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Serum 25-hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Mattila C, Knekt P, Männistö S, Rissanen H, Laaksonen MA, Montonen J, Reunanen A. Diabetes Care. 2007 Oct;30(10):2569-70. Epub 2007 Jul 12. PMID: 17626891 doi: 10.2337/dc07-0292 We found a significant inverse association between serum 25OHD and risk of type 2 diabetes in the simple model. However, the association was attenuated in the multivariate analysis, adjusting for potential risk factors of type 2 diabetes. To our knowledge, this is the first cohort study investigating the association between serum 25OHD and incidence of type 2 diabetes. Our results are in line with those from the Nurses' Health Study (5), where an inverse association was observed for the intake of vitamin D supplements. We could not differentiate whether the results depended on the effect of vitamin D deficiency on β-cell function or on insulin resistance. In summary, the results are in line with the hypothesis that a high serum 25OHD concentration may reduce the risk of type 2 diabetes. Further research is needed to confirm the association and to distinguish between the independent role of vitamin D and the role of healthy dietary and lifestyle patterns in reducing the risk of type 2 diabetes.

Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Palomer X, González-Clemente JM, Blanco-Vaca F, Mauricio D. Diabetes Obes Metab. 2008 Mar;10(3):185-97. Review. PMID: 18269634 DOI: 10.1111/j.1463-1326.2007.00710.x Vitamin D deficiency has been shown to alter insulin synthesis and secretion in both humans and animal models. It has been reported that vitamin D deficiency may predispose to glucose intolerance, altered insulin secretion and type 2 diabetes mellitus. Vitamin D replenishment improves glycaemia and insulin secretion in patients with type 2 diabetes with established hypovitaminosis D, thereby suggesting a role for vitamin D in the pathogenesis of type 2 diabetes mellitus.

Plasma 25-hydroxyvitamin d is associated with markers of the insulin resistant phenotype in nondiabetic adults. Liu E, Meigs JB, Pittas AG, McKeown NM, Economos CD, Booth SL, Jacques PF. J Nutr. 2009 Feb;139(2):329-34. Epub 2008 Dec 23. PMID: 19106328 doi:10.3945/jn.108.093831 After adjusting for age and sex, plasma 25(OH)D was positively associated with ISI(0,120), plasma adiponectin, and HDL cholesterol and inversely associated with plasma triacylglycerol, but these associations were no longer significant after further adjustment for BMI, waist circumference, and current smoking status. 25(OH)D and 2-h post-OGTT glucose were not associated. Among adults without diabetes, vitamin D status was inversely associated with surrogate fasting measures of insulin resistance. These results suggest that vitamin D status may be an important determinant for type 2 diabetes mellitus.

Vitamin D and intervention trials in prostate cancer: from theory to therapy. Schwartz GG. Ann Epidemiol. 2009 Feb;19(2):96-102. Epub 2008 Jul 10. PMID: 18619854 doi:10.1016/j.annepidem.2008.03.007 This suggests that whereas vitamin D (e.g., cholecalciferol) might prevent prostate cancer, existing prostate tumors likely would require treatment with 1,25(OH)(2)D and/or its analogs. The major obstacle to the use of 1,25(OH)(2)D in patients therapeutically is the risk of hypercalcemia. Several maneuvers to reduce this risk, including pulse dosing and the use of less calcemic 1,25(OH)(2)D analogs, have been explored in Phase I-III clinical trials. Once merely a promise, vitamin D-based therapies for prostate cancer may soon be medical practice.

Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M, Arcaro G. Clin Endocrinol (Oxf). 2006 Nov;65(5):593-7. PMID: 17054459 DOI: 10.1111/j.1365-2265.2006.02633.x CONCLUSIONS: Hypovitaminosis D is highly prevalent in type 2 diabetic adults and is strongly and independently associated with increased carotid IMT. Further investigation into whether vitamin D may play a role in the prevention of atherosclerosis appears to be warranted. In conclusion, our results show that type 2 diabetic adults have significant reductions in serum 25(OH)D concentrations (vs matched controls) that predict preclinical atherosclerosis, independent of classical risk factors, renal function tests, inflammatory markers, use of medications and presence of the metabolic syndrome. These findings suggest the need for ongoing evaluation of the possible protective role of vitamin D3 supplementation in the development of atherosclerosis.

nfluence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. Webb AR, Kline L, Holick MF. J Clin Endocrinol Metab. 1988 Aug;67(2):373-8. PMID: 2839537 doi:10.1210/jcem-67-2-373 These results quantify the dramatic influence of changes in solar UVB radiation on cutaneous vitamin D3 synthesis and indicate the latitudinal increase in the length of the "vitamin D winter" during which dietary supplementation of the vitamin may be advisable.

1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Oh J, Weng S, Felton SK, Bhandare S, Riek A, Butler B, Proctor BM, Petty M, Chen Z, Schechtman KB, Bernal-Mizrachi L, Bernal-Mizrachi C. Circulation. 2009 Aug 25;120(8):687-98. Epub 2009 Aug 10. PMID: 19667238 doi: 10.1161/CIRCULATIONAHA.109.856070 Conclusion- These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam cell formation and accelerated cardiovascular disease in diabetic subjects.

Relation of body fat indexes to vitamin D status and deficiency among obese adolescents. Lenders CM, Feldman HA, Von Scheven E, Merewood A, Sweeney C, Wilson DM, Lee PD, Abrams SH, Gitelman SE, Wertz MS, Klish WJ, Taylor GA, Chen TC, Holick MF; Elizabeth Glaser Pediatric Research Network Obesity Study Group. Am J Clin Nutr. 2009 Sep;90(3):459-67. Epub 2009 Jul 29. PMID: 19640956 RESULTS: The mean (+/-SD) age of the adolescents was 14.9 +/- 1.4 y; 38 (66%) were female, and 8 (14%) were black. The mean (+/-SD) body mass index (in kg/m(2)) was 36 +/- 5, FM was 40.0 +/- 5.5%, and VAT was 12.4 +/- 4.3%. Seventeen of the adolescents were vitamin D deficient, but none had elevated PTH concentrations. Bone mineral content and bone mineral density were within 2 SDs of national standards. In a multivariate analysis, 25(OH)D decreased by 0.46 +/- 0.22 ng/mL per 1% increment in FM (beta +/- SE, P = 0.05), whereas PTH decreased by 0.78 +/- 0.29 pg/mL per 1% increment in VAT (P = 0.01). CONCLUSIONS: To the best of our knowledge, our results show for the first time that obese adolescents with 25(OH)D deficiency, but without elevated PTH concentrations, have a bone mass within the range of national standards (+/-2 SD). The findings provide initial evidence that the distribution of fat may be associated with vitamin D status, but this relation may be dependent on metabolic factors

Vitamin D may suppress infections which lead to development of Multiple Sclerosis Steven R Brenner, None (16 August 2007) J Neurol Neurosurg Psychiatry 2008 I read the article with reference to the inverse relationship between multiple sclerosis clinical activity and deficiency of vitamin D by Soilu-Hannienen (1) with interest, and was considering what mechanism could be in play to cause such a relationship. 25-hydroxylated metabolites of vitamin D act as intracellular regulators of the synthesis and action of defensin (2) molecules against bacterial antigens, defensin being an endogenously synthesized antimicrobial substance (2). Human cathelicidin antimicrobial peptide gene is a target of vitamin D receptor and is strongly up-regulated by 1,25-dihydroxyvitamin D3, indicating vitamin D receptor and the 1,25-dihydroxyvitaminD3 regulate primate innate immunity (3)

Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility.\nSimmons JD, Mullighan C, Welsh KI, Jewell DP.\nGut. 2000 Aug;47(2):211-4.\nPMID: 10896912 \ndoi:10.1136/gut.47.2.211

Robert P. Heaney is John A. Creighton University Professor, Creighton University, Omaha, Nebraska, United States. Hominid evolution took place in an environment (equatorial East Africa) that provided a superabundance of both calcium and vitamin D, the first in available foods and the second through conversion of 7-dehydrocholesterol to pre-vitamin D in the skin, a reaction catalysed by the intense solar ultraviolet (UV) radiation. Seemingly as a consequence, the evolving human physiology incorporated provisions to prevent the potential of toxic excesses of both nutrients. For vitamin D the protection was of two sorts: skin pigmentation absorbed the critical UV wavelengths and thereby limited dermal synthesis of cholecalciferol; and slow delivery of vitamin D from the skin into the bloodstream left surplus vitamin in the skin, where continuing sun exposure led to its photolytic degradation to inert compounds. For calcium, the adaptation consisted of very inefficient calcium absorption, together with poor to absent systemic conservation. The latter is reflected in unregulated dermal calcium losses, a high sensitivity of renal obligatory calcium loss to other nutrients in the diet and relatively high quantities of calcium in the digestive secretions. Today, chimpanzees in the original hominid habitat have diets with calcium nutrient densities in the range of 2 to 2.5 mmol per 100 kcal, and hunter-gatherer humans in Africa, South America and New Guinea still have diets very nearly as high in calcium (1.75 to 2 mmol per 100 kcal) (Eaton and Nelson, 1991). With energy expenditure of 3 000 kcal per day (a fairly conservative estimate for a contemporary human doing physical work), such diets would provide substantially in excess of 50 mmol of calcium per day. By contrast, median intake in women in North America and in many European countries today is under 15 mmol per day. Two factors altered the primitive situation: the migration of humans from Africa to higher latitude

Improved cholecalciferol nutrition in rats is noncalcemic, suppresses parathyroid hormone and increases responsiveness to 1, 25-dihydroxycholecalciferol. Vieth R, Milojevic S, Peltekova V. J Nutr. 2000 Mar;130(3):578-84. PMID: 10702588 We conclude suppression of 1,25(OH)(2)D and PTH, and higher renal VDR mRNA and 24-hydroxylase did not involve higher free 1,25(OH)(2)D concentration or a first pass effect at the gut. Thus, 25(OH)D or a metabolite other than 1,25(OH)(2)D is a physiological, transcriptionally and biochemically active, noncalcemic vitamin D metabolite. When viewed from a perspective that starts with higher vitamin D nutrition, the results indicate that low vitamin D nutrition may bring about a form of resistance to 1,25(OH)2D. This situation would explain why, in humans, nutritional rickets and osteomalacia are commonly associated with normal or increased levels of 1,25(OH)2D (Chesney et al. 1981Citation , Eastwood et al. 1979Citation , Garabedian et al. 1983Citation ,Rasmussen et al. 1980Citation )-these are not like the low hormone levels associated with any other endocrine-deficiency disorder. A connection between lower vitamin D nutrition and vitamin D resistance helps to explain why the supposedly inactive compound 25(OH)D is more relevant in diagnosing nutritional rickets than is the active hormone 1,25(OH)2D. If the features of improved vitamin D nutrition shown here were demonstrated for any newly synthesized compound, the compound would be classified as a noncalcemic 1,25(OH)2D analogue (Brown et al. 1989Citation , Finch et al. 1999Citation , Goff et al. 1993Citation , Koshizuka et al. 1999Citation ). Thus, we contend that 25(OH)D or a metabolite of it other than 1,25(OH)2D exists as a physiological and biologically-active noncalcemic vitamin D metabolite whose effects require further examination, particularly in relationship to studies involving the synthetic analogs of 1,25(OH)2D.

"Women from India, Pakistan and Sri Lanka with insulin resistance showed marked improvement after taking vitamin D supplements, says a study. Von Hurst, nutrition lecturer at the Institute of Food, Nutrition and Human Health at Albany, conducted the study for her doctoral thesis. Insulin resistance is largely symptom-free and sufferers are unaware of their condition. 'Once it has fully developed into type-2 diabetes, it can be treated, but not cured,' says Von Hurst. Von Hurst says that while diet and exercise play a major part in the onset of type-2 diabetes, her findings reinforce the importance of vitamin D from the sun and supplements to prevent type-2 diabetes. She also found evidence of vitamin D increasing bone strength in older women. "

Sweat gland epithelial and myoepithelial cells are vitamin D targets. Koike N, Stumpf WE. Exp Dermatol. 2007 Feb;16(2):94-7. PMID: 17222221 DOI: 10.1111/j.1600-0625.2006.00513.x Nuclear receptor binding of 1,25(OH)2-vitamin D3 (vitamin D) in skin keratinocytes of epidermis, hair sheaths and sebaceous glands was discovered through receptor microscopic autoradiography. Extended experiments with 3H-1,25(OH)2-vitamin D3 and its analog 3H-oxacalcitriol (OCT) now demonstrate nuclear receptor binding in sweat gland epithelium of secretory coils and ducts as well as in myoepithelial cells, as studied in paws of nude mice after i.v. injection. The results suggest genomic regulation of cell proliferation and differentiation, as well as of secretory and excretory functions, indicating potential therapies for impaired secretion as in hypohidrosis of aged and diseased skin.

Vitamin D and type 2 diabetes: are we ready for a prevention trial? Scragg R. Diabetes. 2008 Oct;57(10):2565-6. PMID: 18820212 doi: 10.2337/db08-0879 Despite evidence from the current article (3) and the Finnish study (17), doubts still remain about whether low vitamin status is a cause of type 2 diabetes. Further cohort studies are required, assessing baseline vitamin D status using blood 25(OH)D to be sure that the Ely and Finnish studies are not false-positive results. Glucose clamp studies are also required because we are still not sure of the mechanism influenced by vitamin D-whether it is insulin resistance, secretion, or both. But most importantly, given that nearly three decades have passed since the first studies linking vitamin D with insulin metabolism (6,7), well-designed clinical trials of the effect of vitamin D supplementation on glycemia status and diabetes risk are urgently required to settle this question. And they need to prevent past mistakes. In particular, the vitamin D dose given in such trials needs to be high enough-above 2,000 IU per day (19)-to raise blood 25(OH)D levels above 80 nmol/l because diabetes risk is lowest at this level (9,20). If well-designed trials are carried out and confirm a protective effect from vitamin D, it could be used by the general population as a simple and cheap solution to help prevent the diabetes epidemic.

Serum vitamin D and subsequent occurrence of type 2 diabetes. Knekt P, Laaksonen M, Mattila C, Härkänen T, Marniemi J, Heliövaara M, Rissanen H, Montonen J, Reunanen A. Epidemiology. 2008 Sep;19(5):666-71. PMID: 18496468 doi: 10.1097/EDE.0b013e318176b8ad Conclusions: The results support the hypothesis that high vitamin D status provides protection against type 2 diabetes. Residual confounding may contribute to this association.

Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M, Arcaro G. Clin Endocrinol (Oxf). 2006 Nov;65(5):593-7. PMID: 17054459 CONCLUSIONS: Hypovitaminosis D is highly prevalent in type 2 diabetic adults and is strongly and independently associated with increased carotid IMT. Further investigation into whether vitamin D may play a role in the prevention of atherosclerosis appears to be warranted.

Vitamin D as an analgesic for patients with type 2 diabetes and neuropathic pain. Lee P, Chen R. Arch Intern Med. 2008 Apr 14;168(7):771-2. PMID: 18413561

A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases. Amir E, Simmons CE, Freedman OC, Dranitsaris G, Cole DE, Vieth R, Ooi WS, Clemons M. Cancer. 2009 Nov 13. [Epub ahead of print] PMID: 19918922 DOI: 10.1002/cncr.24749 METHODS: Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D3 and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter. CONCLUSIONS: Daily doses of 10,000 IU vitamin D3 for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption. Cancer 2010. © 2009 American Cancer Society.

25-Hydroxyvitamin D and functional outcomes in adolescents. Lamberg-Allardt CJ, Viljakainen HT. Am J Clin Nutr. 2008 Aug;88(2):534S-536S. Review. PMID: 18689396 CONCLUSIONS Cross-sectional studies have shown a relation among serum 25(OH)D concentration, serum PTH concentration, and BMD in adolescents. Long-term randomized controlled intervention studies have shown that vitamin D3 supplementation has a positive effect on BMD in adolescence; some of these studies found an effect with doses as small as 5 µg (200 IU) to 10 µg (400 IU) per day, or without supplemental calcium.