PTH-Vitamin D-Glycemia Interactions Reloaded

Traditionally viewed as a key regulator of musculoskeletal health, recent studies also have pointed to pleiotropic roles of vitamin D in the modulation of metabolic and vascular functions (1). Hypovitaminosis D is associated with obesity (2), and low vitamin D states predict higher fasting glycemia and insulin resistance in population studies (3,4), yet other studies showed no relations between vitamin D status and glucose homeostasis after adjusting for adiposity (5,6). Vitamin D supplementation has not consistently benefited glycemia in intervention trials despite adequate increments into a “normal range” (7). The debate surrounding vitamin D and glucose metabolism continues. Aside from assay variability, subject population, and lifestyle confounders that could complicate data interpretation, a fundamental unanswered question is what constitutes vitamin D sufficiency.

Hormonal axes are classically evaluated on multiple levels, encompassing negative feedback and positive stimulation. The vitamin D hormonal system is chiefly under the regulation of the parathyroid hormone (PTH), which stimulates the conversion of circulating 25-hydroxyvitamin D (25-OH-D) to its active form, 1,25-dihydroxyvitamin D (1,25-(OH)₂D). While best known to occur in the kidneys, local tissue 1α-hydroxylase expression enables active vitamin D synthesis in a paracrine fashion (1). The interactions between endocrine and paracrine vitamin D systems are not well understood and may underscore the apparent dissociation between …