This prospective cohort study reveals an inverse relationship between blood vitamin D25 levels and risk of diabetes. Future research will show if this connection is causative in nature. Certainly there is some physiological and pathophysiological explanation: pancreatic beta cells are known to have vitamin D receptors, that upon VitD metabolites stimulation they produce and release insulin. Secondly, low vitamin d is also a proinflammatory state, an independent risk factor for diabetes development.
It has been reported that higher plasma 25-hydroxyvitamin D is associated with lower risk of type 2 diabetes. However the results to date have been mixed and no adequate data based on a cohort are available for the high end of the normal range, above approximately 32 ng/ml or 80 nmol/L.
We performed a cohort study of 903 adults who were known to be free of diabetes or pre-diabetes during a 1997–1999 visit to a NIH Lipid Research Centers clinic. Plasma 25(OH)D was measured at Visit 8 in 1977–1979. The mean age was 74 years. The visit also included fasting plasma glucose and oral glucose tolerance testing. Follow-up continued through 2009.
There were 47 cases of diabetes and 337 cases of pre-diabetes. Higher 25(OH)D concentrations (> 30 ng/ml) were associated with lower hazard ratios (HR) for diabetes:
For 25VitD 30–39 ng/ml: HR = 0.31, p<0.05
For 25VitD: 40–49 ng/ml: HR = 0.29, p<0.05
For 25VitD: > 50 ng/ml: HR = 0.19, p<0.05
All HRs are compared to < 30 ng/ml. There was an inverse dose-response gradient between 25(OH)D concentration and risk of diabetes with a p for trend of 0.005.
Each 10 ng/mL higher 25(OH)D concentration was associated with a HR of 0.64, p<0.05. 25(OH)D concentrations were more weakly inversely associated with prediabetes risk, and the trend was not significant.
Further research is needed on whether high 25(OH)D might prevent type 2 diabetes or transition of prediabetes to diabetes.
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The public health impact of vitamin D deficiency has received attention due to the discovery of associations between low plasma concentrations of vitamin D metabolites and higher risk of several cancers, cardiovascular disease, bone fractures and the metabolic syndrome. Trends in energy intake and anthropometric characteristics have paralleled the increase in incidence of type 2 diabetes mellitus. It is unclear whether vitamin D deficiency might be contributing to increased risk.
If defining 25(OH)D levels < 32 ng/ml as deficiency, 77% of U.S. adults were deficient. The prevalence of vitamin D deficiency by this criterion has doubled since 1980 in U.S. adults.
Several cohort studies have examined the association of circulating 25(OH)D concentrations with risk of diabetes. Of these, 12 found significantly higher incidence rates in individuals with lower circulating 25(OH)D concentrations . The association of plasma 25(OH)D deficiency with risk of diabetes also has been examined in four meta-analyses and all reported an inverse association of circulating 25(OH)D with risk of diabetes.
The aim of this study was to examine whether lower concentrations of 25(OH)D or 1,25(OH)2D were associated with higher incidence of diabetes and pre-diabetes in a prospective cohort study with an overall follow-up period of 12 years.
This cohort may have a lower than usual prevalence of vitamin D deficiency due to year-round sunshine and good weather in a sunny and clear area of southern California. It may also be possible that the cohort has a lower than usual prevalence of vitamin D deficiency due to a higher standard of education and socioeconomic status and a high proportion of Caucasians.
This cohort has the highest known published median 25(OH)D concentration, 42 ng/ml in men and 39 ng/ml in women of any population that has reported data on diabetes incidence by 25(OH)D. No previous study of the association of 25(OH)D with diabetes has included a substantial population in the high range of > 30 ng/ml.
Individuals with a 25(OH)D concentration > 30 ng/ml had only one-third the incidence of diabetes as those with ≤ 30 ng/ml. Those with a somewhat higher concentration of 25(OH)D > 50 ng/ml had a much lower HR of 0.2.
The association of 25(OH)D with diabetes persisted after exclusion of participants who reported at baseline that they usually took vitamin D or calcium supplements. The inverse association of a higher 25(OH)D concentration ≥ 30 ng/ml was consistent among individuals in higher traditional risk groups for diabetes such as those having metabolic syndrome or established diabetes risk factors according to standard scores for predicting risk of diabetes that are used by CDC and other organizations to predict incidence of diabetes. These include obesity and lack of regular exercise.
The finding of the present study that 25(OH)D concentration had a significantly inverse association with risk of diabetes is biologically plausible. Mice with the vitamin D receptor (VDR) null phenotype have higher incidence rates of diabetes, suggesting that the vitamin D pathway may be relevant to the pathogenesis of diabetes. Pancreatic beta cells have VDR, and vitamin D metabolites stimulate the pancreas to produce insulin.
Active metabolites of vitamin D also have been shown in animal models to protect pancreatic beta cells from cytokine-induced inflammation and apoptosis.
Only the 25(OH)D concentration was associated with lower risk of diabetes in the present study. One of the reasons may be the stability of 25(OH)D in circulation. 25(OH)D has a 75-fold longer half-life than 1,25(OH)2D. Circulating 25(OH)D is also stable with respect to time, even in stored frozen plasma.
Although the number of cases of diabetes was much smaller than that of pre-diabetes, 25(OH)D levels were strongly inversely associated with risk of diabetes and weakly inversely associated with risk of pre-diabetes. This could be because pre-diabetes is a relatively mild condition, and includes many individuals who did not become diabetic.
Another possible reason is that people with pre-diabetes may be healthier due to better life-style behaviors. In our study, pre-diabetes participants were more likely to use vitamin D supplements and had higher HDL-cholesterol levels, lower triglyceride levels, BMI, and waist circumference, and were less likely to smoke cigarettes compared to diabetes patients.
The inverse association of 25(OH)D with diabetes was much stronger in individuals with hyperparathyroidism and who regularly exercised strenuously.
Hyperparathyroidism, regardless of cause, is a common concern in the aged, particularly in women, due to renal deterioration, low estrogen, low calcium intake, and, on occasion, use of furosemide. It is also adversely associated with glucose tolerance and insulin resistance.
In our cohort, individuals with hyperparathyroidism were likely to have higher risk for diabetes.
Nevertheless, our finding that a higher 25(OH)D concentration has a beneficial effect on risk of diabetes is encouraging to older people. The beneficial effect of higher 25(OH)D could be due to improving insulin sensitivity and anti-inflammatory effects although the exact mechanisms by which a higher 25(OH)D concentration lowers diabetes risk remain unclear.
Individuals who were doing regular strenuous exercise were likely to have a lower HR associated with higher 25(OH)D concentration. A similar association was present in those with higher levels of PTH. Skeletal muscle has VDR. Strenuous exercise itself has a favorable effect in controlling diabetes through increasing glucose utilization in muscle and insulin sensitivity.