Low Blood Vitamin D Levels Linked to Diabetes

Liam Davenport

March 03, 2015

Low serum vitamin D levels are more closely associated with diabetes than obesity is, claim Spanish researchers, who go on to suggest that vitamin D deficiency may be linked to an increased risk for type 2 diabetes.

They found that serum 25-hydroxy vitamin D levels are reduced in prediabetic and diabetic individuals compared with those who have normal blood glucose levels, independently of body mass index (BMI).

The study was published online February 23 in the Journal of Clinical Endocrinology & Metabolism.

"Our findings indicate that vitamin D is associated more closely with glucose metabolism than obesity," commented senior author Manuel Macías-González, PhD, of the University of Málaga, Spain. "The study suggests that vitamin D deficiency and obesity interact synergistically to heighten the risk of diabetes and other metabolic disorders.

"The average person may be able to reduce their risk by maintaining a healthy diet and getting enough outdoor activity," he suggested.

However, John S Adams, MD, from the University of Caifornia, Los Angeles Orthopedic Hospital, does not agree with this assessment.

He believes that the paper was not sufficiently well designed and that it does not add substantially to the literature. "Had I reviewed this paper, that would have been my point," he told Medscape Medical News.

"In my mind, this is simply another association study," and as such it is unable to imply the presence of an underlying mechanism, Dr Adams maintained. "There are scads of these association studies out there with total circulating 25-hydroxy vitamin D concentration and diabetes, or obesity, or infection, or heart disease....You name it. What you really want to be able to do is have some sort of a study where you take these people and you do something that will change their situation."

In other words, Dr Adams would like to see studies in which patients are treated with vitamin D to restore their levels and then see whether this affects glucose metabolism, and indeed there are several such studies ongoing, he noted.

"What we are looking for here is cause and effect."

Relationship Between Vitamin D, Diabetes, and Obesity Unclear

The Spanish researchers explain in their paper that the relationship between 25-hydroxyvitamin D and obesity and type 2 diabetes is not completely understood.

In addition, vitamin-D–receptor (VDR) expression in adipose tissue is related to obesity and might be regulated by 1,25-dihydroxyvitamin D3, the biologically active form of 25-hydroxyvitamin D.

Most prior studies that have examined 25-hydroxyvitamin D levels according to BMI failed to consider whether the participants were or were not diabetic, "which is noteworthy because most obese patients have altered glucose metabolism," they point out. This issue needs to be considered "to discern whether vitamin D deficiency is related to obesity by itself or whether it is a consequence of altered carbohydrate metabolism."

So they set out to analyze serum 25-hydroxyvitamin D and VDR gene expression in adipose tissue according to BMI and glycemic status and to examine the effect of 1,25-dihydroxyvitamin D3 on adipose tissue according to BMI in subjects attending their hospital for various surgeries.

They examined two groups: the first consisted of 118 individuals classified as lean, overweight, obese, or morbidly obese and as normoglycemic (fasting glucose levels < 100 mg/dL and homeostasis model of assessment for insulin resistance [HOMA-IR] < 3.5) or prediabetic and diabetic (fasting glucose levels > 100 mg/dL).

The second group comprised 30 obese patients who were also divided into two groups per glycemic status, normoglycemic or prediabetic and diabetic.

Blood samples were obtained either during bariatric surgery in the morbidly obese patients or during operations for hiatal hernia or cholecystectomy in lean, overweight, or obese participants.

Visceral adipose tissue was obtained from three normoglycemic healthy morbidly obese donors and three normoglycemic healthy lean donors.

The team found that serum 25-hydroxy vitamin D levels were lower in prediabetic and diabetic patients than in normoglycemic individuals, a finding that reached significance in the lean and morbidly obese participants (P < .05).

Further analysis indicated that serum 25-hydroxy vitamin D levels were negatively correlated with glucose levels (r = -0.295; P = .001) and HOMA-IR (r = -0.200; P = .032), but not with BMI.

Expression of the VDR gene was significantly higher in morbidly obese patients than in other groups (P < .05). And interestingly, 1,25 dihydroxy vitamin D3 stimulation of adipose tissue from obese patients significantly increased VDR expression, an effect that was not seen in tissue samples from lean participants.

"25-hydroxy vitamin D levels are diminished in prediabetic and diabetic vs normoglycemic subjects, independently of BMI, and are closely related to glucose-metabolism variables, suggesting that vitamin D deficiency is associated more with carbohydrate metabolism than with obesity," the authors conclude.

"Moreover, adipose tissue has a different response to 1,25-dihydroxyvitamin D3 depending on the degree of obesity."

In essence, "The major strength of this study is that it compares vitamin D levels in people at a wide range of weights (from lean to morbidly obese subjects) while taking whether they had diabetes into account," stated study author Mercedes Clemente-Postigo, MSc, Universidad de Málaga, in a US Endocrine Society press release.

But Dr Adams reiterated his objection that this is " simply another association studybecause there's the static measurement of 25-hydroxy vitamin D levels and, if you look at all these people...whether they were lean, overweight, obese, or morbidly obese, they are all vitamin D deficient."

Other Studies Will Better Inform the Issue

Dr Adams went on to explain that there are intervention studies ongoing that will better assess the interplay between vitamin D and risk for diabetes.

One example he cites is the D2d study, for which he serves on the data safety and monitoring board. This is designed to assess whether vitamin D supplementation delays the onset of type 2 diabetes and to try to understand how vitamin D affects glucose metabolism.

Researchers at 20 sites in the United States will enroll people with prediabetes, giving them vitamin D or a placebo and then following them up for 3 years. During that time, participants will be assessed on a maximum of 13 occasions.

Another important one is a substudy within the VITAL trial, which is investigating whether taking supplements of vitamin D3 or omega-3 fatty acids reduces the risk of developing cancer, heart disease, and stroke in subjects without a prior history of the conditions.

In the substudy, nondiabetic patients will be examined to determine whether vitamin D and omega-3 fatty-acid supplementation reduces the risk for type 2 diabetes, with the aim of informing clinical guidelines for prevention.

In the meantime, Dr Adams feels that there is still a long way to go to know whether vitamin D has an impact on glucose metabolism and type 2 diabetes. He said: "I think it's pretty safe to say that if your 25-hydroxy vitamin D levels are lower, you have vitamin D deficiency.

"If you get back into the normal range, then it clearly improves skeletal outcomes, increasing bone mass and decreasing fractures. That's very, very clear. But for the data on a lot of these other extraskeletal manifestations of vitamin D deficiency...I think the jury is still out."

As a final observation on the current paper, he pointed out that "everybody agrees" that the active form of the hormone is 1,25 dihydroxy vitamin D3.

"But all of the adverse outcomes that we've talked about — diabetes, obesity, infections, heart disease, stroke, hypertension — are associated with a low 25-hydroxy vitamin D in the blood," he said.

"That suggests that what has to happen at the tissue level is that there has to be some conversion of 25-hydroxy vitamin D to 1,25 dihydroxy [vitamin D3] inside the target cell. [This] has to have an effect on that cell itself to change gene expression, or it has to get released into the microenvironment to have an effect on another cell in that environment, which is expressing the vitamin D receptor.

"This particular study just doesn't consider that kind of paradigm."

This study was supported by Centros de Investigación Biomédica en Red of the Instituto de Salud Carlos III (ISCIII) and grants from the ISCIII. The authors have reported no relevant financial relationships .

J Clin Endocrinol Metab. Published online February 23, 2015. Abstract

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