Our findings for 25(OH)D and diabetes support the results of earlier clinical and animal studies [5
] and are consistent with other large epidemiological cross-sectional studies that have investigated the relationship between serum 25(OH)D levels and diabetes [5
]. Two recent prospective investigations also support this hypothesis: in the first study, which was conducted among 524 women and men in the United Kingdom, baseline 25(OH)D levels were inversely associated with glycemia and insulin resistance after a 10-year follow-up [16
]. In the second study which used data from two nested case-control studies in Finland, baseline 25(OH)D levels were significantly inversely associated with type 2 diabetes risk after a 22-year follow-up, but only in men [17
]. None of these studies investigated associations with 1,25(OH)2
D nor investigated CHD or hypertension risk.
Several small clinical intervention studies also support that vitamin D, or its active metabolite 1,25(OH)2
D, improves insulin sensitivity, even in subjects with glucose metabolism parameters classified within normal ranges [5
]. The mechanisms proposed to explain this effect include potential relationships with improvements in lean mass, regulation of insulin release, altered insulin receptor expression, and specific effects on insulin action. These actions may be mediated by systemic or local production of 1,25(OH)2
D or by suppression of parathyroid hormone, which may function to negatively affect insulin sensitivity [5
]. However, since our study is cross-sectional, we cannot rule out that being diabetic could modify the regulation of renal synthesis of 1,25(OH)2
D, which would be reflected in the concentration of this hormone in blood.
Vitamin D status is of interest with respect to diabetes because of its potential as a target for intervention. Maintaining adequate vitamin D status has proven to be challenging, as sunlight is the only substantial natural source of vitamin D for humans; given the low intensity of UV light in the winter and many people’s indoor lifestyles, vitamin D supplied through sun exposure is often inadequate to avoid deficiency.
In contrast to our findings, others, but not all, have reported associations between low blood levels of vitamin D and hypertension [4
]; in summary eighteen out of twenty six cross sectional studies (n= 22 - 12,644) and of the two prospective studies only one was positive [2
]. As increased BMI is related to both hypertension and low vitamin D levels it is important to consider it as a confounder in these studies. Only, half of the positive observational studies adjusted for BMI, it should be noted that in our data, a significant association with 25OHD or 1,25(OH)2D concentrations disappeared once BMI was added into the model. Similarly the results from small randomized control trials have been variable with less than half positive [5
]. Three of the large observational studies in the US, UK and Germany reported significant associations between 25(OH)D and hypertension risk after adjustment for diabetes prevalence [2
]. One postulated mechanism for vitamin D-mediated reduction of hypertension involves reno-protective effects i.e., increased activation of the rennin-angiotensin-aldosterone system (RAAS), which is the main regulator of electrolyte and volume homeostasis which contributes to development of arterial hypertension [3
In contrast to our findings, some previous epidemiological studies have found a negative association between serum vitamin D and heart disease [3
], with ten out of twelve observational studies (n=238-4839) of vascular disease (including two peripheral artery disease (PAD), five cardiovascular disease (CVD), five myocardial infarction (MI)) and six out of seven observational studies of heart failure (n=25 - 3299) showing a negative association between lower 25(OH)D levels and disease. Of these studies, only seven out of twelve adjusted for hypertension and diabetes but none of these reported all three conditions separately in the same study [2
]. It is thought that vitamin D plays a role in maintaining cardiovascular homeostasis both through a direct action of 1,25(OH)2
D on cardiomyocytes and indirect actions on circulating parathyroid hormone and calcium levels. The lack of association with CHD seen in these data could have been because of the low repeatability of the self reported nature of this outcome variable and its associated variability compared to that of hypertension or diabetes.
Strengths of the present investigation are its large sample size, relatively low deficiency levels and the fact that the vitamin D analyses were all performed by the same assay method. Moreover, our analysis is unique in reporting, in a large cohort study the association between diabetes and blood levels of 1,25(OH)2
D levels: to our knowledge only associations of 1,25(OH)2
D with hypertension [4
], CHD [3
], BMI [20
] been reported in large epidemiological groups. Important limitations of our study include its cross-sectional design and the reliance upon self-report of diabetes, hypertension and CHD status, however the measures of hypertension and diabetes had high reliability on follow-up. We only had one measure of adiposity (BMI), not total body fat, which is often thought to be more accurate however a recent validation study of BMI and DEXA has reported very favorable correlations [21
]. We only used education as a marker for social class however this has been well accepted as the best marker for social class on an epidemiological level [22
]. In particular, we cannot rule out the possibility that changes in sun exposure and/or diet as a consequence of having diabetes may have led to our findings however, the associations reported here warrant investigation in large prospective studies.