**4. Vitamin D deficiency and type 1 diabetes mellitus**

Type 1 diabetes mellitus is an autoimmune disorder caused by the progressive T-cell-mediated destruction of insulin-producing β-cells in the pancreas. T1D is commonly diagnosed in childhood and young adults, who are ultimately at risk of the long-term complications of diabetes [30]. This autoimmune condition is characterized by a state of hypoinsulinaemia and insulin-like growth factor (IGF-1) deficiency. T1D is triggered by a combination of both genetic and environmental factors including viral infections, dietary antigens, disruption in the gut microbiota, and VD deficiency [31].

Data regarding the presence of VDR in immune cells (B- and T-lymphocytes) and their ability to produce hormonally active form of VD locally, which acts on immune cells in auto-/paracrine manner, give the evidence that VD is an important regulator of multiple pathways of innate and adaptive immunity. In addition to immune-modulating properties, VD seems to play a role in the regulation of insulin secretion from β-cells. Respectively, VD insufficiency/deficiency is frequently reported to be associated with immunological disorders such as T1D, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, inflammatory bowel disease, hepatitis, asthma, and respiratory infections [32]. The link between the state of VD deficiency and T1D is a latter-day considerable area of interest; however, the presence of the clear association and especially causal relationship between low VD status and the occurrence of T1D still remains disputable and controversial.

Most of the international epidemiological and clinical studies have provided evidence to this causal relationship primarily in children. It has been reported previously that low 25OHD concentrations are fairly prevalent in the UK children with T1D [33]. Moreover, it has been shown that genetic factors affecting the VD metabolic pathway during the pregnancy can be related to the development of T1D. Another study emphasized that the fetal environment, including maternal VD metabolism, may be one of those factors that can lead to the early onset of T1D in Finnish children [34]. The study of VD level and its associated factors in Korean youth with T1D showed that serum 25OHD and 1,25(OH)2D levels were lower in T1D cases than in healthy controls [35]. Nevertheless, in other cross-sectional study of subjects in Seoul National University Children's Hospital, there was no significant difference in the frequency of VD deficiency or serum 25OHD level between healthy and pediatric T1D patients [36].

There is much less data available regarding adult patients with T1D. It has been observed that the serum concentration of VD is negatively associated with IR in adult diabetic patients recruited in Poland [37]. In Algerian population, the

**197**

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

status marker (25OHD) in adult T1D patients.

CYP27B1, and 24-hydroxylase (CYP24A1).

the bioavailability and specific effects of VD metabolites.

and to treat this disease.

link between VD deficiency and an increased risk of T1D was also found [38]. In contrast, there was no difference reported between Turkish adult T1D patients and healthy controls according to their vitamin D levels [39]. The exact reason for these conflicting results is unclear; thus, we can assume that the interplay of genetic, nutritional, and environmental factors seems to affect the circulating level of VD

The cellular and molecular mechanisms underlying the VD deficiency in patients with TID deserve further thorough and comprehensive study. More recently, in addition to measuring the level of 25OHD, increased attention has been paid to new experimental directions, in particular, the investigation of the state of the VD auto-/paracrine system, including the following key components: VDR,

Different genetic factors including mutations are known to modify serum 25OHD concentration. Several single nucleotide polymorphisms (SNPs) in the metabolic pathway of VD contribute as the genetic component to VD status. There is a set of studies dedicated to the associations between T1D and mutations related to VD metabolism genes such as VD-binding protein (VDBP), VDR [34, 40, 41], and CYP24A1. Moreover, polymorphisms in CYP2R1 gene encoding the enzyme involved in 25-hydroxylation of VD were also shown to be associated with a higher risk of T1D. Thus, polymorphisms in VD metabolism genes may contribute to susceptibility to T1D in Korean children [35]. Another study linked T-cell proliferation with VDBP level and reported higher levels and frequencies of serum anti-DBP antibodies in patients with T1D vs. healthy controls. This study postulated that VDBP, which was shown to be expressed in cells of pancreatic islets, can act as an autoantigen in T1D [42]. Furthermore, it has been reported that lower maternal third trimester VDBP levels and cord blood VDBP levels have been associated with a higher risk of T1D in offspring [43, 44]. At the same time, there is a lack of studies related to the investigation of the role of CYP27B1 in immune cells, such as monocytes, macrophages, and T-cells, which could shed light on the involvement of impaired VD metabolism in the pathogenesis and/or prevention of T1D. Thus, as VD biosynthesis and its signaling are regulated by genes encoding the VDR and enzymes of VD activation/catabolism, their polymorphisms may significantly alter

Taken together, these data point to a role of VD deficiency in increasing the risk of T1D progression that provides the basis for further prospective studies on developing guidelines for vitamin D intake to prevent VD deficiency in patients with T1D

Since VD is considered a potential diabetes risk modifier, more studies appear to evaluate the role of vitamin D as an adjunctive therapy in improving glycemic control. The recent international study revealed that the majority of participants in Finland, Germany, and Sweden (97–99%) and 50% in the US receiving VD supplements during infancy demonstrated a reduced risk of T1D [45]. In another clinical trial, patients with T1D and low 25OHD concentrations were treated with different doses of cholecalciferol once daily for 3 months depending on their VD status, and as a result, it has been established that cholecalciferol can potentially improve the glycemic control [33]. Recent studies have shown favorable changes in HbA1c, C-peptide, insulin dose, and insulin sensitivity in VD-supplemented patients; therefore, cholecalciferol is increasingly attracting attention as a potential additional therapy in patients with T1D. In a double-blinded randomized controlled trial, which included Indian children with T1D, oral VD supplementation was used for six months in addition to insulin therapy. It has been proven that VD treatment may serve as an adjuvant to insulin therapy for children with T1D due to its effect on augmenting residual β-cell function and improving insulin secretion [46]. Some

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

*Vitamin D Deficiency*

are summarized in **Figure 2**.

and VD deficiency [31].

able and controversial.

healthy and pediatric T1D patients [36].

**4. Vitamin D deficiency and type 1 diabetes mellitus**

leptin). It has been reported in numerous trials using animal models and in several human observational studies that higher VD levels are accompanied by lower inflammatory markers including TNF-α, IL-6, and C-reactive protein in healthy persons, and in those with inflammation-associated diseases, such as arteriosclerosis, inflammatory polyarthritis, and diabetes [28]. As for adipokines, positive correlation was shown between VD and adiponectin, and inverse correlation between VD and leptin [29]. Finally, VD by targeting mitochondrial respiratory functions through multiple mechanisms also attenuates oxidative stress and exerts key beneficial effects on controlling inflammation, impaired energy metabolism, and cell apoptosis. However, this topic is beyond the scope of this chapter. Vitamin D functions associated with the regulation of β-cell function and insulin sensitivity

Type 1 diabetes mellitus is an autoimmune disorder caused by the progressive T-cell-mediated destruction of insulin-producing β-cells in the pancreas. T1D is commonly diagnosed in childhood and young adults, who are ultimately at risk of the long-term complications of diabetes [30]. This autoimmune condition is characterized by a state of hypoinsulinaemia and insulin-like growth factor (IGF-1) deficiency. T1D is triggered by a combination of both genetic and environmental factors including viral infections, dietary antigens, disruption in the gut microbiota,

Data regarding the presence of VDR in immune cells (B- and T-lymphocytes) and their ability to produce hormonally active form of VD locally, which acts on immune cells in auto-/paracrine manner, give the evidence that VD is an important regulator of multiple pathways of innate and adaptive immunity. In addition to immune-modulating properties, VD seems to play a role in the regulation of insulin secretion from β-cells. Respectively, VD insufficiency/deficiency is frequently reported to be associated with immunological disorders such as T1D, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, inflammatory bowel disease, hepatitis, asthma, and respiratory infections [32]. The link between the state of VD deficiency and T1D is a latter-day considerable area of interest; however, the presence of the clear association and especially causal relationship between low VD status and the occurrence of T1D still remains disput-

Most of the international epidemiological and clinical studies have provided evidence to this causal relationship primarily in children. It has been reported previously that low 25OHD concentrations are fairly prevalent in the UK children with T1D [33]. Moreover, it has been shown that genetic factors affecting the VD metabolic pathway during the pregnancy can be related to the development of T1D. Another study emphasized that the fetal environment, including maternal VD metabolism, may be one of those factors that can lead to the early onset of T1D in Finnish children [34]. The study of VD level and its associated factors in Korean youth with T1D showed that serum 25OHD and 1,25(OH)2D levels were lower in T1D cases than in healthy controls [35]. Nevertheless, in other cross-sectional study of subjects in Seoul National University Children's Hospital, there was no significant difference in the frequency of VD deficiency or serum 25OHD level between

There is much less data available regarding adult patients with T1D. It has been observed that the serum concentration of VD is negatively associated with IR in adult diabetic patients recruited in Poland [37]. In Algerian population, the

**196**

link between VD deficiency and an increased risk of T1D was also found [38]. In contrast, there was no difference reported between Turkish adult T1D patients and healthy controls according to their vitamin D levels [39]. The exact reason for these conflicting results is unclear; thus, we can assume that the interplay of genetic, nutritional, and environmental factors seems to affect the circulating level of VD status marker (25OHD) in adult T1D patients.

The cellular and molecular mechanisms underlying the VD deficiency in patients with TID deserve further thorough and comprehensive study. More recently, in addition to measuring the level of 25OHD, increased attention has been paid to new experimental directions, in particular, the investigation of the state of the VD auto-/paracrine system, including the following key components: VDR, CYP27B1, and 24-hydroxylase (CYP24A1).

Different genetic factors including mutations are known to modify serum 25OHD concentration. Several single nucleotide polymorphisms (SNPs) in the metabolic pathway of VD contribute as the genetic component to VD status. There is a set of studies dedicated to the associations between T1D and mutations related to VD metabolism genes such as VD-binding protein (VDBP), VDR [34, 40, 41], and CYP24A1. Moreover, polymorphisms in CYP2R1 gene encoding the enzyme involved in 25-hydroxylation of VD were also shown to be associated with a higher risk of T1D. Thus, polymorphisms in VD metabolism genes may contribute to susceptibility to T1D in Korean children [35]. Another study linked T-cell proliferation with VDBP level and reported higher levels and frequencies of serum anti-DBP antibodies in patients with T1D vs. healthy controls. This study postulated that VDBP, which was shown to be expressed in cells of pancreatic islets, can act as an autoantigen in T1D [42]. Furthermore, it has been reported that lower maternal third trimester VDBP levels and cord blood VDBP levels have been associated with a higher risk of T1D in offspring [43, 44]. At the same time, there is a lack of studies related to the investigation of the role of CYP27B1 in immune cells, such as monocytes, macrophages, and T-cells, which could shed light on the involvement of impaired VD metabolism in the pathogenesis and/or prevention of T1D. Thus, as VD biosynthesis and its signaling are regulated by genes encoding the VDR and enzymes of VD activation/catabolism, their polymorphisms may significantly alter the bioavailability and specific effects of VD metabolites.

Taken together, these data point to a role of VD deficiency in increasing the risk of T1D progression that provides the basis for further prospective studies on developing guidelines for vitamin D intake to prevent VD deficiency in patients with T1D and to treat this disease.

Since VD is considered a potential diabetes risk modifier, more studies appear to evaluate the role of vitamin D as an adjunctive therapy in improving glycemic control. The recent international study revealed that the majority of participants in Finland, Germany, and Sweden (97–99%) and 50% in the US receiving VD supplements during infancy demonstrated a reduced risk of T1D [45]. In another clinical trial, patients with T1D and low 25OHD concentrations were treated with different doses of cholecalciferol once daily for 3 months depending on their VD status, and as a result, it has been established that cholecalciferol can potentially improve the glycemic control [33]. Recent studies have shown favorable changes in HbA1c, C-peptide, insulin dose, and insulin sensitivity in VD-supplemented patients; therefore, cholecalciferol is increasingly attracting attention as a potential additional therapy in patients with T1D. In a double-blinded randomized controlled trial, which included Indian children with T1D, oral VD supplementation was used for six months in addition to insulin therapy. It has been proven that VD treatment may serve as an adjuvant to insulin therapy for children with T1D due to its effect on augmenting residual β-cell function and improving insulin secretion [46]. Some

representative studies on mechanisms of VD action in T1D described a beneficial effect of its supplementation on regulatory T-cells, with an increase in their percentage [47], suppressive capacity [48], and reduced progression to undetectable C-peptide.

However, some other studies have not demonstrated a beneficial effect of VD supplementation in preventing/improving the course of T1D or its complications. The prospective Environmental Determinants of Diabetes in the Young (TEDDY) Study demonstrated no benefit of maternal VD supplementation during pregnancy on the risk of islet autoimmunity in the offspring [49]. According to the review [32], there was no beneficial impact of VD supplementation on β-cell function, HbA1c levels, or insulin requirement.

The reason for these conflicting results is unclear. Nevertheless, we can presume the presence of a plethora of factors that may affect the results. Differences in study design, seasonal differences, stages in the progression of diabetes, ethnic origin of the populations, age and gender of patients may contribute. Therefore, further randomized controlled trials with a larger sample of patients are needed to gain more insight into the relationship between VD and T1D and to investigate VD replacement in preventing T1D.

The life expectancy of T1D patients has increased substantially during the last decades due to the availability of exogenous insulin, though it is still shorter than that of healthy people and associated with the development of chronic complications. Traditionally, the diabetic complications have been classified as either microvascular (retinopathy, nephropathy, and neuropathy) or macrovascular (cardiovascular disease, cerebrovascular accidents, and peripheral vascular disease). Although intensive glycemic control significantly reduced the incidence of microvascular and macrovascular manifestations, the majority of patients with T1D are still developing these outcomes. Most clinical trials related to the influence of VD supplementation on diabetes-associated complications have been performed in patients with T2D. To date, a limited number of experimental and clinical trials are available regarding the effect of VD on complications associated with T1D.

Diabetic ketoacidosis, which is the most dangerous and life-threatening complication of mainly T1D that results from insulin deficiency or excess of adrenaline or cortisol, is found to be associated with low VD level. VD is known to protect against viral and bacterial infections, which were shown to be triggering factors for diabetic ketoacidosis [50]; as a result, VD supplementation can become an integral part of diabetic ketoacidosis prevention and management. Nephropathy is another well-characterized complication of T1D, resulting in proteinuria and urinary loss of micronutrients. It has been previously found that the dietary supplements may modulate VD balance, attenuate polyuria, proteinuria, and renal hypertrophy in experimental T1D [51]. In addition, it has been reported that VD may reduce diabetic nephropathy not only by improving blood glucose and insulin levels but also by modulating hexosamine pathways in kidneys [52]. More recently, it has been shown that 1,25(OH)2D may improve diabetic cardiomyopathy in T1D rats by modulating autophagy through the β-catenin/TCF4/GSK-3β and mTOR pathway [53]. Several studies have also demonstrated an association between low VD levels and diabetic peripheral neuropathy. Since VD is a well-known neurosteroid, a possible beneficial effect of its supplementation on preventing diabetic peripheral neuropathy can be assumed; nevertheless, further studies are needed.

Type 1 diabetes mellitus is a secondary cause of osteoporosis, characterized by reduced bone mass and disturbed bone microarchitecture. Patients with T1D have increased fracture risk that may be determined by the low 25OHD levels. Diabetic retinopathy, advanced cortical cataracts, and diabetic neuropathy are the risk factors for increased number of falls and, as a result, fracture because of

**199**

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

as a consequence, amputations.

associated protein) [58–60].

prevention of T1D-associated osteoporosis [55].

visual impairment and alterations in balance [54]. Replacement of VD along with calcium has been found to improve the bone mineral density in children with T1D; therefore, an adequate calcium level and VD supplementation are important for the

According to available experimental and clinical data, new recommendations for T1M patients have been developed including obligatory assessment of serum 25OHD level and prescription of personalized doses of vitamin D in order to avoid

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,

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 obesity-

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

the development of T1M complications or at least detain its progression.

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

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

*Vitamin D Deficiency*

HbA1c levels, or insulin requirement.

replacement in preventing T1D.

C-peptide.

representative studies on mechanisms of VD action in T1D described a beneficial effect of its supplementation on regulatory T-cells, with an increase in their percentage [47], suppressive capacity [48], and reduced progression to undetectable

However, some other studies have not demonstrated a beneficial effect of VD supplementation in preventing/improving the course of T1D or its complications. The prospective Environmental Determinants of Diabetes in the Young (TEDDY) Study demonstrated no benefit of maternal VD supplementation during pregnancy on the risk of islet autoimmunity in the offspring [49]. According to the review [32], there was no beneficial impact of VD supplementation on β-cell function,

The reason for these conflicting results is unclear. Nevertheless, we can presume

The life expectancy of T1D patients has increased substantially during the last decades due to the availability of exogenous insulin, though it is still shorter than that of healthy people and associated with the development of chronic complications. Traditionally, the diabetic complications have been classified as either microvascular (retinopathy, nephropathy, and neuropathy) or macrovascular (cardiovascular disease, cerebrovascular accidents, and peripheral vascular disease). Although intensive glycemic control significantly reduced the incidence of microvascular and macrovascular manifestations, the majority of patients with T1D are still developing these outcomes. Most clinical trials related to the influence of VD supplementation on diabetes-associated complications have been performed in patients with T2D. To date, a limited number of experimental and clinical trials are

the presence of a plethora of factors that may affect the results. Differences in study design, seasonal differences, stages in the progression of diabetes, ethnic origin of the populations, age and gender of patients may contribute. Therefore, further randomized controlled trials with a larger sample of patients are needed to gain more insight into the relationship between VD and T1D and to investigate VD

available regarding the effect of VD on complications associated with T1D.

neuropathy can be assumed; nevertheless, further studies are needed.

Type 1 diabetes mellitus is a secondary cause of osteoporosis, characterized by reduced bone mass and disturbed bone microarchitecture. Patients with T1D have increased fracture risk that may be determined by the low 25OHD levels. Diabetic retinopathy, advanced cortical cataracts, and diabetic neuropathy are the risk factors for increased number of falls and, as a result, fracture because of

Diabetic ketoacidosis, which is the most dangerous and life-threatening complication of mainly T1D that results from insulin deficiency or excess of adrenaline or cortisol, is found to be associated with low VD level. VD is known to protect against viral and bacterial infections, which were shown to be triggering factors for diabetic ketoacidosis [50]; as a result, VD supplementation can become an integral part of diabetic ketoacidosis prevention and management. Nephropathy is another well-characterized complication of T1D, resulting in proteinuria and urinary loss of micronutrients. It has been previously found that the dietary supplements may modulate VD balance, attenuate polyuria, proteinuria, and renal hypertrophy in experimental T1D [51]. In addition, it has been reported that VD may reduce diabetic nephropathy not only by improving blood glucose and insulin levels but also by modulating hexosamine pathways in kidneys [52]. More recently, it has been shown that 1,25(OH)2D may improve diabetic cardiomyopathy in T1D rats by modulating autophagy through the β-catenin/TCF4/GSK-3β and mTOR pathway [53]. Several studies have also demonstrated an association between low VD levels and diabetic peripheral neuropathy. Since VD is a well-known neurosteroid, a possible beneficial effect of its supplementation on preventing diabetic peripheral

**198**

visual impairment and alterations in balance [54]. Replacement of VD along with calcium has been found to improve the bone mineral density in children with T1D; therefore, an adequate calcium level and VD supplementation are important for the prevention of T1D-associated osteoporosis [55].

According to available experimental and clinical data, new recommendations for T1M patients have been developed including obligatory assessment of serum 25OHD level and prescription of personalized doses of vitamin D in order to avoid the development of T1M complications or at least detain its progression.
