Low levels of vitamin D are unlikely to cause type 2 diabetes, new research suggests.

The findings were published online October 1 in Lancet Diabetes & Endocrinology by Zheng Ye, PhD, of the MRC Epidemiologic Unit, University of Cambridge School of Medicine, United Kingdom, and colleagues.

Previous observational studies have found an inverse relationship between levels of vitamin- D, as assessed using the marker 25-hydroxyvitamin D (25[OH]D), and the development of type 2 diabetes, but those studies have not determined whether the association was causal.

In an attempt to eliminate confounding by external factors that could contribute to both low vitamin D and increased diabetes risk, Dr. Ye and colleagues used several data sources from populations of European descent to examine the relationship between 4 genetic variants associated with innate plasma 25(OH)D concentrations and type 2 diabetes.

There was no significant relationship between expression of the 4 genes and the risk for developing type 2 diabetes (odds ratio [OR], 0.93). The finding suggests little justification for efforts to increase concentrations of vitamin D by supplementation or other means for the purpose of preventing type 2 diabetes, the authors say.

"While the role of vitamin D for bone health is well established from other research," and guidelines with regard to this should be adhered to, "we found no support for its role in the prevention of type 2 diabetes," senior author Nita Forouhi, MD, PhD, of the MRC Epidemiology Unit, University of Cambridge, told Medscape Medical News.

"On the other hand, we do have high-quality research evidence showing that the maintenance of a healthy weight and healthy lifestyles, including a healthy diet and physical activity, are the main ways to prevent the onset of type 2 diabetes," she added.

In an accompanying editorial, Brian Buijsse, PhD, of the German Institute of Human Nutrition, Potsdam-Rehbruuecke, Nuthetal, said this new study makes "an important contribution by reporting the results of a Mendelian randomization study, which makes use of the interindividual variability in circulating 25(OH)D concentrations caused by common genetic variants."

Because allocation of genetic variants at conception is independent of behavioral and environmental factors, their associations with disease are less likely to be affected by confounding or reverse causation, he observes.

The sky is becoming rather clouded for vitamin D in the context of preventing type 2 diabetes.

Dr. Ye and colleagues' study, together with the recent negative results of a meta-analysis of 35 short-term trials of supplementation with vitamin D (J Clin Endocrinol Metab. 2014. Abstract) do not offer much hope that vitamin D supplementation can be used to prevent type 2 diabetes, he adds. "The sky is becoming rather clouded for vitamin D in the context of preventing type 2 diabetes."

The "Unconfounded" Association

Dr. Ye and colleagues analyzed the association between 2 gene variants involved in 25[OH]D synthesis, 1 in 25[OH]D transport, and 1 in 25[OH]D catabolism — based on 28,144 cases and 76,344 noncases of type 2 diabetes from a case-cohort study and 4 case-control studies.

Odds ratios for the 4 gene variants and risk for type 2 diabetes ranged from 0.95 to 1.03, with an average of 0.93; none reached statistical significance. In sensitivity analysis, the odds ratio for 1-standard-deviation-lower 25[OH]D concentration was 0.97 for all 4 gene variants combined.

And in an analysis of summary data from 46,368 Europeans without diabetes, the 4 variants were not significantly associated with fasting glucose, 2-hour glucose, fasting insulin, or HbA 1c .

In contrast, an update of the investigators' own prior meta-analysis involving a total 8492 cases of type 2 diabetes and 89,698 noncases in 22 prospective observational studies did show a significant inverse association between 25[OH]D and type 2 diabetes, with an odds ratio of 1.22 (Diabetologia. 2012;55:2173-2182. Article)

Dr. Forouhi told Medscape Medical News that observational studies can't account for factors that can distort true associations, such as reverse causation, in which the presence of clinical or subclinical disease might affect levels of vitamin D, rather than the other way around.

Or physical activity could be a confounding factor because it reduces the risk for type 2 diabetes but it also often takes place outdoors and is therefore independently related to sunlight exposure, which also influences vitamin D status. What's more, physical activity and other confounders are often self-reported in observational studies, which also can lead to bias, she noted.

In contrast, "when we apply the genetic approach of Mendelian randomization, as we did, this can offer a way of analyzing that is free from these limitations and therefore provides more realistic estimates of the association between vitamin D levels and risk of diabetes," she told Medscape Medical News.

Future Studies

Dr. Buijsse says one way of trying to address reverse causation might be to investigate potential mechanisms such as reduced 25(OH)D concentration resulting from pathophysiological processes leading to type 2 diabetes, such as liver dysfunction. "If so, then stratifying the analysis for parameters of liver function might be worthwhile."

Indeed, Dr. Forouhi told Medscape Medical News that her group is now looking at liver function, among other parameters.

"This remains an important scientific area. We are undertaking several next steps such as completing the measurement of 25-hydroxyvitamin D levels in a large study of diabetes risk, where we also have information on other relevant metabolic markers such as liver function, as well as further genetic data."

The group is also complementing this with a trial of different types of supplements of vitamin D to see whether there is an effect on metabolic markers of diabetes risk, while in yet other studies they're actually measuring physical activity rather than relying on self-report and quantifying body-fat distribution to investigate the relationships with levels of vitamin D.

And she told Medscape Medical News that the supplement issue isn't dead yet: "There are also some ongoing clinical trials of vitamin D supplementation from other groups that are eagerly awaited and will help to shed more light on the possible effects of vitamin D both for the prevention and management of type 2 diabetes."

This study was funded by the UK Medical Research Council. Dr. Ye, Dr. Forouhi, and coauthors and Dr. Buijsse have reported no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online October 1, 2014. Abstract