We report, using the Ely population-based prospective study, that baseline vitamin D status [25(OH)D concentration] in nondiabetic participants is inversely associated with glucose status, insulin resistance, and metabolic syndrome risk at the 10-year follow-up. Among these individuals, higher baseline 25(OH)D was associated with significant decreases in 10-year follow-up 2-h glucose, fasting insulin, HOMA index, and metabolic syndrome risk z score in analyses adjusted for a comprehensive range of potential confounders and mediators. These findings appear to be novel, with no previous study we can find of prospective associations between baseline serum 25(OH)D and future risk of disturbed glucose metabolism or metabolic syndrome risk as assessed using continuous quantitative metabolic traits.
Our findings confirm previously reported cross-sectional observations. For instance, among 8,421 U.S. adults, those with metabolic syndrome had lower 25(OH)D concentrations (67.1 nmol/l) than those without (75.9 nmol/l) (6
). Among 6,810 Caucasians in the 1958 birth cohort, aged 45 years, serum 25(OH)D was associated inversely with metabolic syndrome risk cross-sectionally, with independent associations for high A1C, blood pressure, and triglycerides after adjustment (7
). Although we found an inverse association between baseline serum 25(OH)D and incident continuous metabolic syndrome risk z score, we did not observe this association for individual components, such as for blood pressure. The association of blood markers of vitamin D with blood pressure or hypertension is complex, and there are inconsistent findings ranging from no association to inverse or positive association (previously discussed by Scragg et al. [31
]). A recent study (32
) of the association of plasma 25(OH)D with incident hypertension reported an inverse association, but study limitations included using predicted vitamin D levels and self-reported hypertension rather than actual measurement in some of the included cohorts in that study. Notably, we did report a significant inverse association between serum 25(OH)D and systolic and diastolic blood pressure at baseline but did not find this prospectively. Further study of such associations is warranted in larger cohorts.
While there was evidence of interaction between 25(OH)D and IGF-1 on metabolic syndrome risk in a previous study [metabolic syndrome risk being least when both 25(OH)D and IGF-1 were highest] (7
), we found no such interaction for 10 year risk of metabolic syndrome measured as a continuous risk z score, or for any individual metabolic component. We did find significant interaction between baseline IGFBP-1 and 25(OH)D on fasting and 2-h glucose at 10 years when significantly lower glycemia with increasing 25(OH)D was found in those with low, but not high, IGFBP-1. Notably, in the Ely cohort we have previously reported interaction between IGF-1 and IGFBP-1 on 4.5-year follow-up 2-h glucose concentration; those with lower, but not higher, IGFBP-1 having decreasing concentrations of 2-h glucose with increasing tertiles of baseline IGF-1 (19
). Since IGF-1 increases with 25(OH)D at baseline in our cohort, as in the 1958 birth cohort (7
), this may explain our 4.5-year findings. Our present 10-year follow-up data suggest, as previously reported (17
), that biological interactions between IGFBP-1 axis and 25(OH)D are potentially important in glucose homeostasis long term and that IGF-1 axis and vitamin D axis interactions should be studied further. For example, IGFBP-1 concentrations may reflect variations in insulin secretion or hepatic insulin sensitivity, important components in glucose regulation (33
Studies are emerging on vitamin D supplementation and glucometabolic risk. A post hoc analysis within a trial designed for bone health reported that calcium and vitamin D supplementation had no effect on fasting glucose or HOMA-IR over 3 years in 314 individuals (34
). This study did, however, find that among those with impaired fasting glucose (but not with normoglycemia), there was a modest attenuation of the rise over time in fasting glucose and in HOMA-IR (P
for treatment vs. placebo, 0.042 and 0.031, respectively) (34
). That study measured serum 25(OH)D in a subset, which increased with intervention, but did not report on its associations with the metabolic outcomes. Since dietary intake, including supplementation, provides little vitamin D and sunlight exposure providing the major source through skin synthesis, it is important that further studies include assessment of individual vitamin D status [serum 25(OH)D concentration]. A recent larger, clinical trial (23
) of vitamin D plus calcium supplementation (400 IU and 1,000 mg, respectively, daily versus placebo) in ~34,000 nondiabetic women (the Women's Health Initiative Study) also included 2,020 women for whom repeat measures of fasting glucose and fasting insulin were available. There was no significant effect of supplementation on these metabolic parameters at 3 or 6 years of follow-up. Notably, there was also no significant association with incident diabetes risk over 7 years (hazard ratio 1.01 [95% CI 0.94–1.10], with 2,291 cases of incident type 2 diabetes). However, the independent effect of vitamin D could not be assessed as the supplementation was in combination with calcium, and, as the authors suggest, the dose of vitamin D given (400 IU) was modest and likely to be inadequate (23
). Furthermore, since dietary intake is a poor source of vitamin D, compared with sunlight-induced endogenous skin production, such studies require serum 25(OH)D data as well, in at least a representative subsample.
What mechanisms may explain the associations of lower serum vitamin D status with risks of greater levels of glycemia and insulin resistance we have observed? Possibilities include direct effects of vitamin D on pancreatic β-cell secretory function through their nuclear VDRs, effects on insulin sensitivity through stimulation of insulin receptor expression regulation of intracellular calcium since an effector part of the vitamin D pathway is the vitamin D–dependent calcium-binding protein required for postinsulin receptor effects in insulin-responsive tissues, and also indirect effects through inflammatory processes (35
). Furthermore, inadequate vitamin D usually leads to increased serum PTH, which in turn has been found to be inversely associated with insulin sensitivity in healthy adults (37
). Finally, VDR
gene polymorphisms have been associated with variation in insulin secretion among a British Bangladeshi South Asian population (14
) and in glycemia among community-based older American adults (38
), and other gene polymorphisms may affect glucose metabolism, as recently reviewed (39
Limitations of our study include that it was of modest size, and the included cohort with complete data comprised ~50% of the initial cohort, which could have potentially biased our results. However, when comparing baseline characteristics among included and excluded participants, included participants tended to be younger and healthier (lower blood pressure, lower BMI, lower fasting and 2-h glucose, and lower fasting insulin) than nonparticipants. This is in keeping with the frequently observed “healthy participant effect” in epidemiological studies, which, if anything, would lead to a more conservative estimate of association. On an a priori basis, we did not study the association with clinical outcomes such as diabetes, as we had inadequate statistical power (<20% power with 54 incident events of diabetes) but restricted our outcomes to continuous quantitative traits. While we could study association with future glucose concentration, we could not examine association with A1C, a longer-term marker of glycemic status, as we did not measure A1C at baseline in our study. While we measured baseline serum 25(OH)D, we do not have data for sun exposure (including holidays in the sun), for supplement use, nor any interval measures of vitamin D status. We have, however, previously found remarkably close correlations between measures of vitamin D status for each month over 2–3 years in British South Asians from east London (Boucher BJ, Mannan N, and Noonan K, unpublished data). Though stability of vitamin D status across the years is unknown for European Caucasians, as in our study, it is likely to be similar in view of the regularity of seasonal variations over time. Our findings, valid within a population of European Caucasians, cannot be extrapolated to other ethnic groups, given the previously reported heterogeneity by ethnicity (10
). Despite these limitations, strengths of our study include the population-based nature of the study; the use of a direct, objective measure of vitamin D status, rather than relying on self-reported vitamin D intake or sunlight exposure; and the comprehensive range of quantitative metabolic markers (at baseline and at 10-year follow-up), including glucose measurement with oral glucose tolerance tests, fasting insulin, and derived markers of insulin resistance (HOMA-IR) and a continuous metabolic syndrome risk z score. Furthermore, we have been able to adjust our analyses for a robust range of potential confounders and mediators, including PTH and calcium status (rarely included in other studies of such associations), as well as for smoking, physical activity, season, obesity, social class, age, and sex, which increases confidence in the independence of the observed associations. However, we acknowledge that residual confounding from measured and unmeasured factors cannot be excluded. Our data also demonstrate that mean serum 25(OH)D concentrations were <75 nmol/l (hypovitaminosis D) for 10 months of the year and <50 nmol/l for 4 months of the year (vitamin D insufficiency) in this cohort. There is evidence of a high prevalence of hypovitaminosis D worldwide (40
), and our data are indicative of the chronically inadequate vitamin D repletion common to northern latitudes (41
). This widespread problem, combined with our finding that higher vitamin D status [25(OH)D] may have a beneficial effect on future glucometabolic risk profile, raises a matter of public health importance deserving serious further investigation.
In conclusion, we have demonstrated inverse associations of baseline serum vitamin D concentration with future glucose levels and insulin resistance in a prospective population-based study, such that higher baseline vitamin D is associated with significantly lower future glucose, insulin, and HOMA-IR. These associations are independent of risk factors and potential confounders and are potentially important in understanding the etiology of metabolic disturbances associated with type 2 diabetes. Despite mounting evidence linking inadequate vitamin D repletion with abnormalities of glucose and insulin metabolism, the role of vitamin D is not fully understood and deserves further investigation in both larger, specifically designed prospective studies and with randomized controlled trials of supplementation. Demonstration of a causal role for hypovitaminosis D in these disorders would lead to new targets for efforts to prevent type 2 diabetes at the population level and, possibly, for its treatment.