A Critical Analysis of the (Near) Legendary Status of Vitamin D

Ashlee McMillan; Jason Hicks; Christopher Isabella; Gerald M Higa


Expert Rev Endocrinol Metab. 2012;7(1):103-119. 

In This Article

Abstract and Introduction


Labels such as food constituent, nutrient and supplement do not convey a sense of being essential. Yet these rather mundane descriptors, even if correct, belie the true significance of vitamin D. Long believed to be merely a functioning cofactor akin to vitamin C, deficiency of this secosteroid hormone is clearly associated with morbid complications of calcium and bone mineral metabolism, and because the hormonal effects are mediated by nuclear receptors that regulate the expression of many subordinate genes, the vitamin's pleiotropic mode of action can influence numerous metabolic pathways and, possibly, a number of different diseases. Although the vitamin is under intensive investigation, much still remains unknown, even in bone health, as the identity of osteoporosis susceptibility genes remains uncertain. This article focuses on various aspects of the basic science and molecular biology of the vitamin D endocrine system. The primary goal is to critically examine the evidence supporting its role in bone metabolism, diabetes and cancer.


Vitamin D is arguably the most intensively studied nutritional substance, as evidenced by the abundant data that continue to add to its growing stature. While research related to its role in calcium homeostasis alone would engender near proprietary status, the lay public has given the vitamin a quasi-social status as well. However, the purported association with a number of metabolic and tumorigenic processes may elevate vitamin D to the cusp of virtual legendary status. The latter position is supported by a plethora of data that suggest that vitamin D deficiency may contribute directly to, or have an ancillary role in, the pathogenesis of Type 1 and Type 2 diabetes mellitus.[1,2] In addition to altered glucose regulation, other observations indicate that hypovitaminosis D may adversely affect other components of the metabolic syndrome, including high-density lipoproteins, triglycerides[3] and blood pressure.[4] There are also intriguing data that the differentiating and antiproliferative effects of the vitamin could be therapeutically beneficial in the prevention and treatment of cancer.[5,6]

These findings notwithstanding, it is almost counterintuitive to believe that results of scientific research can increase the uncertainty of already controversial issues in health and disease. However, this belief is apparently true for vitamin D. Now, perhaps even more than nearly 100 years ago when the first experimental studies were performed to elucidate the underlying etiology of rickets,[7] research has revealed that the effects of the vitamin D endocrine system are not restricted to the maintenance of calcium homeostasis and skeletal health, but appear to include a profound holistic effect on the human body. This article merges our increased, although by no means complete, understanding of vitamin D and attempts to reconcile several issues that have been subject to much debate. As such, results of selected preclinical and human studies are included, analyses of which provide a balanced perspective of the vitamin's actions. Also ensconced in the published literature are a number of plausible molecular mechanisms that may explain some of these novel effects. In order to enhance reader appreciation, a detailed overview of the basic and molecular biology of vitamin D is presented, which provides insight into the vast number of interactions involved in order to accomplish the desired effect on target tissue.


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