Vitamin D Update - The Support Continues
I was looking back over previous articles recently and realized it has been over two years since writing on the topic of vitamin D and its many actions in human health! (See Complementary Corner, March 2007). Since the 2007 article, more clinical research has supported vitamin D replacement for reducing depression, increasing magnesium levels, improving vessel function in people with diabetes, and improving kidney function - including for patients on dialysis. Results on the effects of vitamin D on insulin sensitivity are mixed. In addition, recent basic science research suggests a possible mechanism of action for vitamin D in protecting against heart disease. Also interesting are reports of increased vitamin D in patients given statins to lower cholesterol! As we approach the winter season, when vitamin D levels naturally decline, it is even more important to have your vitamin D measured and replaced. In the following article, I’ll highlight some recent research findings supporting an important role for vitamin D for living in optimal health!
Vitamin D and Depression
As described in previous articles, vitamin D helps regulate neurotransmitter levels including serotonin. As vitamin D levels decline in the fall and winter, our bodies tell us it’s time to hibernate by shifting away from serotonin production toward melatonin production. As increasing serotonin levels is one action of many antidepressant drugs, you might hypothesize that simply replacing vitamin D, instead of taking antidepressant drugs, may be an effective option for depression.
Two recent clinical trials support this notion. A very small open-label trial by Shipowick et al. replaced vitamin D in six women with established deficiency, resulting in 10-point improvements in standardized depression questionnaires.(1) Much stronger research support for a role of vitamin D in depression treatment is provided by Jorde et al. who randomized 441 overweight or obese participants to receive either 20,000 IU/day or 40,000 IU/day of vitamin D or placebo. After one year of vitamin D supplementation, participants in both vitamin D treatment groups had reductions in depressive symptoms.(2)
Vitamin D and Magnesium
Although we typically think of vitamin D related to calcium absorption, vitamin D is also known to help regulate magnesium absorption.(3) As magnesium is one of our primary electrolytes - helping to maintain blood pressure, cellular energy production, and insulin sensitivity - improving magnesium status may be very important for the treatment and prevention of numerous chronic disease, including diabetes. For example, although not demonstrated with supplements, diets high in magnesium-rich foods are associated with reduced risk for developing diabetes, high blood pressure and the metabolic syndrome. (4)
Although a relationship between vitamin D and magnesium has been suspected for some time, only recently has vitamin D replacement been shown to improve magnesium status. Specifically, Farhanghi et al. administered large doses of vitamin D (600,000 IU as D2) to 82 overweight and obese women and measured an improvement in blood magnesium status.(5) Although this evidence is preliminary due to its weak, uncontrolled design, the trial does support the concept that vitamin D replacement can improve magnesium status, independent of magnesium supplementation.
Vitamin D and Insulin Release and Sensitivity
Vitamin D is known to act in the insulin-producing beta cells of the pancreas, and deficiencies of vitamin D have been associated with reduced sensitivity to insulin, and reduced insulin production.(6, 7) Recent research also supports the notion that vitamin D is involved in the maintenance of normal pancreatic function and insulin sensitivity. Although not in patients with diabetes, Kotsa et al. recently demonstrated improved insulin secretion and improved cholesterol profiles in 15 obese women with polycystic ovarian syndrome, a condition of insulin resistance known to be a risk factor for developing diabetes.(8) Although the investigators used a synthetic version of vitamin D3, improvements in first phase insulin response (the rapid and early release of insulin following a meal) were observed.
Further support for a role for vitamin D in protecting pancreatic function comes from Li et al. who performed a six-month, randomized, controlled trial of synthetic vitamin D3 in patients with latent autoimmune diabetes in adults (LADA).(9) LADA is an autoimmune form of diabetes similar to type 1 diabetes in which the pancreatic beta cells are destroyed by an autoimmune process. Compared to insulin-treated patients alone, patients treated with insulin plus vitamin D3 had elevated levels of both fasting and meal stimulated c-peptide, a marker for longer-term insulin production.
Vitamin D and Heart Disease
Past research has demonstrated associations between low vitamin D status and more rapid progression of heart disease in people with diabetes.(10) Adding to this support is the prospective, observational study by Dobnig et al. in over 3,200 patients presenting for an angiogram (a test to measure the amount of blockage in the arteries of the heart). Their results demonstrated a two-fold increase in risk for death from any cause, and death from cardiovascular causes in the group with the lowest vs. highest vitamin D status. Two findings are worth consideration from this research. First, the “highest” vitamin D status group had average levels of 28.4 ng/ml, which is still considered deficient by most experts. And, in this study, vitamin D levels were associated with biomarkers of atherosclerosis, inflammation, and oxidative stress including adhesion molecules, C-reactive protein, measures of lipid oxidation, and antioxidant status.(11)
Further research suggests vitamin D improves endothelial function in patients with type 2 diabetes. Sugden et al. completed a randomized, controlled trial measuring flow-mediated dilation in 34 patients with type 2 diabetes before and after a single dose of 100,000 IU of vitamin D2.(12) After eight weeks, flow-mediated dilation, (a test for vessel opening, or dilation), was significantly improved and blood pressure significantly lower (14 mmHg reduction) in patients who received vitamin D compared to placebo-treated patients.
Although highly suggestive that vitamin D has a protective role against the development of heart disease, not all recent evidence has been supportive. For example, evidence for vitamin D supplementation actually lowering C-reactive protein is not supported by the recent randomized trial by Bjorkman et al. in which over 200 bed-ridden adults were randomized to 400 IU/day or 1,200 IU/day of vitamin D for six months- and no reduction of C-reactive protein was found.(13) Also, despite trial results and observations that vitamin D repletion may reduce blood pressure, a sub-study in the large Women’s Health Initiative trial of over 32,000 women does not support daily dosing of 400 IU vitamin D3 for reducing the development of high blood pressure.(14)
The role for vitamin D in heart disease deserves to continue as an active area of research investigation. Although the evidence related to vitamin D and heart disease is mixed with several observational studies showing associations, while clinical trials show mixed results, recent basic science research supports a mechanism for vitamin D in protecting against the development of vascular disease. Oh et al. collected immune cells (called macrophages) from patients with and without diabetes. Culture media was then supplemented with vitamin D. Vitamin D supplementation prevented the formation of “foam” cells, or macrophages engorged with oxidized LDL cholesterol.(15) This finding is particularly interesting as it, for the first time, shows a particular mechanism by which vitamin D may be directly protective against the formation of vascular disease.
Ironically, vitamin D repletion may also be involved in the cardiovascular protection offered by statin medications. Yavuz et al. recently demonstrated a 1.5-fold increase in serum vitamin D concentration in a randomized trial of rosuvastatin in 91 patients with elevated cholesterol following just 8 weeks of treatment.(16) Although the significance of increases in vitamin D compared to the LDL-lowering properties of statins demands additional study, reductions in “foam” cell formation, and improvements in vascular function demonstrated from vitamin D supplementation alone suggest the possibility of interactions between statins and diet, as well as changes in vitamin D metabolism, which may contribute to observed benefits of these medications.
Vitamin D and Kidney Function
The effects of replacing vitamin D to normal levels in patients with kidney disease is gaining research support. In a registry-based, retrospective cohort study, Naves-Diaz reports that 7,200 patients with kidney disease requiring dialysis who received oral vitamin D supplements had increased survival overall, as well as lower death from infections, cardiovascular disease, and cancers, compared with the 8,800 patients who did not take vitamin D.(17) Although this is an observational finding, a recent randomized, controlled trial reported beneficial effects of synthetic vitamin D in patients with earlier stages of kidney disease. Fishbane et al. randomly assigned 61 participants with chronic kidney disease and elevated urinary protein losses to receive placebo or synthetic vitamin D.(18) After the 6-month intervention, urinary protein losses were significantly reduced compared to placebo-treated patients, with increases in protein loss measured in the placebo group and reductions in protein losses measured in the vitamin D treatment group. As changes in magnesium status have also been reported in chronic kidney failure, the direct action of vitamin D on renal function, versus a secondary role improving magnesium status, remains unknown.(19)
Getting Your Vitamin D Level Checked & Replaced
Having your vitamin D status measured and replaced as needed is important to your overall health, whether you have diabetes or not. If you have diabetes, the evidence supports an important role for vitamin D in pancreatic function, cholesterol metabolism, vascular function, kidney function and perhaps a slower progression of atherosclerotic disease. Measuring your vitamin D status requires a simple blood test. However, despite medical school, many doctors order the incorrect test. You should ask your doctor to measure the “storage” form of vitamin D, called “25-hydroxycholecalciferol” (25-OHD). Because the more active form, “1,25-dihydroxycholecalciferol” has a very short half-life, i.e. it is cleared from circulation very quickly, testing for this concentration does not adequately provide information on long term vitamin D status or intake.
Replacing vitamin D can be accomplished in many ways, including daily dosing of small doses, or infrequent dosing of very high doses. Recently, Leventis et al. compared the safety and efficacy of administering 300,000 IU of either vitamin D2 or D3 to 69 patients with rheumatic conditions. (20) After 24 weeks, both D2 and D3 showed safety and efficacy, however vitamin D3 led to more sustained concentrations of 25-OHD in the blood. Similar results were reported by Holick, et al. who compared the effects of 1,000 IU vitamin D2/day, 1,000 IU of vitamin D3/day, or 500 IU/day or both vitamin D2 and D3 for eleven weeks.(21) At the end of the intervention, all groups had increased 25-OHD and there was no difference between groups, however 1,000 IU per day did not raise 25-OHD levels into the normal laboratory range. Although these findings suggest vitamin D2 and D3 are relatively equivalent in their actions to increased blood levels, more research testing differential actions of vitamin D2 vs. vitamin D3 on risk of cancer, heart disease and diabetes is still needed.
The optimal daily dose of vitamin D is still debated, but clearly depends on your vitamin D status. Typical recommendations are for between 2,000 IU/day and 10,000 IU/day, depending on sun exposure and baseline status. Recent investigations suggest for patients with baseline status of 25-OHD< 25ng/ml the optimal daily dose is 5,000 IU/day, while the optimal dose drops to 3,800 IU/day if blood levels are above 25 ng/ml. (22)
Fortunately, thanks to the generous research support of Diabetes Action, we are going to learn more about the safety and effects of vitamin D3 nutritional supplements in the near future. Clinical researchers at Bastyr University, including myself, are beginning a randomized clinical trial, supported by Diabetes Action, to compare the effects of three different vitamin D3 supplements at a daily dose of 10,000 IU/day in 90 healthy, but vitamin D deficient, adults. This study will compare oil-emulsified, chewable, and dry, encapsulated supplements for their relative effects at replacing 25-OHD. In addition to changes in 25-OHD, the study will also measure changes in blood glucose, hemoglobin A1c, cholesterol, and estimates of insulin sensitivity. Stay tuned for the results of this exciting study due in Fall of 2010, and please continue to support Diabetes Action in their efforts to improve your health!
In the last two years evidence for vitamin D having an active role in depression prevention, improved pancreatic and kidney function, and possible protection against developing heart disease continues to mount. Although the exact mechanisms for all of these actions are still under active investigation, getting your vitamin D levels measured, and then using appropriate doses to correct deficiency will dramatically reduce your risk for numerous chronic conditions, including cancer, and may improve function, despite diabetes or kidney disease. Ideally, vitamin D replacement should be monitored by an experienced health care provider who has knowledge of appropriate tests and optimal levels!
I will continue to keep you informed as we learn more about this important “vitamin”!
In Health- Ryan Bradley, ND, MPH
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2. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. Dec 2008;264(6):599-609.
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11. Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. Jun 23 2008;168(12):1340-1349.
12. Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med. Mar 2008;25(3):320-325.
13. Bjorkman MP, Sorva AJ, Tilvis RS. C-reactive protein and fibrinogen of bedridden older patients in a six-month vitamin D supplementation trial. J Nutr Health Aging. May 2009;13(5):435-439.
14. Margolis KL, Ray RM, Van Horn L, et al. Effect of calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative Randomized Trial. Hypertension. Nov 2008;52(5):847-855.
15. Oh J, Weng S, Felton SK, et al. 1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation. Aug 25 2009;120(8):687-698.
16. Yavuz B, Ertugrul DT, Cil H, et al. Increased levels of 25 hydroxyvitamin D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins? Cardiovasc Drugs Ther. Aug 2009;23(4):295-299.
17. Naves-Diaz M, Alvarez-Hernandez D, Passlick-Deetjen J, et al. Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int. Oct 2008;74(8):1070-1078.
18. Fishbane S, Chittineni H, Packman M, Dutka P, Ali N, Durie N. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am J Kidney Dis. Oct 2009;54(4):647-652.
19. Mountokalakis TD. Magnesium metabolism in chronic renal failure. Magnes Res. Jun 1990;3(2):121-127.
20. Leventis P, Kiely PD. The tolerability and biochemical effects of high-dose bolus vitamin D2 and D3 supplementation in patients with vitamin D insufficiency. Scand J Rheumatol. Mar-Apr 2009;38(2):149-153.
21. Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab. Mar 2008;93(3):677-681.
22. Aloia JF, Patel M, Dimaano R, et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. Jun 2008;87(6):1952-1958.