Anthony W. Norman

RESEARCH directed at defining the molecular mode of action of vitamin D is currently at its apex. There is now evidence implicating the essential involvement of vitamin D metabolites in a host of cellular processes, including calcium homeostasis, immunology, cell differentiation, and regulation of gene transcription. Further, there is evidence that the hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], may generate biological responses via both regulation of gene transcription as well as via nongenomic pathways, some of which involve opening of voltage-gated Ca2+ channels. In addition, there are many examples of pathological disruption of the normal state in which a drug form of a vitamin D metabolite is proposed to be a (potentially) useful form of treatment, e.g. renal osteodystrophy, psoriasis, leukemia, breast cancer, and osteoporosis. The importance of the molecule vitamin D in the biological systems of higher animals has been recognized since its discovery by Mellanby in 1920 (1). It was in the interval of 1920–1930 that vitamin D officially became classified as a “vitamin” that was essential for the normal development of the skeleton and maintenance of Ca2+ homeostasis. The chemical structure of vitamin D was not determined until 1932 (2), and it was only then that it was apparent that this important nutritional substance was in reality a steroid, more specifically, a secosteroid, indicating that one of the rings of the cyclopentanoperhydrophenanthrene ring structure (the 9–10 carbon-carbon bond of ring B) was broken (see Section II).

The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is the major biologically active metabolite of vitamin D3. (Secosteroids are those in which one of the rings has undergone fission; in vitamin D, this is ring B.) 1,25(OH)2D3 is recognized as the principal mediator within the sphere of action of vitamin D in the regulation of bone and mineral metabolism in humans.1 2 3 Recent evidence has suggested a wider biologic role of 1,25(OH)2D3 in tissues not primarily related to mineral metabolism.Vitamin D MetabolismMetabolic ActivationAn overview of vitamin D . . .

The effects of a vitamin D deficiency on insulin and glucagon release was determined in the isolated perfused rat pancreas by radioimmunoassay of the secreted proteins. During a 30-minute period of perfusion with glucose and arginine, pancreases from vitamin D-deficient rats exhibited a 48 percent reduction in insulin secretion compared to that for pancreases from vitamin D-deficient rats that had been replenished with vitamin D. Vitamin D status had no effect on pancreatic glucagon secretion. This result, along with the previously demonstrated presence in the pancreas of a vitamin D-dependent calcium-binding protein and cytosol receptor for the hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, indicates an important role for vitamin D in the endocrine functioning of the pancreas.