Evidence Mounting for Vitamin D Link to Diabetes Risk

Liam Davenport

People with low vitamin D levels may be at increased risk of type 2 diabetes, according to the results of a new US epidemiological study.

The analysis of more than 900 individuals from southern California found that having plasma levels of 25-hydroxyvitamin D (25[OH]D) greater than 30 ng/mL was associated with a significant and substantial reduction in later diabetes risk.

"We found that participants with blood levels of 25-hydroxyvitamin D that were above 30 ng/mL had one third of the risk of diabetes, and those with levels above 50 ng/mL had one fifth of the risk of developing diabetes [compared with those whose levels were < 30 ng/mL]," said lead author Sue K. Park, MD, Seoul National University College of Medicine, South Korea, in a press release by the University of California, San Diego (UCSD), where some of the team are based.

The research, published online April 19 in PLoS One, also showed that every 10 ng/mL increase in 25(OH)D levels above 30 ng/mL was associated with a 36% reduction in diabetes risk.

However, second author Cedric F. Garland, DrPH, of UCSD, emphasized that the epidemiological nature of the study means the findings are not able to demonstrate causality.

"Further research is needed on whether high 25-hydroxyvitamin D levels might prevent type 2 diabetes or the transition from prediabetes to diabetes. But this paper and past research indicate there is a strong association," he said.

Examining the Issue at the High End of Normal Median Vitamin D Levels

In their article, Park and colleagues note that higher plasma 25(OH)D levels have previously been associated with a 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 (80 nmol/L)."

Overall, 77% of US adults have been found to have vitamin D deficiency, defined as less than 32 ng/mL, with the prevalence doubling since 1980, they note.

The team studied participants from the Rancho Bernardo Study of Health Aging to examine the association between 25(OH)D levels and incidence of diabetes or prediabetes in a cohort with an unusually high median vitamin D concentration. Specifically, they included 903 primarily older, middle-income, community-dwelling white adults without a history of diabetes from a southern California suburb.

Researchers explain that the cohort may have a lower than usual prevalence of vitamin D deficiency because of year-round sunshine and good weather in a sunny and clear area of southern California, and because of a higher standard of education, and a greater socioeconomic status and proportion of whites.

The cohort has the highest known published median 25(OH)D concentration, 42 ng/mL (105 nmol/L) in men and 39 ng/mL (98 nmol/L) in women, of any population that has reported data on diabetes incidence by vitamin D levels.

At baseline (1997–1999), participants underwent anthropomorphic assessments and completed standardized questionnaires on current medications, cigarette smoking, alcohol consumption, physical exercise, and any history of myocardial infarction, stroke, angina pectoris, or peripheral claudication. In addition, plasma 25(OH)D levels were measured.

Blood samples were then collected every 2 years for 8-h fasting plasma glucose (FPG) testing, with an oral glucose tolerance test performed if the 8-h FPG level was ≥ 100 mg/dL (5.5 mmol/L).

At baseline, participants were a mean age of 74.1 years and had an average body mass index (BMI) of 25.4 kg/m2.

Strong Association With Diabetes, Weaker Link With Prediabetes

Over a mean follow-up of 12.5 years, 47 individuals developed incident type 2 diabetes, defined as an 8-h FPG ≥ 126 mg/dL (7.0 mmol/L). A further 337 developed prediabetes, defined as an 8-h FPG 100–125 mg/dL (5.5–6.9 mmol/L).

Individuals who developed diabetes, compared with those who had not, had a significantly higher average BMI, waist circumference, triglyceride concentration, systolic blood pressure, and FPG at baseline (P < .001 for all).

A similar pattern was seen in those who developed prediabetes.

Those who developed diabetes or prediabetes were more likely to be men than those who didn't (P < .001 for both). However, alcohol use, smoking, and self-reported regular strenuous exercise were not significantly associated with diabetes or prediabetes incidence.

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.

On multivariate analysis, the team found that increased plasma 25(OH)D levels were associated with a reduced risk of diabetes.

Compared with a plasma 25(OH)D level < 30 ng/mL, individuals with levels of 30–39 ng/mL had a hazard ratio (HR) of developing incident type 2 diabetes of 0.31, which decreased to an HR of 0.29 among those with levels of 40–49 ng/mL, and an HR of 0.19 in those with levels ≥ 50 ng/mL (P = .005 for trend).

The association between plasma 25(OH)D levels and prediabetes was, in contrast, weak and nonsignificant, with substantial heterogeneity.

"This could be because prediabetes is a relatively mild condition and includes many individuals who did not become diabetic...[and/or] that people with prediabetes may be healthier due to better lifestyle behaviors," the team writes.

What's the Norm, and How Is it Best Achieved?

In their discussion, Park and colleagues note that their findings contrast with those of a recent well-designed multicenter cohort study that found no association between plasma 25(OH)D levels and risk of diabetes (Diabet Med. 2014;31:564-569).

One possible explanation for these seemingly disparate findings, they say, is that the mean 25(OH)D concentration in that study was 23 ng/mL (58 nmol/L), as participants came from much more northern latitudes of the United States, "compared to 42 ng/mL (105 nmol/L) in the present study."

"It might be that the 25(OH)D concentrations in the subjects in the previous study tended to be in a range that is below the range in which 25(OH)D is inversely related to incidence of diabetes," they write.

In the current study, researchers assumed the minimum healthy plasma level of 25(OH)D to be 30 ng/mL, which is 10 ng/mL above the level recommended in 2010 by the US Institute of Medicine, now part of the National Academies, a health advisory group to the federal government. Many groups, however, have argued for higher serum levels of vitamin D, as much as 50 ng/mL, and the matter remains hotly debated, say Park and colleagues.

"There are still unresolved concerns about the desirable plasma target for 25(OH)D," they note in the article, adding that they "tentatively suggest" the target be no less than 40 ng/mL (100 nmol/L). Other analysts considering the same data could reasonably choose other desired targets, such as 30 ng/mL (75 nmol/L), as proposed by the Endocrine Society, they observe.

And, they stress, "Our study does not solve the basic question of whether individuals may need to seek vitamin D supplementation if needed to maintain a concentration of 30 ng/mL (75 nmol/L), despite the possibility of any toxicity. A recent placebo-controlled, randomized trial of a vitamin D weekly bolus supplement for prediabetes patients failed to prove a beneficial effect on 5-year incidence of diabetes."

Sufficient 25(OH)D levels obtained naturally from sunlight and food, not supplementation, might be more relevant to reduce diabetes risk, they indicate.

The study was supported by the National Institutes of Health, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases. The authors have reported no relevant financial relationships.

PLoS One. 2018;13:e0193070. Full text

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