients with diabetes. Continued exploration of the role of vitamin D in diabetes could provide a valuable reference for clinical treatment and improve public health.

Vitamin D affects insulin secretion and insulin sensitivity

Insulin is secreted by pancreatic β cells. To compensate for IR, β-cells initially secrete more insulin, leading to hyperinsulinemia. However, chronic IR and sustained metabolic stress can eventually lead to β-cell dysfunction and failure, resulting in first a relative and then an absolute decline in insulin secretion. Normalizing β-cell insulin secretion helps control blood glucose levels. Vitamin D promotes insulin synthesis, regulates insulin secretion, and protects the function of pancreatic β cells (Figure 2). Multiple animal studies have demonstrated that VDD impairs glucose-mediated insulin secretion by pancreatic β cells in rats.⁴⁶ Vitamin D regulates insulin synthesis and secretion in many ways. Ca²⁺ plays a key role in many cell activities managed by insulin (Figure 3). These activities take place in specific tissues, such as muscle and adipose tissue. Ca²⁺ is essential for the proper action of insulin. Under physiological conditions, elevated blood glucose levels promote the release of insulin. Glucose enters pancreatic β cells through glucose transporter 2 (GLUT2), where it is converted to fructose-2,6-bisphosphate (F-2,6-P2). F-2,6-P2 enters the tricarboxylic acid cycle (TCA cycle) and glycolysis pathway, resulting in elevated ATP levels. Increased ATP levels inhibit ATP-sensitive potassium channels, resulting in cell membrane depolarization, followed by the activation of L-type voltage-gated channels, generating localized Ca²⁺ bursts, which trigger insulin secretion.⁴⁷ Impaired insulin signaling may result from alterations in intracellular Ca²⁺ concentrations within target tissues. It can decrease the activity of glucose transporter 4 (GLUT4) and consequently induce IR in peripheral tissue. Cellular free Ca²⁺ levels inhibit insulin-induced glucose uptake in isolated rat adipocytes.⁴⁸ Therefore, 1,25VD influences insulin sensitivity by regulating the extracellular Ca²⁺ concentration and Ca²⁺ flux across the cell membrane. Secondarily, vitamin D stimulates PLC production and activates inositol trisphosphate (IP₃), thereby promoting the release of Ca²⁺ from the endoplasmic reticulum within cells. There are a series of calcium-binding proteins in the human body, including calmodulin (CaM), calbindin, and calcineurin. CaM is a protein that can specifically bind and transport Ca²⁺, thereby maintaining calcium balance both within and outside cells.⁴⁹ Vitamin D can regulate the activity of CaM and promote its expression. The binding of vitamin D to VDR can affect insulin secretion. However, insulin secretion is impaired in mice lacking functional VDR under high-glucose conditions.⁵⁰ Furthermore, Jin et al. reported GLUT2 deficiency in monosodium L-glutamate (MSG)-fed rats and the restoration of GLUT2 expression by 1,25VD; these findings indicate that 1,25VD improves glucose metabolism and insulin sensitivity in MSG-induced obese rats.⁵¹ Overall, the results of numerous studies indicate that vitamin D promotes insulin secretion. Vitamin D supplementation may offer potential health benefits for patients with diabetes.

Figure 3.

Vitamin D can affect insulin secretion

Insulin is secreted by pancreatic β-cells. Vitamin D affects insulin secretion through its regulatory effects on Ca²⁺. Under physiological circumstances, glucose enters pancreatic β-cells via GLUT2. Then, through the tricarboxylic acid (TCA) cycle and glycolytic pathway, the intracellular ATP level increases. This elevation in the ATP level activates L-type voltage-gated calcium channels, leading to a localized Ca²⁺ surge that triggers insulin secretion. Vitamin D also acts through other pathways: it promotes the synthesis of phospholipase C (PLC) and activates inositol trisphosphate (IP₃), which in turn triggers the release of Ca²⁺ from the endoplasmic reticulum. Moreover, vitamin D can regulate the expression of calmodulin (CaM), a key protein that binds to Ca²⁺.

Obesity can cause chronic inflammation, which can progress to IR and metabolic-associated fatty liver disease.⁵² The presence of macrophages in metabolic tissues increases the secretion of proinflammatory cytokines and contributes to disease progression.⁵³ In a diet-induced obesity (DIO) mouse model, liver macrophages or Kupffer cells become active, triggering an inflammatory response. This process promotes the formation of fatty liver, ultimately leading to a decrease in insulin sensitivity in liver cells. Hepatic macrophages have the highest expression of VDR, but hepatic cells have extremely low VDR levels.⁵⁴ Dong et al. reported that VDR activation leads to strong anti-inflammatory effects on liver macrophages in mice. Under chronic inflammatory conditions in a DIO model, the use of vitamin D analogs (calcitriol) to activate VDR can alleviate liver inflammation and fatty degeneration and significantly improve insulin sensitivity.⁵⁵ Among overweight adolescents undergoing hyperinsulinemic-euglycemic clamp testing, lower free 25(OH)D levels were associated with reduced insulin sensitivity.⁵⁶ Because Ca²⁺ is important for regulating insulin secretion, drugs targeting calcium signaling pathways (such as calcium channel agonists) may become potential treatments for diabetes in the future. VDR is expressed in insulin-sensitive tissues such as adipose, skeletal muscle, liver, and pancreatic tissue.⁵⁷ Therefore, vitamin D can improve insulin sensitivity by regulating these tissues.

The regulatory effects of vitamin D on various immune cells may contribute to ameliorating immune dysregulation in diabetes. An exploration of the role of vitamin D in the immune system revealed that macrophage-specific VDR deficiency can induce IR by promoting a proinflammatory macrophage phenotype in metabolic tissues.⁵⁸ By subcutaneously injecting newborn Wistar rats with MSG at a dosage of 4 g/kg/day for seven consecutive days, Jin et al. established a rat model of MSG-induced obesity. After eight weeks of treatment, compared with the MSG-fed rats in the control group, the MSG-fed rats in the 1,25VD group had significantly lower body weights, blood glucose levels, and plasma insulin levels. In rats with MSG-induced obesity, marked fibrosis was observed in the pancreas, whereas MSG rats treated with 1,25VD exhibited minimal fibrosis and overall more regular, rounded pancreatic islet morphology. Moreover, 1,25VD increased the frequency of CD4⁺CD25⁺FoxP3⁺ Tregs in insulin-targeted tissues such as the liver, adipose tissue, and muscle.⁵¹ These findings suggest that Tregs play a protective role in the pathogenesis of IR and that 1,25VD might exert a general therapeutic effect on diabetes through increased secretion or infiltration. Vitamin D can inhibit excessive activation of the immune system and reduce the levels of proinflammatory factors in the circulation. In T2DM, macrophage infiltration is typically observed within the islets.⁵⁹ The proinflammatory cytokines secreted by these macrophages can directly inhibit insulin synthesis and secretion by β cells and induce β apoptosis. Galectin-3 (Gal3) is a β-galactoside-binding protein that belongs to the galectin family. It is widely expressed in immune cells such as macrophages and monocytes and participates in various physiological and pathological processes, including inflammatory responses, apoptosis, and metabolic regulation.⁶⁰ In the islets of high-fat diet (HFD)-fed and diabetic db/db mice, the levels of Gal3, which is primarily produced and secreted by macrophages, increase. Gal3 rapidly reduces insulin secretion in both mouse and human islets. Inhibiting Gal3 via genetic or pharmacological pathways improves insulin secretion and glucose homeostasis in HFD-fed and db/db mice.⁶¹ Vitamin D can increase the activity of natural killer (NK) cells, thereby strengthening immune surveillance and reducing immune dysregulation associated with metabolic abnormalities.⁶² In conclusion, vitamin D protects β-cell function by regulating calcium metabolism and the immune system, therefore promoting insulin secretion.

Vitamin D ameliorates insulin resistance

IR is a complex metabolic disorder that cannot be explained by a single mechanism and is characterized by reduced glucose uptake by skeletal muscle, liver and adipose tissue and reduced gluconeogenesis in the liver. In particular, patients with the severe insulin-resistant diabetes subtype not only present with metabolic abnormalities but also have a higher risk of cardiovascular, renal, and hepatic comorbidities.⁶³ Elevated blood glucose levels can elevate chronic inflammatory marker levels and increase the production of reactive oxygen species (ROS), ultimately contributing to vascular dysfunction. Furthermore, increased oxidative stress and inflammation may exacerbate IR and impair insulin secretion (Figure 4).⁶⁴ Moreover, adipose tissue is closely linked to T2DM and IR. Mammalian adipose tissue can be categorized into two primary types: white adipose tissue (WAT) and brown adipose tissue (BAT), with WAT having the greater effect on metabolism. Many clinical studies have shown that vitamin D supplementation can reduce blood lipid levels, HbA1c levels, and other metabolic parameters in patients with T2DM and reduce the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score.⁶⁵ These studies suggest that VDD is associated with IR.

Figure 4.

Vitamin D can reduce oxidative stress and inflammatory responses

In obesity, an excess supply of electron transport chain (ETC) molecules leads to an increase in the NADH/NAD⁺ ratio, resulting in mitochondrial dysfunction, impaired SIRT-3 activity, and increased generation of reactive oxygen species (ROS). Vitamin D can negatively regulate the ETC, improve mitochondrial function, and increase SIRT3 activity. Ferroptosis can also result in the production of many types of ROS, and vitamin D can inhibit ferroptosis through multiple signaling pathways. Furthermore, vitamin D can inhibit the activity of the NLRP3 inflammasome, thereby decreasing the production of inflammatory factors such as IL-1β and IL-18. Therefore, vitamin D can ameliorate insulin resistance by reducing oxidative stress and inflammatory responses.

Vitamin D can ameliorate IR by alleviating oxidative stress (Figure 4). VDR is widely expressed in mitochondria and has a negative regulatory effect on the respiratory chain.⁶⁶ Moreover, studies have shown that lipid and protein peroxidation are increased in patients with VDD, whereas mitochondrial function is improved in patients with low back pain after 5 weeks of vitamin D supplementation.⁶⁷ Mitochondria are strongly associated with energy metabolism and are important sources of ROS. The electron transport chain (ETC) in mitochondria can continuously produce ROS.⁶⁸ At present, the mechanism by which vitamin D regulates oxidative stress is still unclear, but according to existing studies, it is closely related to mitochondria. A previous study using a VDR knockout mouse model revealed that VDR may reduce lipid catabolism and activate the acetyl-CoA pathway for ATP production in mitochondria.⁶⁹ Moreover, nicotinamide adenine dinucleotide (NAD⁺) is the main electron carrier in the metabolic reoxidation reduction process. As the supply of electrons increases, more NAD⁺ is reduced to NADH. A cross-sectional study suggested that several polymorphisms in genes encoding mitochondrial respiratory chain proteins may be associated with body mass index (BMI) variation.⁷⁰ Sirtuins (SIRTs), a group of protein deacetylases, utilize NAD⁺ as a cofactor. Obesity inhibits the oxidation of NADH by the ETC in mitochondria, thereby maintaining a high NADH/NAD⁺ ratio. Metabolic disorders are characterized by high NADH/NAD⁺ ratios caused by electron oversupply, which result in mitochondrial dysfunction and diminished sirtuin-3 (SIRT-3) function, both of which contribute to oxidative stress. Because NADH is oxidized by complex I in the ETC, factors that inhibit complex I, such as acetylation, cardiolipin peroxidation, and glutathione, affect SIRT3 function by increasing the NADH/NAD⁺ ratio.⁷¹ They are involved in controlling several cellular processes, such as aging, metabolism, the stress response, and inflammation. SIRT3 mainly regulates the acetylation of mitochondrial proteins. The role of SIRT3 in alleviating the metabolic stress associated with diabetes is mediated through the deacetylation of forkhead box protein O3 (FOXO3), isocitrate dehydrogenase 2, and manganese superoxide dismutase.⁷² 1,25VD can significantly increase the expression of VDR, SIRT1 and SIRT3 in cells; alleviate skeletal muscle atrophy; and decrease apoptosis.⁷³ Manna et al. reported that vitamin D supplementation inhibits oxidative stress and activates the SIRT1/AMP-activated protein kinase (AMPK)/GLUT4 cascade in the adipose cells of diabetic mice fed a high-fat diet and 3T3L1 adipocytes treated with high glucose concentrations.⁷⁴

SIRT1 is an NAD⁺-dependent deacetylase. In addition, SIRT1 promotes AMPK activation via deacetylation.⁷⁵ AMPK is responsible for regulating the energy metabolism of cells once it becomes activated and increases the uptake and usage of glucose. Furthermore, it inhibits liver gluconeogenesis and decreases the amount of glucose produced by the liver.⁷⁶ Skeletal muscle, cardiac muscle, white adipose tissue, and brown adipose tissue contain GLUT4. It responds to insulin signals and regulates the transport of glucose into fat and muscle tissues.⁷⁷ Through the inhibition of oxidative stress, vitamin D can indirectly impact these processes. Mitochondria help control how cells react to oxidative stress. The normal activity of SIRT1, AMPK, and GLUT4 is interrupted by oxidative stress. Vitamin D can improve mitochondrial function and SIRT activity, reduce oxidative stress, and hence ameliorate IR. However, more research is needed to confirm these findings.

Oxidative stress plays a role in the development of T2DM and its complications by regulating multiple signaling pathways involved in β-cell dysfunction and IR. At the molecular level, the mechanisms involving oxidative stress in diabetes are intricately connected to the metabolism of glucose and fats. ROS are generated through different metabolic pathways, including glycolysis and the metabolic pathways of aminohexose, protein kinase C, polyols, and advanced glycation end products, and these pathways are often activated in patients with diabetes.⁴⁰ Ferroptosis is a form of regulated cell death reliant on iron and is characterized by the accumulation of lipid peroxides (LPOs). This process differs from apoptosis, necrosis, and various other forms of programmed cell death. Under conditions of iron overload, excessive iron generates significant quantities of lipid peroxidation products via the Fenton reaction.⁷⁸ An excess of iron donates electrons to hydrogen peroxide, initiating the generation of superoxide anions and hydroxyl radicals and consequently the generation of ROS. This process is referred to as the Fenton reaction. Under normal physiological conditions, LPOs are transformed into their respective lipid alcohols via the cystine/glutathione/glutathione peroxidase 4 (GPX4) pathway. GPX4 is a glutathione peroxidase that reduces lipoxygenase (LOX) activity and prevents its overactivation. It can additionally eliminate LPOs that build up because of excessive iron, thus effectively preventing cell membrane damage resulting from LPOs.⁷⁹ The accumulation of LPOs leads to oxidative stress in cells and consequently to cell dysfunction. Forkhead box O (FOXO) proteins, which are transcription factors, influence many physiological processes. Current research focuses mainly on alleviating diabetes symptoms by inhibiting abnormal FOXO1 activity or regulating its downstream pathways. FOXO1 can activate genes that encode key enzymes involved in gluconeogenesis, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), in the liver, subsequently promoting glucose production. In fat and muscle tissues, its excessive activation inhibits insulin-mediated glucose uptake, exacerbating IR. Numerous studies have shown that FOXO1 reduces insulin production and secretion in the pancreas.⁸⁰ In previous studies, we reported that 1,25VD/VDR can inhibit ferroptosis in pancreatic cells in a T2DM model in rats by downregulating FOXO1 expression.⁵⁰ A study of mice treated with D-galactose and VDR knockout agents revealed that 1,25VD can alleviate D-galactose-induced ferroptosis. Specifically, it alleviates mitochondrial structural damage, increases glutathione levels, and reduces lipid peroxidation marker levels. 1,25VD exerts these effects by activating the expression of VDR and its downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/GPX4 signaling pathway.⁸¹

Vitamin D can also have anti-inflammatory effects (Figure 2). Therefore, vitamin D can alleviate insulin resistance by reducing inflammation. Prostaglandins (PGs) are a group of bioactive lipid mediators involved in numerous pathological conditions, and cyclooxygenase (COX) is a membrane-binding protein that serves as a key enzyme in PG synthesis. Several researchers have reported that vitamin D downregulates the expression of COX-2 and its PG products in macrophages and decreases the release of inflammatory cytokines in mice.⁸² Lipopolysaccharide (LPS) is a component of the cell wall of gram-negative bacteria that induces the production of cytokines by monocytes/macrophages.⁸³ The mechanism by which vitamin D inhibits LPS-activated monocytes/macrophages in mice involves the inhibition of the LPS-induced production of cytokines, including IL-6 and TNF-α.⁸⁴ Morris et al. reported that high-dose 25(OH)D supplementation improves liver growth after LPS injection and decreases the mRNA level of IL-1β.⁸⁵ VDD is linked to unfavorable clinical outcomes following ischemic stroke, and VDR-deficient microglia/macrophages exhibit a proinflammatory phenotype and secrete large amounts of TNF-α and IFN-γ.⁸⁶ M1 macrophages serve as proinflammatory agents, in contrast to M2 macrophages, which perform anti-inflammatory functions. 1,25VD notably suppresses M1 macrophage activation while increasing M2 macrophage activation. It can also increase the levels of the anti-inflammatory cytokine IL-10 while lowering the levels of markers linked to M1 macrophages.⁸⁷ Clinical studies have shown that among patients with chronic inflammatory diseases, vitamin D levels are significantly associated with the severity of inflammation. In patients with Crohn’s disease and ulcerative colitis, the recurrence rate decreases after vitamin D supplementation.⁸⁸ In addition, vitamin D can suppress chronic inflammatory responses associated with diabetes through multiple pathways.

Inflammasomes are complexes composed of multiple proteins that can initiate the activation of inflammatory caspases and the maturation of inflammatory factors. Among them, the nucleotide-binding domain protein 3 (NLRP3) inflammasome is the most representative. The NLRP3 inflammasome plays a crucial role in the microinflammatory state of diabetes (Figure 4).⁸⁹ Various endogenous and exogenous stimuli can activate NLRP3, promoting the maturation and secretion of key proinflammatory factors such as IL-1β and IL-18 and thus ultimately leading to inflammation.⁹⁰ ATP produced by mitochondria is an endogenous activator of NLRP3. The LPS-induced exposure of macrophages to extracellular ATP can activate caspase-1 in an NLRP3-dependent manner.⁹¹ NLRP3 inflammasome activation interferes with insulin signal transduction. In the islets of Nlrp3^−/− mice, IL-1β concentrations are significantly lower than those in wild-type islets.⁹² The expression of NLRP3 and IL-1β decreases in mice treated with 1.25% VD.⁹³ Vitamin D reduces NLRP1 and NLRP3 inflammasome expression in placental explant samples from mothers of preterm infants cultured with hydrogen peroxide.⁹⁴ On this basis, vitamin D supplementation may have similar effects in patients with diabetes. SIRT3 activates superoxide dismutase 2 (SOD2) through direct binding and deacetylation and subsequently regulates the balance of mitochondrial reactive oxygen species (mtROS) and the activation of the NLRP3 inflammasome.⁹⁵ NLRP3 is a key factor in the inflammatory process induced by nitrogen mustard (NM).⁹⁶ NM promotes COX-2 expression both in vivo and in vitro and activates the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. Vitamin D can inhibit the activity of the NLRP3 inflammasome through SIRT3–SOD2–mtROS signaling.⁹⁷

The role of adipose tissue and adipocytes in the pathogenesis of various insulin resistance-related diseases (such as T2DM, metabolic-related fatty liver disease, and polycystic ovary syndrome) has been widely confirmed. VDR is present in adipocytes, as well as in visceral and subcutaneous adipose tissues.⁹⁸ Therefore, adipose tissue is a direct target of vitamin D. Vitamin D can alleviate IR by affecting fat metabolism. Peroxisome proliferator-activated receptor (PPAR) is a transcription factor that regulates energy metabolism in the liver, adipose tissue, and muscles. It is usually classified into three types: α, β/δ, and γ.⁹⁹ PPAR-γ is an essential factor in the differentiation of preadipocytes into mature adipocytes. Inhibiting its activity can reduce adipocyte generation and prevent the excessive proliferation of adipose tissue. The CCAAT enhancer-binding protein (C/EBP) subfamily belongs to the basic leucine zipper (bZIP) transcription factor family and includes members such as C/EBP-α, β, δ, γ, and ε. It is also a key early regulatory factor in the process of fat formation.¹⁰⁰ Interestingly, vitamin D can inhibit the activity of PPAR-γ and C/EBP, thereby reducing fat production.¹⁰¹ Enlarged fat cells and adipose tissue release free fatty acids (FFAs), ROS, and proinflammatory cytokines, which cause IR. A study of prepubescent children revealed that when serum 25(OH)D levels decrease, the levels of soluble fatty acid synthase (FASN) in the circulation increase accordingly.¹⁰² After chicken embryos were injected with 25(OH)D or 1,25VD, the expression levels of fat production-related markers, including PPAR-γ, FASN, and fatty acid binding protein 4 (FABP4), increased.¹⁰³ Vitamin D can suppress the synthesis and storage of triglycerides in adipocytes, thereby preventing adipocyte hypertrophy. WAT is the most common type of adipose tissue and secretes adipokines such as adiponectin and leptin, which are involved in the regulation of energy balance.¹⁰⁴ Vitamin D can regulate the expression of adiponectin and leptin in visceral adipose tissue.^105,106 When adiponectin binds to the AdipoR1 and AdipoR2 receptors, it triggers a series of signal transduction processes. These processes include the phosphorylation of AMPK and p38 mitogen-activated protein kinase (p38 MAPK) and an increase in PPAR-α activity.¹⁰⁷ Adiponectin levels are decreased in obese/diabetic mice.¹⁰⁸ Injecting these animals with adiponectin globular structure fragments can ameliorate insulin resistance, which may be related to enhanced fatty acid β-oxidation in skeletal muscle and reduced gluconeogenesis in the liver.¹⁰⁹ Leptin promotes the expression of adiponectin and increases fatty acid oxidation in the liver, pancreas, and skeletal muscles.¹¹⁰ Leptin can regulate appetite and eating behavior and control energy expenditure.¹¹¹ When skeletal muscle cells, adipose tissue, and macrophages are cocultured in vitro, the expression of proinflammatory cytokines (such as TNF-α and IL-6) increases, while the expression of anti-inflammatory cytokines (such as IL-10 and IL-15) decreases. Additionally, calcitriol upregulates the mRNA expression of leptin, IL-1β, C/EBP-β, and PPAR-γ while downregulating adiponectin expression.¹¹² VDD can lead to excessive lipid storage in fat cells. Researchers have administered several concentrations of 1,25VD to 3T3-L1 fat cells. The treatment of these cells with 100 nmol/L 1,25VD for 24 h results in a significant inhibition of intracellular fat accumulation and increases the basal lipolysis rate. The expression levels of lipid production-related genes are also downregulated in the cells. These findings suggest that vitamin D plays an important role in improving the metabolic activity of adipocytes.¹¹³ Changes in the expression of adipogenesis markers, including triglyceride accumulation, in human preadipocytes treated with 1,25VD are dose-dependent.¹¹⁴ These findings show that the mechanism by which vitamin D alters lipid metabolism is complex. Different levels of vitamin D have different effects on adipose tissue metabolism. The maintenance of high vitamin D levels clearly helps alleviate lipid metabolism disorders and thereby ameliorates IR.

In T2DM, oxidative stress and inflammation have a very complex relationship. The normal metabolic function of the liver is affected by the vicious cycle between oxidative stress and the inflammatory response in patients with diabetes. The fluctuating blood sugar levels and oxidative stress in people with diabetes can lead to abnormal intracellular iron metabolism, which may trigger ferroptosis. Pancreatic β-cell function is impaired, and insulin secretion is affected, promoting disease progression. Research has indicated that vitamin D can modulate pathological processes that may exacerbate insulin resistance; however, its efficacy depends on baseline vitamin D levels. Specifically, its ability to alleviate oxidative stress and inflammatory states and improve lipid metabolism is more pronounced in vitamin D-deficient subjects. Therefore, while vitamin D has clinical importance, its application and the interpretation of research findings must account for this heterogeneity. Further studies are needed to elucidate its mechanisms of action within specific physiological contexts.¹¹⁵

Clinical studies of vitamin D and diabetes

Currently, in the medical field, domestic and international scholars have devoted significant time and effort to actively conducting clinical studies on the relationship between vitamin D and T2DM. To investigate the role of vitamin D in the onset, development, and treatment of T2DM, researchers have adopted multidimensional research methods and analytical approaches. Some studies have shown that vitamin D has preventive and therapeutic effects on T2DM, whereas others have failed to reach similar conclusions. The existence of this controversy confuses clinicians when deciding whether to prescribe vitamin D supplements for patients with T2DM and hinders the advancement of subsequent clinical research. Identifying the potential factors that influence these differences in research results might provide new ideas and directions for subsequent clinical research. Through in-depth analyses of the causes of these differences, we can more accurately design new studies, select appropriate research subjects and research methods, and thus improve the reliability and effectiveness of the research.

Vitamin D deficiency may increase the risk of diabetes

Data from the Irish Longitudinal Study of Aging (TILDA), a prospective cohort study, suggested that VDD could be connected to a 50% increased likelihood of developing diabetes and a 62% increased likelihood of developing prediabetes.¹¹⁶ A four-year community-based follow-up study in Chengdu, China, revealed that among 490 participants who did not have prediabetes or diabetes at baseline, 95 (48.5%) developed prediabetes, and 31 (15.8%) developed diabetes during the 4-year follow-up. Low 25(OH)D levels were strongly associated with the risk of prediabetes and T2DM.¹¹⁷ However, in a randomized controlled trial of 2,423 participants published in the New England Journal of Medicine, the researchers randomly assigned adults who met at least two of the three blood glucose criteria for prediabetes but did not meet the diagnostic criteria for diabetes (fasting blood glucose levels, 100–125 mg/dL; blood glucose level 2 h after an oral glucose load of 75 g, 140–199 mg/dL; HbA1c levels, 5.7–6.4%), regardless of the baseline serum 25(OH)D levels, to receive either 4000 IU of vitamin D₃ per day or the placebo. After a median follow-up of 2.5 years, no significant difference in the incidence of diabetes was observed between the vitamin D group and the placebo group.¹¹⁸

Multiple epidemiological studies have demonstrated a close association between VDD and an increased risk of T2DM. However, the results of these studies are not entirely consistent and exhibit certain discrepancies. This inconsistency may be related to differences in the characteristics of the study subjects (such as age, baseline health status, and geographical distribution). A critical question remains: is low vitamin D status merely a “companion phenomenon” or a genuine “pathogenic factor” in abnormal glucose metabolism? To clarify this issue, more rigorously designed studies are needed. As an illustration, unhealthy lifestyle habits such as prolonged sitting, reduced outdoor exposure, and an unbalanced diet can lead to VDD, which in turn directly disrupts glucose metabolism. The presence of this “common confounding factor” further blurs the boundaries between the “correlation” and “causal relationship” between VDD and T2DM. Moreover, the academic community has yet to reach a consensus regarding whether vitamin D supplements should be included as a routine intervention for high-risk populations with diabetes.

Vitamin D is associated with multiple complications of diabetes

The body may suffer multiple negative effects when blood glucose levels increase for long periods. When blood glucose levels remain high for a long time, they can trigger changes in the endothelium of large blood vessels. These changes, in turn, increase the risk of ischemic heart disease and cerebrovascular and peripheral vascular diseases. Furthermore, these developments can lead to microvascular disease, such as diabetic nephropathy (DN) and diabetic retinopathy (DR).¹¹⁹ Damage to peripheral nerves caused by diabetes is known as diabetic peripheral neuropathy (DPN). The next section highlights recent research on vitamin D and diabetic complications.

In a 5-year observational study, researchers reported a relationship between the 25(OH)D concentration and the incidence of macrovascular and microvascular diseases. The cumulative incidence of macrovascular and microvascular events was higher in patients with blood 25(OH)D concentrations <50 nmol/L than in those with 25(OH)D concentrations ≥50 nmol/L.¹²⁰ A systematic review of two research databases for articles on the link between VDD and various eye disorders revealed that 48 of 54 studies reported an association between VDD and DR.¹²¹ Zoppini et al. collected data from 715 regular T2DM outpatients; evaluated participants for microvascular complications; measured serum 25(OH)D levels through clinical assessment; and performed fundus, urine, and biochemical examinations, leading to the conclusion that serum 25(OH)D levels were associated with the severity of retinopathy or nephropathy.¹²² Another cross-sectional study of 815 patients with T2DM revealed that VDD was independently associated with a greater risk of DPN and DN in patients with T2DM but not with DR risk. In addition, it might serve as an indicator of the likelihood and severity of DPN and DN.¹²³ Coincidentally, Reddy et al. reported that VDD may be associated with T2DM but not with DR.¹²⁴

Vitamin D regulates endothelial function, the renin‒angiotensin‒aldosterone system, podocyte retention, and inflammation. DN is the leading cause of end-stage renal disease worldwide. Many studies support vitamin D as a kidney protectant that may delay the onset of DN.¹²⁵ The Third National Health and Nutrition Examination Survey (NHANES III) revealed that a reduction in 25(OH)D levels is correlated with an increase in the incidence of albuminuria among the general population.¹²⁶ The finding that albuminuria is an indicator of abnormal kidney function highlights the strong link between vitamin D and kidney health. A prospective study of 14,709 patients with T2DM without microvascular complications from the UK Biobank used detailed electronic health records to determine the incidence of microvascular complications in patients with diabetes. They reported that higher serum 25(OH)D concentrations are significantly associated with a lower risk of diabetic microvascular complications, including DR, DN, and DPN, and that maintaining adequate vitamin D levels has a potentially beneficial role in preventing diabetic microvascular complications.¹²⁷ A related study was also conducted in China by researchers who gathered data on symptoms and signs related to DPN, all diabetic microvascular complications, and nerve conduction capacity from a derived cohort of 1192 patients with T2DM. Through an in-depth analysis of these comprehensive data, important conclusions were drawn. Patients with DPN have lower levels of vitamin D than individuals without DPN do. Individuals with vitamin D concentrations less than 30 nmol/L often experience more neurological issues related to DPN, such as paresthesia, tingling, abnormal body temperature, reduced ankle reflexes, and poor nerve conduction. These findings strongly suggest that vitamin D is closely associated with DPN and other microvascular complications (DN and DR).¹²⁸ Moreover, 1,202 adult participants with DN from the NHANES were observed from 2001 to 2014 in a previous study. During the study, the researchers observed a common phenomenon, namely, the prevalence of vitamin D deficiency or insufficiency in patients with DN. After adjusting for confounding variables, they reported that a higher 25(OH)D concentration was significantly associated with a lower risk of death.¹²⁹ DN typically manifests as an elevated urine albumin-to-creatinine ratio (UACR). Data from a study conducted at a hospital in Shenzhen, China, suggest a nonlinear relationship between the 25(OH)D concentration and the UACR. When 25(OH)D levels are less than 67 nmol/L, a negative correlation exists between the 25(OH)D concentration and the UACR.¹³⁰ These results provide important information for the treatment and prognostic evaluation of patients with DN. Karonova et al. randomly divided 67 patients with T2DM with peripheral neuropathy (34 females) into two treatment groups. One group received 5000 IU of cholecalciferol once a week for 24 weeks, and the other group received 40000 IU of cholecalciferol for the same duration. Neuropathy severity, skin microcirculation parameters, and inflammatory markers were evaluated before and after treatment. The results revealed that 78% of the 62 participants who completed the study had vitamin D deficiency. After the patients received 40000 IU of cholecalciferol/week, the severity of neuropathy significantly decreased, and the skin microcirculation parameters were altered. After 24 weeks of vitamin D supplementation, IL-6 levels decreased, and IL-10 levels increased in this group, whereas no changes were detected in the 5000 IU/week cholecalciferol group. These findings suggest that the effect of vitamin D on DPN might be dose dependent.¹³¹

The above findings confirm that VDD is associated with different complications of diabetes. Studies suggest that greater severity of diabetic complications may be associated with lower serum vitamin D levels in patients with diabetes. Thus, the findings support the hypothesis that “vitamin D may be a protective factor against diabetic complications.” However, there are some inconsistencies in the prevailing evidence: some studies have not reported any association between VDD and DR but have found an association between only VDD and both DN and DPN.¹²³ This mismatch indicates that vitamin D is linked to specific complications of diabetes; this link varies by race, sample, and duration, underscoring the need for stratification analysis to obtain more concrete findings. Maintaining vitamin D levels may be a cost-effective strategy to reduce complications and is especially applicable in the long-term management of patients with diabetes. The dose response of patients to vitamin D is not clear at present, and the optimal dose is not known. Therefore, further research is needed to reach a consensus on the therapeutic dose. In addition, safety data on the high-dose usage of vitamin D are unclear at present, and a balance of efficacy and risk will need to be established to develop personalized supplementation plans. Complications in patients with T2DM lead to poor outcomes; vitamin D supplementation may improve outcomes in such patients.

Effects of vitamin D supplementation on diabetes prevention and treatment

Observational studies suggest a negative correlation between vitamin D levels and diabetes risk, but evidence from population-based intervention trials remains inconsistent. As shown in Table 1, six meta-analyses published between 2017 and 2024 on vitamin D interventions indicate that vitamin D effectively reduces the risk of developing diabetes in adults with prediabetes.^{132,133,134,135,136,137} Zhang et al. reported that among 548 participants who received vitamin D supplementation, 116 individuals (21.2%) recovered from prediabetes, achieving normal blood glucose levels. Furthermore, a subgroup analysis of the participants showed that vitamin D supplementation failed to reduce the risk of new-onset diabetes in patients with obesity (mean BMI ≥30 kg/m²). However, vitamin D reduced the risk of new-onset diabetes by 27% in nonobese individuals (mean BMI <30 kg/m²).¹³⁴ Li et al. summarized data from 20 studies on 25(OH)D, FBG, HbA1c, and fasting insulin levels and HOMA-IR scores and confirmed that vitamin D supplementation effectively increased serum 25(OH)D levels and reduced IR. This effect was particularly notable with high-dose vitamin D supplementation over a short duration and in nonobese patients with vitamin D deficiency or with good baseline glycemic control.¹³³ Chen et al. reported that vitamin D supplementation significantly reduced FBG levels, HbA1c levels, HOMA-IR scores, and insulin levels in patients with T2DM. Their subgroup analysis indicated that the effect of vitamin D supplementation on glycemic control in patients with diabetes depended on the dosage and duration of supplementation, the patient’s baseline 25(OH)D level, and the body mass index of the patient. The effects were particularly evident when vitamin D was administered in short-term, high-dose regimens to vitamin D-deficient, overweight, or patients with T2DM with baseline HbA1c levels of 8% or higher.¹³⁷ A double-blind, randomized clinical trial revealed that administering high doses of vitamin D to patients with prediabetes and VDD can increase insulin sensitivity and reduce the risk of progression to diabetes.¹³⁸ Another randomized controlled trial revealed that long-term supplementation with vitamin D significantly decreased fasting insulin levels, the HOMA-IR index, non-HDL cholesterol levels, high-sensitivity C-reactive protein (hs-CRP) levels, and uric acid levels in middle-aged and elderly patients with T2DM; however, vitamin D status, sex, and baseline obesity may influence the effects of vitamin D supplementation.¹³⁹ Davidson et al. reported that postrandomization bias may affect the estimation of the effect of vitamin D supplementation in diabetes prevention trials, and the group allocation in the trial and the 25(OH)D level in the trial showed an interaction effect on the prediction of diabetes risk. According to the test results, maintaining serum 25(OH)D levels ≥100 nmol/L through vitamin D supplementation is a promising method for reducing prediabetes and diabetes risk in adults.¹⁴⁰ In a study of 1774 overweight/obese adults at high risk for T2DM (prediabetes) who were randomly assigned to receive 4000 IU of vitamin D3 or a matching placebo daily for 24 months, supplementation with vitamin D3 for 24 months did not improve the beta cell function index in participants who were not selected on the basis of their baseline vitamin D status. After baseline screening, however, participants whose baseline 25(OH)D concentration was less than 12 ng/mL had improved beta cell function.¹¹⁵ Additionally, Karonova et al. reported that vitamin D supplementation may have a dose-dependent effect on the treatment of diabetic complications.¹³¹

Table 1.

Meta-analyses of RCTs regarding the effect of vitamin D supplementation on diabetes prevention and treatment

Author	No. of Trials Included	Study Populations	Outcome
Wu et al.132	24 RCTs	Subjects with T2DM	Vitamin D supplementation was associated with reduced HbA1c levels (SMD:-0.25;95% CI:-0.45 to −0.05), but had no effect on FBG levels (SMD:-0.14;95% CI:-0.31 to 0.03).
Li et al.133	20 RCTs	Subjects with T2DM	Vitamin D supplementation increased serum 25OHD levels (WMD:33.98; 95% CI:24.60 to 43.37) and improved HOMA-IR (SMD:-0.57; 95% CI: −1.09 to −0.04), but had no effect on FBG, HbA1c, or fasting insulin.
Zhang et al.134	8 RCTs	Subjects with Prediabetes	Vitamin D supplementation reduced the risk of T2DM (risk ratio,0.89;95% CI: 0.80 to 0.99).
Pittas et al.135	3 RCTs	Subjects with Prediabetes	Vitamin D reduced risk for diabetes by 15% (hazard ratio, 0.85;95% CI: 0.75 to 0.96), with a 3-year absolute risk reduction of 3.3% (95% CI:0.6%–6.0%).
Afraie et al.136	61 RCTs	Subjects with T2DM	Vitamin D supplementation reduced mean HbA1c (SMD: −0.15; 95% CI: −0.29 to −0.20) and mean FBG (SMD: −0.28; 95% CI: −0.40 to −0.15).
Chen et al.137	39 RCTs	Subjects with T2DM	Vitamin D supplementation reduced FBG (WMD: −0.49;95% CI: −0.69 to −0.28),HbA1c (WMD:-0.30%;95% CI: −0.43 to −0.18), HOMA-IR (WMD:-0.39;95% CI: −0.64 to −0.14), and insulin (WMD:-1.31;95% CI: −2.06 to −0.56) levels.

Generally, the benefits of vitamin D supplements for diabetes prevention and treatment are controversial. Theoretically, through its anti-inflammatory, antioxidant, and metabolic regulatory functions, vitamin D may reduce the risk of diabetes and its complications. However, the results of clinical research are inconsistent. On the one hand, some studies have shown that vitamin D supplementation has a positive effect on the prevention and treatment of diabetes; on the other hand, many studies have not reported any significant beneficial effects. There may be many reasons for this discrepancy. First, it may be related to the study design. Several studies had small sample sizes, which limits the statistical power to detect subtle but clinically meaningful differences. The results from larger studies had greater statistical power. However, the study populations were heterogeneous, and the results were limited by negative conclusions. In a randomized controlled experiment, if the blinding process is not carried out strictly, it can introduce bias and thus affect the results. Another contributing factor is the study participants, which can cause variations. Differences in baseline vitamin D levels may result in varying responses to supplementation, and individuals in the early versus late stages of diabetes may exhibit distinct reactions to vitamin D. Patients with comorbidities such as hypertension, hyperlipidemia, or other chronic kidney diseases can exhibit more complex pathophysiological mechanisms that might obscure the potential effects of vitamin D. The dosage and duration of vitamin D supplementation can influence outcomes. A low dose may not be effective, whereas a high dose will cause different side effects that may negatively affect the results. Short-term supplementation may correct only VDD. Long-term studies often have low patient compliance. Patients may discontinue taking their medication on their own or not take it regularly, which can affect the results. Moreover, vitamin D influences many physiological functions. In addition to regulating calcium and phosphorus metabolism, it also regulates the immune system and inhibits inflammation. Furthermore, it protects pancreatic β cells. The mechanisms of diabetes and its complications are not fully understood, and the design of the pathways involved is still under study. For example, some protective effects of vitamin D depend on the expression of VDR, and patients with abnormal VDR expression may suffer from “supplementation failure.” Future research is essential, particularly studies that are tailored to individual characteristics, to more accurately investigate the role of vitamin D supplements in the prevention and treatment of T2DM. Additionally, further optimization of the study design is necessary to minimize potential bias and increase the reliability of the research findings.

The research evidence is complex and multifaceted. To clearly present the evidence base for each perspective, we have compiled the relevant studies in Table 2.

Table 2.

Current research status on the relationship between vitamin D and type 2 diabetes mellitus

Viewpoint	Observational study	Clinical Evidence	Preclinical Evidence
Vitamin D affects insulin secretion and insulin sensitivity.	Cross-sectional study: Adolescents with lower 25(OH)D concentrations exhibited reduced insulin sensitivity (Bacha et al.56).	Randomized controlled trial: For individuals with prediabetes and vitamin D deficiency, high-dose vitamin D supplementation can improve insulin sensitivity (Niroomand et al.138).	Animal studies:1,25-dihydroxyvitamin D improves insulin secretion and β-cell activity (Ding et al.50) as well as pancreatic function and lipid metabolism (Jin et al.51); and VDR activation by calcipotriol reduces hepatic inflammation and steatosis, thereby improving insulin sensitivity (Dong et al.55).
Vitamin D improves insulin resistance.	NA	Randomized controlled trial: Vitamin D supplementation significantly reduced fasting insulin levels and HOMA-IR in middle-aged and elderly patients with type 2 diabetes mellitus (Hu et al.139).Meta-analyses: Vitamin D supplementation has been shown to effectively increase serum 25(OH)D levels and reduce insulin resistance (Li et al.133). Vitamin D supplementation significantly reduces serum FBG, HbA1c, HOMA-IR, and fasting insulin levels in patients with type 2 diabetes mellitus (Chen et al.137).	Animal studies: Vitamin D deficiency contributes to the development of insulin resistance within fat cells (Oh et al.58). 1,25-dihydroxyvitamin D improves oxidative stress and glucose metabolism in adipose tissue or fat cells (Manna et al.74).
Vitamin D deficiency increases the risk of type 2 diabetes mellitus.	Cross-sectional studies: vitamin D deficiency in men is linked to a higher likelihood of impaired glucose tolerance (Wang et al.44); low vitamin D levels show a strong correlation with the development of prediabetes (McCarthy et al.116); and vitamin D deficiency is consistently associated with type 2 diabetes mellitus (Reddy et al.124).	Prospective Study: Low levels of 25(OH)D may be associated with the incidence of prediabetes or type 2 diabetes mellitus in the Chinese population (Gao et al.117).	NA
Vitamin D supplementation may be effective in preventing and treating type 2 diabetes mellitus and its complications.	Cross-sectional studies:25(OH)D levels <67 nmol/L inversely correlate with UACR (Liang et al.130); deficiency is associated with increased macrovascular/microvascular events (Herrmann et al.120) and a higher prevalence of microvascular complications (Zoppini et al.122); and it independently raises the risk of diabetic peripheral neuropathy and nephropathy (Zhao et al.123).	Prospective Study: Elevated serum 25(OH)D concentrations are significantly associated with a reduced risk of diabetic microvascular complications (Chen et al.127).Randomized controlled trial: High-dose vitamin D supplementation helps improve microcirculation and reduce inflammation in patients with diabetic neuropathy (Karonova et al.131).Meta-analyses: Vitamin D supplementation may improve glycemic control in individuals with vitamin D deficiency or non-obese T2DM (Wu et al.132), reduce the risk of progression from prediabetes to T2DM (Zhang et al.134; Pittas et al.135), and significantly improve glycemic control while reducing complication risk in established T2DM (Afraie et al.136).	NA

Discussion

On the basis of a systematic analysis of existing evidence, the role of vitamin D supplementation in diabetes prevention and treatment is both promising and complex. Observational studies consistently indicate that lower serum 25(OH)D levels are associated with a higher risk of diabetes. In adults with prediabetes, vitamin D supplementation can effectively reduce the risk of progression to diabetes.^134,135 Conclusions from interventional studies, however, are not entirely consistent. The preventive effects of vitamin D do not uniformly apply to all individuals. Research has indicated that factors such as obesity status, baseline vitamin D levels, dosage, duration of supplementation, and population heterogeneity can influence the efficacy of vitamin D supplementation. Below is a summary analysis of the key factors affecting the effectiveness of vitamin D supplementation. The preventive benefits of vitamin D supplementation exhibit significant weight-related heterogeneity. In nonobese individuals (average BMI <30 kg/m²), vitamin D supplementation significantly reduces the risk of developing new-onset diabetes.¹³⁴ In contrast, the same intervention fails to demonstrate significant preventive effects in obese individuals. The reasons for these results may include the following: First, vitamin D is fat-soluble and stored in fat cells. Therefore, obese individuals require a higher vitamin D loading dose than individuals of normal weight to achieve a comparable increase in the serum 25(OH)D concentration.¹⁴¹ Second, obesity affects the metabolism of 25(OH)D. Research confirms that obesity reduces hepatic 25-hydroxylase activity, thereby decreasing serum 25(OH)D levels.¹⁴² Therefore, vitamin D supplementation does not show significant effects in obese individuals with prediabetes.

When is vitamin D supplementation needed, and does everyone require it? This is a key question for everyone. In individuals with prediabetes and severe vitamin D deficiency (25(OH)D < 12 ng/mL), vitamin D supplementation significantly improves pancreatic beta-cell function.¹¹⁵ This strongly suggests that the primary beneficiaries of supplementation are those with true vitamin D insufficiency. In large-scale trials that did not screen for baseline vitamin D levels, the positive effects observed in the deficient subgroup may have been diluted by the lack of effect in the large number of individuals who already had adequate vitamin D levels, potentially leading to neutral overall results. As demonstrated by Li et al., vitamin D supplementation at daily doses exceeding 2000 IU is associated with higher postexperimental vitamin D levels and more significant improvements in blood glucose indicators.¹⁴³ Additionally, vitamin D supplementation at a minimum dosage of 4000 IU/day may significantly reduce serum FPG and HbA1c levels and HOMA-IR scores.¹⁴⁴ Higher doses increase the likelihood of correcting vitamin D deficiency, but supraphysiological doses may be harmful. The optimal supplementation dose remains a matter of debate. A dosage of 4000 IU/day has been demonstrated to be relatively reasonable. The effects of vitamin D supplementation are primarily observed within a short period of three months.¹⁴⁵ This may be because the study used HbA1c as an indicator, which reflects the average blood glucose level over the prior two to three months, whereas other factors in long-term studies, such as medication adjustments and lifestyle modifications, may interfere with the observed effects. Current research findings suggest that a high-dose, short-term vitamin D supplementation regimen may be a suitable option. For patients already diagnosed with T2DM, vitamin D supplementation can effectively reduce glucose metabolism indicators. Additionally, it can lower the levels of certain cardiovascular risk-related markers.^137,139This effect is particularly notable in patients with T2DM who have poor glycemic control (HbA1c ≥ 8%).¹³⁷ Vitamin D supplements produce varying effects across different ethnic groups but exhibit a consistent pattern: individuals of Middle Eastern descent demonstrate the most pronounced blood sugar-lowering effects, followed by other Asian populations, while improvements are minimal among the remaining ethnic groups.¹³³ Individuals with darker skin tones and cultural tendencies to limit sun exposure (characteristic of Middle Eastern populations) are more prone to vitamin D deficiency and benefit significantly from supplementation.^146,147

Cojic et al. reported that compared with the T2DM group treated with metformin alone, the group receiving both metformin and vitamin D at the recommended dosage demonstrated significantly lower HbA1c levels after 3 and 6 months of vitamin D supplementation.¹⁴⁸ Their team also conducted a 6-month follow-up randomized controlled trial involving 140 patients with type 2 diabetes with well-controlled metabolism. The participants were randomly assigned to two groups (70 per group). Patients in the first group (intervention group) were assigned to receive either 50,000 IU or 14,000 IU of vitamin D3 on the basis of their baseline vitamin D levels. The second group (the metformin group) continued taking metformin alone throughout the 6-month study period. After 6 months, myeloperoxidase activity and xanthine oxidase activity were significantly reduced in the intervention group, with more pronounced effects than in patients treated with metformin alone.¹⁴⁹ These findings clearly demonstrate that vitamin D can reduce oxidative stress risk in patients with T2DM. Similar findings were reported in studies by Nada et al.¹⁵⁰ Animal studies have similarly indicated that vitamin D and metformin exhibit synergistic effects in the treatment of T2DM.¹⁵¹ Currently, research on the combined use of vitamin D supplements with hypoglycemic agents such as DPP-4 inhibitors, insulin, SGLT2 inhibitors, and GLP-1 receptor agonists is extremely limited. No studies have yet provided evidence confirming synergistic effects between these two approaches. There is currently insufficient evidence-based medical data to establish vitamin D as a core intervention for diabetes management. However, it may serve as an individualized adjunctive supplement. Clinically, on the basis of serum vitamin D levels in patients with diabetes, appropriate supplementation protocols can be developed and administered as needed for individuals with deficiency or insufficiency.

On the basis of the current evidence, individuals with prediabetes and severe vitamin D deficiency (25(OH)D < 12 ng/mL), nonobese prediabetic individuals (BMI <30 kg/m²), or those with diagnosed T2DM and poor glycemic control may benefit from vitamin D supplementation. However, obese patients with T2DM with normal or adequate baseline vitamin D levels may not experience significant benefits. Current research remains limited, with no clear consensus on the optimal vitamin D supplementation dosage or duration. These areas warrant future research. More detailed population stratification and larger datasets are needed to answer these questions.

Future research and perspectives

T2DM is a global public health problem. Patients with diabetes tend to suffer from vascular lesions and are predisposed to DN, diabetic cardiomyopathy, and other conditions. The search for new effective treatments for T2DM is critically important. It is now known that vitamin D/VDR ameliorates diabetes. From basic research and clinical research perspectives, vitamin D and VDR activators can alleviate clinical symptoms and improve outcomes in patients with diabetes through anti-inflammatory, antioxidative stress, and fat metabolism-related regulatory effects. Some individuals still debate the role of vitamin D in diabetes. Nevertheless, vitamin D supplementation is useful for patients with diabetes. In the future, more large-scale, multicenter, long-term clinical studies are needed to evaluate the optimal dose and duration for vitamin D supplementation. Clinical guidelines do not recommend routine screening for vitamin D deficiency in the general population to avoid overtesting. However, targeted assessment may be considered for individuals with specific risk factors (e.g., prediabetic individuals and nonobese patients with T2DM) or those belonging to groups at extremely high risk of severe deficiency. In such cases, the diagnosis and treatment of VDD can serve as part of measures to improve patient health and optimize diabetes management.

Acknowledgments

Figures were compiled using Biorender. The research was supported by the Chongqing Science and Health Joint Medical Research General Project (2026MSXM024), the Science and Health Joint Project of Dazu District Science and Technology Bureau (DZKJ2024JSYJ-KWXM1002, DZKJ2025JSYJ-KWXM1005), the Research project of the State Administration of Traditional Chinese Medicine on the collaborative chronic disease management of traditional Chinese medicine and western medicine: (CXZH2024087), the Chongqing Medical Leading Talent Project (YXLJ202514), the Chronic Disease Management Research Project of National Health Commission Capacity Building and Continuing Education Center (GWJJMB202510024191), and the General project of Chongqing Natural Science Foundation (CSTB2023NSCQ-MSX0246).

Author contributions

X.F.C. and S.Q. contributed equally. X.F.C., S.Q., J.J., and Q.N.W. performed the literature review and analysis. J.J. and Q.N.W. are the guarantors of this work and, as such, had full access to all the data in the article and take responsibility for the integrity of the data and the accuracy of the data analysis.

Declaration of interests

The authors declare no competing interests.