Vitamin D Update of Latest Findings of Interest (Cardiometabolic, Diabetes,  High Blood Pressure)

James Meschino DC, MS, ROHP

Vitamin D receptors found on:

• Brain
• Breast
• Prostate
• Colon
• Pancreas
• Immune Cells

Established Biological Functions:

• Bone metabolism
• Modulation of Immune Response
• Regulator of Cell Proliferation
• Regulator of Cell Differentiation

Evidence Suggests May Play A Role:

Modifying Risk of Cardiometabolic Conditions – Diabetes, Hypertension, CVD

Diabetes Mellitus
Vitamin D deficiency has been shown to increase insulin resistance. The postulated mechanisms include:

• Inherited gene polymorphism (Vit D-binding protein, Vit D receptor, Vit d 1 alpha –hydroxylase gene)
• Activating innate and adaptive immunity and cytokine release
• By upregulation of immunoregulatory NF kb and inducing TNF-alpha
• By low calcium status, which increases insulin resistance
• Vitamin D deficiency triggers release of PTH (to resorb calcium from bone to regulate serum calcium). High PTH levels increases insulin resistance and suppresses insulin release. Thus, optimal Vitamin D status inhibits PTH release and indirectly improves insulin sensitivity.
• Some evidence that Vitamin D is required for up-regulation of insulin receptor synthesis
• Note: in obesity more Vitamin D is stored in fat tissue, bringing about low serum Vitamin D (leading to vitamin D deficiency state). As such, obesity increases insulin resistance, promotes inflammatory cytokine secretion and reduces serum Vitamin D, all of which increase DM risk or aggravate the DM condition.

Vitamin D Synthesis
Vitamin D is obtained from several sources, including exposure to sunlight, certain foods, fortified foods, and dietary supplements. Exposure of the skin to solar ultraviolet B radiation (wavelength, 290 to 315 nm), induces the conversion of 7-dehydrocholesterol to previtamin D₃₎, which is rapidly converted to vitamin D₃ (cholecalciferol).  The cholecalciferol made in the skin and the cholecalciferol obtained from food, Vitamin D fortified foods (e.g. milk) and supplements is transported in the blood by circulating vitamin D-binding protein (DBP) to the liver. DBP is a specific Vitamin D-binding protein that is synthesized in the liver. Upon arrival in the liver, cholecalciferol is hydroxylated by a specific phase I detoxification enzyme to 25-hydrocholecalciferol (25-hydroxyvitamin D), which is the major circulating metabolite of Vitamin D, and used to determine an individual’s vitamin D status. Almost all 25-hydroxyvitamin D is transported through the blood by DBP and is filtered by the kidneys and reabsorbed by the proximal convoluted tubules. In the kidney, 25 hydroxycholecalciferol undergoes endocytic internalization and is further metabolized to 1,25- dihydroxycholecalciferol in the promixal tubule by the enzyme 25-hydroxyvitamin D₃ 1α-hydroxylase (CYP27B). 1,25 -dihydroxycholecalciferol is the most potent form of Vitamin D found in the blood and is also known as calcitriol.Production of calcitriol increases when serum calcium and/or phosphorous levels decline.

Vitamin D Receptors (VDR) and Extrarenal Vitamin D Effects
Vitamin D receptors have been found on more than 38 types of tissue. Once entering the cell,25-hydroxyvitamin D is converted to 1,25-dihydroxycholecalciferol and bound to VDR, which ultimately transports Vitamin D to the nucleus of the cell in concert with the retinoid receptor (RXR) (forming a heterodimer). In turn, 1,25- dihydroxyvitamin has profound effects on the nucleus of the cellcontrolling vital genes related to bone metabolism, oxidative damage, chronic diseases, and inflammation.

In fact, more than 200 genes are controlled by 1,25-dihydroxyvitamin D directly or indirectly. Most importantly, this form of Vitamin D has been shown t to regulate cellular proliferation, differentiation, apoptosis, and angiogenesis, which are important in cancer prevention and management.  For example, breast, colon, prostate, and other tissues have been shown to convert 25-hydroxyvitamin D to 1,25 – dihydroxyvitamin D, which has been shown to control proliferation, including p21 and p27 tumor suppressor genes,  as well as genes that inhibit angiogenesis and induce differentiation and apoptosis of old cell, infected cells and emerging cancer cells.

1,25-dihydroxyvitamin D is also an immunomodulator, tending to down regulate over –aggressive immune behavior in autoimmune conditions by inducing  greater tolerance of dendritic cells and more selective expression of immunoglobulin-like transcript 3 (ILT3).

Vitamin D may help regulate blood pressure a 1,25-dihydroxyvitamin D has been shown to inhibit rennin synthesis. It also increases insulin production, which may help reduce risk of diabetes mellitus and improve type 2 diabetes management.

Vitamin D has also been shown to increase myocardial contractility, which may help prevent and manage congestive heart failure. It has also been shown to increase hair growth.

Vitamin D Deficiency
Vitamin D deficiency is linked to several types of cancer, autoimmune disease, and metabolic diseases such as type 1 Diabetes Mellitus and type 2 Diabetes Mellitus.

More than 30–50% of all children and adults appear to be at risk of vitamin D deficiency, defined as a serum 25-hydroxyvitamin D level below 50 nmol/L.

Vitamin D and Diabetes
1, 25-dihydroxyvitamin D plays an important role in glucose regulation via different mechanisms. 1, 25-dihydroxyvitamin D improves insulin sensitivity of the target cells (liver, skeletal muscle, and adipose tissue) and enhances and improves β-cell function, enabling a greater amount of insulin secretion. In addition, 1, 25-dihydroxyvitamin D protects β-cells from detrimental immune attacks, directly by its action on β-cells, and indirectly by acting on different immune cells, including inflammatory macrophages, dendritic cells, and a variety of T cells. Macrophages, dendritic cells, T lymphocytes, and B lymphocytes can synthesize 1,25-dihydroxyvitamin D, all contributing to the regulation of local immune responses.Defects in pancreatic B-cell function, insulin sensitivity and systemic inflammation, all contribute to development of type 2 Diabetes Mellitus. Importantly, 1, 25 –dihydroxyvitamin D has been shown to regulate all three of these risk factors to a significant degree.

In addition, insulin secretion is a calcium-dependent process, and therefore alterations in calcium flux can have adverse effects on β-cell secretary function. Regulating serum calcium levels is a primary function of Vitamin D, and thus, Vitamin D may also favorable influence insulin secretion via its regulatory effects on serum calcium (1).

African Americans are at Higher Risk for Diabetes/Related Cardiometabolic Problems and Vitamin D Deficiency
Studies show that African Americans suffer disproportionately from diabetes and cardiovascular disease and are significantly more likely to have suboptimal concentrations of circulating 25-hydroxyvitamin D. African Americans also tend to have lower serum Vitamin D levels, which may be contributing to these health problems. The higher levels of melanin in the skin of African Americans acts as a sunscreen, filtering out wavelengths required to synthesize cholecalciferol.  A 2012investigated whether daily supplementation with 4000 IU vitamin D₃ for 1 year would eliminate any disparities in circulating concentrations of 25-hydroxyvitamin D between African American and white men. At the outset of the study it was shown that serum concentrations of 25 hyroxyvitamin D were measured every 2 months in 47 subjects who received a daily oral dose of 4000 IU vitamin D₃ for 1 year.More than 90% of African Americans had serum concentrations of 25-hydroxyvitamin<32 ng/mL, and approximately two-thirds had serum concentrations <20 ng/mL. As well, there were significant disparities in serum concentrations of 25-hydroxyvitamin D between African American and white men. The study showed that supplementation with 4000 IU/d for 1 year eliminated any significant differences in circulating concentrations of 25-hydroxyvitamin d between African American and white men. This study suggests that darker-skinned individuals, living in areas with low solar radiation (usually between October and May) may require daily supplementation with 4000 IU (or more) of Vitamin D in order achieve optimal serum levels of 25-hydroxyvitamin D (above 80 nmol/L) (6).

Genetic Influence on DBP, VDR and 1 –alpha hydroxylase enzyme (Polymorphism)
Polymorphism is defined as the occurrence of different forms, stages, or types in individual organisms or in organisms of the same species, independent of sexual variations. With respect to Vitamin D, some individuals have altered forms of the Vitamin D binding protein (DBP) and/or Vitamin D receptors (VDR) and/or the 1-alpha hydroxylase enzyme that converts 25 hydroxycholecalciferol to 1, 25 dihydroxycholecalciferol (calcitriol).  In such cases Vitamin D metabolism and/or Vitamin regulatory effects can be impaired to some degree. Some evidence suggests that individuals who inherit variants (polymorphism) of the DBP, and/or VDR and/or 1-alpha hydroxylase enzyme are at greater risk for Diabetes Mellitus, Vitamin D deficiency and possibly autoimmune disease and cancer.

Vitamin D and Immune Regulation: Protective effects for DM and autoimmune disease
1, 25 – dihydroxycholecalciferol appears to play an important role in defense against autoimmune disease and diabetes via its effects on immune regulation. More specifically, 1,25-dihydroxyvitamin D  has been shown to exert an inhibitory effect on the adaptive immune system by modifying the capacity of antigen-presenting cells (APCs) to induce T lymphocyte activation, proliferation and cytokine secretion.  1,25-dihydroxyvitamin D also decreases the maturation of dendritic cells and inhibits the release of inflammatory and up-regulating cytokines such as interleukin-12 (IL-12) (stimulating T-helper 1 cell development), IL-2, interferon-γ (INF-γ), and tumor necrosis factor α (TNFα), which involves the destruction of β-cells resulting in insulin resistance.

Overall, 1,25-dihydroxyvitamin D directly modulates T-cell proliferation and cytokine production, decreases the development of T helper 1 (T_H1) cells, inhibits T_H17 cell development, and increases the production of Thelper 2 (T_H2) cells and T regulatory cells. These immunomodulatory effects of 1,25-dihydroxyvitamin D are linked to the protection of target tissues, such as β-cells. These immune regulation effects may also calm down immune attack of healthy tissue, in the prevention and management of various autoimmune diseases.

In regard to autoimmune disease and other inflammatory states, several studies show that 1,25-dihydroxyvitamin D is an anti-inflammatory agent. For example, 1, 25-dihydroxyvitamin has been shown to inhibit the release of Nuclear Factor-kappa beta (NF-kb), which is often activated by the release of TNF-alpha from macrophages – a major driving force in inflammation associated with autoimmune disease and in chronic inflammatory states.

In fact, the administration of Vitamin D to patients with type Diabetes Mellitus showed down-regulation of monocyte synthesis and secretion of  specific activation and inflammatory cytokines, including TNFα, IL-6, IL-1, IL-8, cyclooxygenase-2, intercellular adhesion molecule-1, and B7-1. Overall, 1,25-dihydroxyvitamin D inhibits the release of the pro-inflammatory cytokine TNFα and regulates the activity of NF-κB, and suppresses the expressions of TLR2 and TLR4 proteins and mRNA in human monocytes, reducing the release of cytokines. Therefore, vitamin D has been shown to have multi-modal effects on taming inflammatory states and may also reduce insulin resistance and the risk of diabetes by decreasing inflammatory responses (1).  It’s important to note that inflammatory insults have been shown to reduce serum levels of 25-hydroxyvitamin D. Thus, individuals experiencing inflammatory flare-up and post-surgical patients, may require additional Vitamin D supplementation to re-establish or preserve their Vitamin D status. In one study of post-surgical patients, virtually all subjects had serum Vitamin D levels below 50nmol/L (5).

Vitamin D Supplementation Studies
The optimal vitamin D serum concentrationof 25 hydroxycholecalciferol for reducing insulin resistance has been shown to be between 80 to 119 nmol/L. In most cases this level is only attainable via Vitamin D supplementation. In a single case study Vitamin D supplementation to correct a Vitamin D deficiency state level was shown to ameliorate glucose tolerance in a hypocalcemic woman.  A New Zealand study showed that south Asian women with insulin resistance improved markedly after taking vitamin D supplements. In some rare case, however, Vitamin D supplementation has increased glucose intolerance. These conflicting results suggest that the dose and method of supplementation, and the genetic background and baseline vitamin D status of individuals, may be more important factors influencing the effects of Vitamin D supplementation in a particular case. Overall, the evidence suggests that widespread Vitamin D deficiency in our society is a contributing factor to high rates of Diabetes Mellitus and is also likely affecting risk of autoimmune disease, cancer, as well as its well known influence on osteoporosis (1).

In individuals with limited sunlight exposure (live at a latitude above the 40 degree parallel, the elderly etc) supplementation with 2000 IU per day of Vitamin D has been shown to elevate serum levels of 25 hydroxyvitamin D to 71 nmol/L in a 5 month period (2).

Studies have shown that obese adolescents are at a greater risk of vitamin D deficiency because vitamin D is thought to be sequestered by excess adipose tissue. In turn, poor vitamin D status is associated with a higher prevalence of the metabolic syndrome, type 2 diabetes, or both in adults and adolescents. In a study by A. Belenchia et al, the efficacy and safety of 4000 IU vitamin D₃ per day was administered to a group of obese (avg BMI above 39.8) diabetic adolescence.  Compared the control group, the Vitamin D supplemented group showed significant increase in serum 25 hydroxyvitamin D levels, fasting insulin and improved insulin sensitivity. The researchers concluded thatthe correction of sub-optimal vitamin D status through dietary supplementation may be an effective addition to the standard treatment of obesity and its associated insulin resistance (3).

A 2010 study showed that women who took a vitamin D supplement (400 IU per day) had an associated 24% reduction in breast cancer. In this observational study breast cancer cases, aged 25–74 y (diagnosed 2002–2003), were identified through the Ontario Cancer Registry. Controls were identified by using random digit dialing. In total 3101 cases and 3471 controls completed epidemiologic and food-frequency questionnaires. The study suggested that Vitamin D from supplements (not from food) was independently associated with reduced breast cancer risk (4).

Reference:

1. Sung CC, Liao MT, Lu KC, Wu CC. Role of Vitamin D in insulin resistance: Review article. Journal of Biomedicine and Biotechnology. 2012. (Hindawi Publishing Corporation)http://www.hindawi.com/journals/bmri/2012/634195
2. Smith SM, Gardner KK, Locke J, Zwart SR. Vitamin D supplementation during antarctic winter Am J Clin NutrApril 2009 89 no. 4 1092-1098
3. Belanchia, AM, Tosh AK, Hillman LS and Peterson CA. Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial. Am J Clin Nutr. 2013. 050013
4. Anderson LN, Cotterchio M, Veith R, Knight JA. Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women. Am J Clin Nutr. 2010. 91 no. 6 1699-1707
5. Reid D, Toole BJ, Knox S et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. Am J Clin Nutr. (2011) 93 no. 5 1006-1011
6. Garrett-Mayer E, Wagner CL, Hollis BW et al. Vitamin D3 supplementation (4000 IU/d for 1y) eliminates differences in circulatin 25-hydroxyvitamin D between African American and white men. Am J Clin Nutr. 2012. 96 no. 2 332-336