The main novelty obtained in this study is that, in a large population of newly diagnosed hypertensive patients, with different glucose tolerance status, there is an inverse and strong relationship between 25(OH)D levels and 1-h post-load glucose in normo-glycemic subjects. In fact, regarding to post-load plasma glucose, NGT ≥ 155 subjects showed reduced 25(OH)D levels compared to NGT < 155 and similar to those of IGT group. Of interest, this result persists after adjustment for all significant covariates, able to interfere with glycemic metabolism. To our knowledge, this is the first study demonstrating this association that has a clinical importance because NGT subjects are considered at low cardiovascular risk. On the contrary, we have recently demonstrated that NGT with 1-h post-load glucose ≥155 have a worse metabolic and cardiovascular profile, showing a multiple subclinical organ damage [20–24]. Thus, our data consent to reconsider the concept that NGT subjects are a homogeneous group with a low cardiovascular and metabolic risk profile.
Present results may be explained by the pathophysiological mechanisms related to pleiotropic action of vitamin D. In particular, vitamin D may affect both directly, via activation of vitamin D receptors, and indirectly, via regulation of calcium availability, glucose and insulin homeostasis by modulating β-cell function and immune response, and improving peripheral insulin sensitivity [1, 2, 15]. In keeping with this, there are experimental data demonstrating that hypovitaminosis D causes impairment in insulin receptor expression and insulin secretion in animal models and humans [15, 16], while treatment with vitamin D improves β-cell function and glucose tolerance [31, 32]. In addition to these actions on glucose metabolism, low levels of vitamin D are associated to the apperance and progression of pro-inflammatory status that, in turn, induces a worsening of glucose tolerance status until the clinical onset of diabetes [33, 34]. According with this, NGT ≥155 subjects, both in basal condition and after 1-hour during OGTT, are more insulin-resistant and have higher levels of hs-CRP than NGT < 155. On the basis of these evidences, present data contribute to extend previous knowledge about the association between hypovitaminosis D and cardiovascular events [3–6]. Additional mechanism involved in this association is the regulatory effect of vitamin D on the renin-angiotensin system activity. In fact, there are previously published human and animal studies demonstrating that low plasma vitamin D levels result in up-regulation of the renin-angiotensin system [16, 35] that interferes with insulin signaling in different tissues [36–38].
Even if data from several studies have demonstrated that circulating levels of vitamin D are involved in the pathogenesis of type-2 diabetes in humans [7–15], it is probable that other associated functional modifications or clinical conditions contribute to its biological effects. So as observed in our study, vitamin D deficiency is also associated with elevated PTH levels that reproduce a secondary hyperparathyroidism that may contribute, through the reduction of insulin sensitivity and by promoting cardiac and vascular remodeling, to the development of glucose intolerance and cardiovascular complications . Of interest, present data were obtained in subjects with normal renal function. In addition, reduced levels of vitamin D may be operating in diabetes-related obesity; in fact, hypovitaminosis D of obese subjects is due, not only to less exposure to sunlight for the reduction of physical activity, but also because vitamin D is trapped in adipose tissue and it is no longer bioavailable [40, 41]. It follows that the biological action of vitamin D is multifactorial and complex, especially as regards to the glucose metabolism. In keeping with this, recently some study have been published with the aim to evaluate the effects of vitamin D supplementation on glucose metabolism and insulin resistance in different setting of patients [42–46]. However, despite the significant increase of vitamin D levels, the absence of consistent results may be explained with the short duration of treatment.
Another important finding emerged from this study is that the number of subjects with sufficient vitamin D levels is low and significantly decreases with the worsening of tolerance status, while the condition of vitamin D deficiency significantly increases. This is a surprise not easily explained, since all our patients live in a sunny area of South Italy and spend many hours outdoors, maybe the season period of study may affect the levels. On the other hand, average levels of vitamin D detected in our subjects are similar to the national average; probably, it is necessary to accurately investigate the causes of this phenomenon.