**5. Vitamin D deficiency and type 2 diabetes mellitus**

Type 2 diabetes mellitus, formerly known as adult-onset diabetes, is a complex chronic metabolic disorder that has become one of the most serious public healthcare problems worldwide. According to the data of the World Health Organization, 2.2 million people died from diabetes in 2012 and 1.6 million people died in 2015, and diabetes is expected to be the 7th cause of death by 2030. The incidence of T2D is estimated to account for 90% of all diabetes cases. T2D is characterized by dysfunction of pancreatic β-cell, systemic inflammation, and hyperglycemia due to insufficient insulin production, insulin action, or both [56]. A high diabetes-associated concentration of glucose in the blood over an extended period can cause heart disease, diabetic retinopathy, renal failure, poor blood circulation in the limbs, and, as a consequence, amputations.

T2D mainly develops as a result of the summation of genetic, environmental, and other risk factors [57]. To date, an increased risk of developing T2D in monozygotic twins with a statistical reliability of about 96% has been convincingly shown. Moreover, the risk of developing this disease in children from diabetic parents is 40% higher than in the offspring of healthy parents. T2D is now regarded as an endocrine-metabolic disease of a polygenic nature. About 75 loci have already been identified, damage to the sequences of which can be directly associated with the risk of developing T2D. These genes encode proteins with very different functions, such as ion channels (KCNJ11; potassium inwardly rectifying channel, subfamily J, and member 11), various transcription factors (TCF7L2, transcription factor 7-like 2), receptors (IRS1, insulin receptor substrate 1; MTNR1B, melatonin-receptor gene; and PPARγ2), growth factors (IGF2BP2, insulin-like growth factor two binding protein 2), as well as CDKN2A (cyclin-dependent kinase inhibitor 2A), HHEX (hematopoietically expressed homeobox protein), and FTO (fat mass and obesityassociated protein) [58–60].

Despite the growing body of data on the relationship between the risk of developing T2D and certain genes, improper food behavior and the sedentary lifestyle are still considered the key reasons for the development of the disease. In a number of experimental and clinical studies, VD has been shown to exhibit various nonskeletal properties that significantly regulate glucose metabolism. Furthermore, human studies have clearly revealed an inverse association between vitamin D status and the prevalence of T2D. It was found in numerous observational studies that the concentration of 25OHD negatively correlates with deteriorated glucose homeostasis, IR, and impaired β-cell function [61]. Low blood serum 25OHD levels were associated with the negative changes in a number of metabolic parameters, indicative of IR, including BMI (body mass index), HOMA-IR (homeostatic model assessment for IR), TG (triglycerides), HDL (high-density lipoproteins), LDL (low-density lipoproteins), TC (total cholesterol), and HbA1c [62]. More recently, large-scale epidemiological studies have been carried out as for the dependence of the risk of T2D developing on the availability of VD. VD deficiency has been shown to be widespread in both men and women in different age groups among Saudi citizens, and this was accompanied by hyperglycemia in 90 percent of patients [63]. T2D patients studied in India also showed VD deficiency of varying severity in 77% of subjects [64]. The association between a low serum of 25OHD concentration and an increased risk of developing T2D can be partially explained by an increase in fat mass. A study of serum 25OHD in patients with T2D from the urban area of Cairo with limited exposure to the sun and overdressing habit revealed a decrease of its level by 13% compared with the control. Depleted level of the prohormone has been found to be related to a higher risk of insulin resistance [65].

However, as it turned out, not all studies confirmed a decrease in VD contents in patients with T2D. Using the method of high-performance liquid chromatography in tandem with mass spectrometry, significantly higher levels of VD were demonstrated in patients with T1D and T2D in comparison with the control group [66].

Overall, most of the data presented here suggest a pivotal role of VD in the regulation of insulin secretion and confirm that the decreased insulin sensitivity at target organs may be attributable to VD inadequacy [67]. The relationship between VD deficiency and IR could be realized at the level of modulation of immune processes and inflammation, since VD deficiency is associated with an increase in inflammatory markers. In addition, genetic polymorphisms of VD-related genes such as VDR, CYP2R1, and CYP27B1 may predispose to impaired glycemic control and T2D [68].

As we mentioned earlier, VD mediates its biological activity through VDR, which belongs to the family of steroid hormone receptors. Many VDR gene SNPs have been identified to be related to T2D, in particular to insulin synthesis and release [69]. The most reported VDR SNPs associated with diabetes are Fok1, Bsm1, Taq1, and Apa1. Recently, the study of these polymorphisms is becoming increasingly popular because their detection can be a reliable diagnostic characteristic in determining the risk of T2D development. The association between VDR polymorphisms and abdominal obesity has shown that patients with Bsm1 and Apa1 polymorphisms have low vitamin D status, which is accompanied by an increase in the concentrations of TC, LDL, and TG [69]. The results of another study show that body weight and BMI were significantly associated with polymorphisms Bsm1 and Taq1, while Bsm1 strongly correlated with elevated HbA1c level. The frequency of the heterozygous genotype of the Bsm1 polymorphism was significantly greater in type 2 diabetics than in controls [70]. A study of this parameter in a group of patients with T2D from India revealed that it was Taq1 and Bsm1 polymorphisms that were closely associated with diabetes [71]. Thus, it can be concluded that the detection of different types of VDR gene polymorphisms is a reliable prognostic parameter for the risk of T2D. In addition, the type of polymorphism appears to be race-specific.

Despite a large amount of data on the association of CYP27B1 polymorphisms with the risk of T1D, the effect of different SNP variants of this gene in the development of T2D is unclear to this day [72, 73].

While the closest relationship between VDR polymorphism in T2D has long been established, the discovery of the effect of CYP2R1 gene polymorphisms on the risk of developing this disease was a real step forward. Among a large group of tested SNPs of CYP2R1 gene, only two of them showed reliable association with the incidence of T2D. However, none of the tested polymorphisms were independently associated with serum 25OHD levels [74].

The effect of VD supplementation on glucose metabolism in patients with T2D remains controversial. It was shown that replenishing VD deficiency with high doses of cholecalciferol helped to reduce non-HDL cholesterol and caused significant normalizing changes in metabolic parameters of glucose homeostasis

**201**

*Vitamin D Deficiency and Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.89543*

risk of diabetic retinopathy [80, 81].

macrovascular disease [83].

(fasting glucose and serum insulin) and a decrease in oxidative stress and DNA damage [75, 76]. VD supplementation also caused an increase in insulin secretion and insulin sensitivity in T2D patients [77]. Nevertheless, some research groups did not find any effect, or only a slight decrease in fasting plasma glucose and an improvement in IR were seen. Basically, patients with VD deficiency and impaired

In addition to the ability of VD to reduce the risk of T2D, an adequate level of this vitamin in the body is also important for correcting diabetes-related pathologies such as retinopathy, nephropathy, neuropathy, and secondary osteoporosis caused by diabetes. Moreover, patients with already diagnosed T2D also have a risk of developing VD deficiency, in particular, due to the progression of nephropathy caused by diabetes [78]. Serum 25OHD was shown to be significantly reduced in patients with diabetic nephropathy [79]. Thus, the relationship between VD deficiency and the incidence of type 2 diabetes and related complications is likely to be bilateral.

Continuing the discussion on diabetic complications, we may note that vitamin D deficiency correlates with the risk of diabetic retinopathy. However, the reliable establishment of this relationship is problematic due to a number of limiting factors: cross-sectional structure, small sample size, ethnic variation, and heterogeneity in criteria that do not contribute to the identification of VD deficiency. Nevertheless, at least two state-of-the-art meta-analyses of observational studies indicate that D hypovitaminosis among T2D patients is associated with a significantly increased

A meta-analysis of data on the relationship between VD deficiency and the development of diabetes-induced neuropathy also revealed a strong correlation. Recovery of insulin secretion, increasing insulin sensitivity of target tissues, and reducing the inflammatory response have been proposed as potential mechanisms for improving the clinical manifestations of diabetic neuropathy following VD supplementation [82]. Furthermore, several independent studies have established serum 25OHD levels to predict cardiovascular complications or to assess the possible protective role of VD intake in patients with T2D. Diabetic patients with 25OHD < 36 nmol/L manifested approximately 21% higher risk for developing

There is no doubt that achieving normal levels of 25OHD is an important factor in preventing the onset of T2D or for eliminating the complications associated with the disease. However, at the moment, the question of the VD dosage and duration of the complex therapy of patients with T2D remains unresolved. Based on interventional trials, it can be postulated that the VD dose needs to be more than 2000 IU per day to raise blood 25OHD levels above 80 nmol/L, which is considered to be sufficient to reduce the risk of T2D [84]. However, the results of a double-blinded, placebo-controlled, randomized trial with 4000 IU of VD did not improve HbA1c or OGTT (oral glucose tolerance test)-based indices of β-cell function or insulin secretion in patients with stable T2D. The ambiguity of the results may be due to the following factors: the baseline 25OHD concentration was too high (<27 ng/mL), whereas a significant reduction in HbA1c and fasting glucose after VD supplementation was reported only among patients with baseline 25OHD < 20 ng/mL; VD may have no detectable effect in persons with well-controlled diabetes (good glycemic control, HbA1c-6.6%); and/or metformin treatment, which may have masked a small effect of VD supplementation [85]. These data indicate the need for individual VD therapy for each patient with a risk of development or with an already established diagnosis of T2D. When choosing this type of therapy, it is necessary to take into account the initial level of 25OHD in the patient's blood, changes in this level during therapy, as well as the presence of other drugs in the treatment regimen

that can affect the manifestation of the beneficial effects of VD.

glucose tolerance at baseline demonstrated these latter effects [68].

#### *Vitamin D Deficiency and Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.89543*

*Vitamin D Deficiency*

and T2D [68].

race-specific.

ment of T2D is unclear to this day [72, 73].

associated with serum 25OHD levels [74].

to be widespread in both men and women in different age groups among Saudi citizens, and this was accompanied by hyperglycemia in 90 percent of patients [63]. T2D patients studied in India also showed VD deficiency of varying severity in 77% of subjects [64]. The association between a low serum of 25OHD concentration and an increased risk of developing T2D can be partially explained by an increase in fat mass. A study of serum 25OHD in patients with T2D from the urban area of Cairo with limited exposure to the sun and overdressing habit revealed a decrease of its level by 13% compared with the control. Depleted level of the prohormone has been

However, as it turned out, not all studies confirmed a decrease in VD contents in patients with T2D. Using the method of high-performance liquid chromatography in tandem with mass spectrometry, significantly higher levels of VD were demonstrated in patients with T1D and T2D in comparison with the control group [66]. Overall, most of the data presented here suggest a pivotal role of VD in the regulation of insulin secretion and confirm that the decreased insulin sensitivity at target organs may be attributable to VD inadequacy [67]. The relationship between VD deficiency and IR could be realized at the level of modulation of immune processes and inflammation, since VD deficiency is associated with an increase in inflammatory markers. In addition, genetic polymorphisms of VD-related genes such as VDR, CYP2R1, and CYP27B1 may predispose to impaired glycemic control

As we mentioned earlier, VD mediates its biological activity through VDR, which belongs to the family of steroid hormone receptors. Many VDR gene SNPs have been identified to be related to T2D, in particular to insulin synthesis and release [69]. The most reported VDR SNPs associated with diabetes are Fok1, Bsm1, Taq1, and Apa1. Recently, the study of these polymorphisms is becoming increasingly popular because their detection can be a reliable diagnostic characteristic in determining the risk of T2D development. The association between VDR polymorphisms and abdominal obesity has shown that patients with Bsm1 and Apa1 polymorphisms have low vitamin D status, which is accompanied by an increase in the concentrations of TC, LDL, and TG [69]. The results of another study show that body weight and BMI were significantly associated with polymorphisms Bsm1 and Taq1, while Bsm1 strongly correlated with elevated HbA1c level. The frequency of the heterozygous genotype of the Bsm1 polymorphism was significantly greater in type 2 diabetics than in controls [70]. A study of this parameter in a group of patients with T2D from India revealed that it was Taq1 and Bsm1 polymorphisms that were closely associated with diabetes [71]. Thus, it can be concluded that the detection of different types of VDR gene polymorphisms is a reliable prognostic parameter for the risk of T2D. In addition, the type of polymorphism appears to be

Despite a large amount of data on the association of CYP27B1 polymorphisms with the risk of T1D, the effect of different SNP variants of this gene in the develop-

While the closest relationship between VDR polymorphism in T2D has long been established, the discovery of the effect of CYP2R1 gene polymorphisms on the risk of developing this disease was a real step forward. Among a large group of tested SNPs of CYP2R1 gene, only two of them showed reliable association with the incidence of T2D. However, none of the tested polymorphisms were independently

The effect of VD supplementation on glucose metabolism in patients with T2D remains controversial. It was shown that replenishing VD deficiency with high doses of cholecalciferol helped to reduce non-HDL cholesterol and caused significant normalizing changes in metabolic parameters of glucose homeostasis

found to be related to a higher risk of insulin resistance [65].

**200**

(fasting glucose and serum insulin) and a decrease in oxidative stress and DNA damage [75, 76]. VD supplementation also caused an increase in insulin secretion and insulin sensitivity in T2D patients [77]. Nevertheless, some research groups did not find any effect, or only a slight decrease in fasting plasma glucose and an improvement in IR were seen. Basically, patients with VD deficiency and impaired glucose tolerance at baseline demonstrated these latter effects [68].

In addition to the ability of VD to reduce the risk of T2D, an adequate level of this vitamin in the body is also important for correcting diabetes-related pathologies such as retinopathy, nephropathy, neuropathy, and secondary osteoporosis caused by diabetes. Moreover, patients with already diagnosed T2D also have a risk of developing VD deficiency, in particular, due to the progression of nephropathy caused by diabetes [78]. Serum 25OHD was shown to be significantly reduced in patients with diabetic nephropathy [79]. Thus, the relationship between VD deficiency and the incidence of type 2 diabetes and related complications is likely to be bilateral.

Continuing the discussion on diabetic complications, we may note that vitamin D deficiency correlates with the risk of diabetic retinopathy. However, the reliable establishment of this relationship is problematic due to a number of limiting factors: cross-sectional structure, small sample size, ethnic variation, and heterogeneity in criteria that do not contribute to the identification of VD deficiency. Nevertheless, at least two state-of-the-art meta-analyses of observational studies indicate that D hypovitaminosis among T2D patients is associated with a significantly increased risk of diabetic retinopathy [80, 81].

A meta-analysis of data on the relationship between VD deficiency and the development of diabetes-induced neuropathy also revealed a strong correlation. Recovery of insulin secretion, increasing insulin sensitivity of target tissues, and reducing the inflammatory response have been proposed as potential mechanisms for improving the clinical manifestations of diabetic neuropathy following VD supplementation [82]. Furthermore, several independent studies have established serum 25OHD levels to predict cardiovascular complications or to assess the possible protective role of VD intake in patients with T2D. Diabetic patients with 25OHD < 36 nmol/L manifested approximately 21% higher risk for developing macrovascular disease [83].

There is no doubt that achieving normal levels of 25OHD is an important factor in preventing the onset of T2D or for eliminating the complications associated with the disease. However, at the moment, the question of the VD dosage and duration of the complex therapy of patients with T2D remains unresolved. Based on interventional trials, it can be postulated that the VD dose needs to be more than 2000 IU per day to raise blood 25OHD levels above 80 nmol/L, which is considered to be sufficient to reduce the risk of T2D [84]. However, the results of a double-blinded, placebo-controlled, randomized trial with 4000 IU of VD did not improve HbA1c or OGTT (oral glucose tolerance test)-based indices of β-cell function or insulin secretion in patients with stable T2D. The ambiguity of the results may be due to the following factors: the baseline 25OHD concentration was too high (<27 ng/mL), whereas a significant reduction in HbA1c and fasting glucose after VD supplementation was reported only among patients with baseline 25OHD < 20 ng/mL; VD may have no detectable effect in persons with well-controlled diabetes (good glycemic control, HbA1c-6.6%); and/or metformin treatment, which may have masked a small effect of VD supplementation [85]. These data indicate the need for individual VD therapy for each patient with a risk of development or with an already established diagnosis of T2D. When choosing this type of therapy, it is necessary to take into account the initial level of 25OHD in the patient's blood, changes in this level during therapy, as well as the presence of other drugs in the treatment regimen that can affect the manifestation of the beneficial effects of VD.
