Vitamin D supplementation as an adjuvant therapy for patients with T2DM: an 18-month prospective interventional study

In recent years, vitamin D deficiency has gained unprecedented attention in the fields of preventive cardiology and endocrinology, primarily because of the extra-skeletal pleiotropic effects of this hormone, and the association of its deficit with insulin resistance, diabetes mellitus and an increased cardiovascular risk [1‐3]. A unifying factor that links diabetes mellitus types 1 and 2 (T1DM and T2DM, respectively) is the expression of vitamin D receptors (VDRs) in more than 30 biological tissues, including the pancreatic islet cells [3‐5]. On the other hand, it is common for patients with T1DM and T2DM to have vitamin D deficiency [6]. Furthermore, several longitudinal and observational studies have demonstrated that low levels of serum 25-hydroxyvitamin D predict T2DM risk in Europeans [7, 8], African-Americans [9], South Asians [10] and native American children [11]. Vitamin D correction, therefore, may increase insulin secretion and improve glucose homeostasis; however, its effects on healthy individuals or in those with impaired glucose tolerance remain unclear [6].

In the Middle East and North Africa (MENA), vitamin D deficiency is startlingly high as compared to other geographical regions [12]. Specifically, in the kingdom of Saudi Arabia (KSA), where the intensity of sunlight is paradoxically directly proportional to the prevalence of vitamin D deficiency [13], hypovitaminosis D has been implicated not only as a significant predictor of osteoporosis among apparently healthy men and post-menopausal women [14, 15], but also significantly associated to cardiometabolic risk factors in both children and adults [16, 17]. Interestingly, there is an equally alarming prevalence of chronic non-communicable diseases in KSA, including T2DM, obesity, the metabolic syndrome, and cardiovascular diseases [18].

Previously we demonstrated a modest reversal of metabolic syndrome manifestations among a cohort of adult Saudis who were advised vitamin D correction through increased sun exposure and dietary vitamin D intake [19]. In the current interventional study, we aimed to determine the metabolic effects of oral vitamin D supplementation in a cohort of T2DM Saudi subjects over time. This study may shed light as to whether oral vitamin D supplementation can be an adjunct therapy in T2DM Saudi patients, and on the importance of optimizing vitamin D levels in the prevention and improved management of chronic non-communicable diseases such as T2DM.

The findings of this study indicate that the metabolic profile of T2DM subjects, particularly females, is significantly improved over a period of 18 months after the onset of vitamin D3 supplementation, suggesting that vitamin D correction is a promising cardio-protective intervention in vitamin D-deficient populations. The gender effect can be attributed indirectly to either differences in hormone secretion and/or target tissue effects and body fat distribution, both of which can contribute to degrees of insulin resistance, or sample size effect. The current study adds to an increasing body of evidence that vitamin D supplementation is most beneficial not only to those who are at risk for osteoporosis and other bone-related diseases, but also to those who are deficient and have other extra skeletal chronic diseases, such as diabetes T2DM and cardiovascular disease. The available evidence, however, has been quite mixed. In a recent study, Eftekhari and colleagues were not able to elicit the same improved metabolic profile in an Iranian T2DM population, which was probably due to a shorter duration of supplementation (12 weeks) [21]. Other studies also found no improvement of insulin sensitivity after a high dose vitamin D intervention. This was probably partly due to the supplementation itself and/or because the subjects were apparently healthy [22, 23]. Increased insulin resistance post supplementation was observed in a cohort of middle-aged adults, and increased insulin sensitivity in first time GDM patients [24, 25]. In the present study, the apparent health benefits were observed after 6 months of supplementation, aside from the expected increase in circulating vitamin D levels, suggesting that sustained and prolonged supplementation might be necessary to achieve desirable metabolic effects.

Several mechanisms explain how vitamin D can theoretically improve metabolic functions. One mechanism may involve direct promotion of large HDL particle formation, via elevations in serum apolipoprotein A1 (ApoA1) concentrations, a process that increases reverse cholesterol transport [26]. Furthermore, the improved lipid profile of the DMT2 subjects can also be attributed to lipid-lowering drugs, which were administered in almost half of the study population. Statins (rosuvastatin) were shown to increase levels of 25-hydroxyvitamin D and 1, 25 dihydroxyvitamin D in a cohort of hyperlipidemic patients [27]. Nevertheless, there is enough evidence to support that vitamin D supplementation can independently improve cardiovascular health secondary to its significant associations with cardiometabolic risk factors in both human and animal models, including blood pressure, insulin resistance and aortic media fragmentation, respectively [28‐30]. The increase in serum calcium was expected, secondary to increased vitamin D levels. This in turn results in a parallel increase in localized calcium influx in pancreatic β cells that stimulate islet insulin secretion [31‐33]. Lastly, the inverse association to free albumin was also expected, as it is one of the proteins (vitamin D binding protein being the other one) that transport 25(OH)D in the blood [34].

Several caveats should be mentioned. First, the lack of a placebo-control group, second that the study included only patients with T2DM, and third, the difficulty in the verification of quality of life issues. Findings therefore are limited to patients with T2DM, since variations in metabolic changes differ not only by gender but also by the presence of the disease itself [35]. The increase in both insulin resistance and sensitivity should be interpreted with caution since these were computed indirectly rather than directly. Nevertheless, several hard outcomes were measured overtime, while HOMA-β function would be difficult to elicit in a control group. The improved HOMA-β function specifically in females can be also explained by several confounders that were not accounted for, such as the type of anti-diabetic drugs taken, compliance of the patients and duration of diabetes. Metformin for instance, does not confer changes in vitamin D status, while thiazolidinediones affect vitamin D by selective agonism of peroxisome proliferator activated receptors gamma (PPAR-γ), which are present in muscle, liver and adipose tissue [36].

In summary, the present interventional study performed in an Arab population suggests that daily 2000 IU vitamin D3 supplementation in a vitamin D deficient T2DM population is associated with measurable cardioprotective indices. Supplementation to achieve higher levels of vitamin D remains a promising adjuvant therapy for T2DM patients. Further studies are needed, with the inclusion of a placebo group, to validate the present findings.