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Vitamin D deficiency: A possible driver of type 2 diabetes
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The relationship between vitamin D and bone health is well-established, particularly in terms of reducing osteoporosis risk. According to the most recent clinical practice guideline released by the Endocrine Society, vitamin D deficiency leads to abnormalities in calcium, phosphorus and bone metabolism. Because vitamin D is not present in many foods, the guideline recommends supplementation at suggested daily intake and tolerable upper-limit levels and advises testing of serum 25-hydroxyvitamin D in patients at risk for deficiency.
Recently, possible correlations between 25-(OH)D deficiency and type 2 diabetes have generated further interest in the potential preventive value of vitamin D supplementation. Experimental and epidemiologic studies have suggested an association between vitamin D deficiency and decreased insulin delivery, insulin resistance and type 2 diabetes.
However, larger studies are needed to fully understand this connection.
“In a number of observational studies, low 25-(OH)D levels correlate with increased risk of type 2 diabetes, and rates of both vitamin D deficiency and type 2 diabetes have been increasing dramatically across the globe,” Carolyn B. Becker, MD, associate professor of medicine and master clinician educator in the division of endocrinology, diabetes and hypertension at Brigham and Women’s Hospital, told Endocrine Today. “It remains unclear whether these trends are simply correlated with each other or truly causally linked.”
Becker spoke with Endocrine Today about the connection between vitamin D and diabetes, the possible mechanisms of this connection, and the advisability of supplementing with vitamin D to prevent type 2 diabetes.
What is known on the connection between vitamin D and diabetes?
Becker: In cross-sectional studies, patients with diabetic microvascular and macrovascular complications tend to have lower vitamin D levels than diabetic patients without these complications. Unfortunately, intervention trials have not convincingly shown that vitamin D supplementation prevents either diabetes or prediabetes, or that it improves glycemic control in those with pre-existing type 2 diabetes. Most of these studies were designed to look at other primary outcomes or were underpowered to show definitive outcomes on this measure. Thus, we need to await large clinical trials to answer whether vitamin D supplementation can prevent the onset of diabetes, reverse prediabetes, improve glycemic control or prevent complications. Although current evidence does not support widespread use of vitamin D supplementation in those with diabetes, it seems reasonable to treat patients with marked deficiencies [in which 25-(OH)D is less than 20 ng/mL or 50 nmol/L] given that skeletal fragility is common in this population.
Are the mechanisms of the connection between vitamin D and diabetes known, or are we just seeing correlations between vitamin D levels and glucose levels and heart disease risk?
Becker: In animals and humans, the vitamin D receptor is found in numerous cell types, including pancreatic beta cells, myocardial cells, skeletal muscle and adipose tissue cells. Polymorphisms in the vitamin D receptor and alterations in vitamin D levels affect insulin secretion and sensitivity and cause changes in the immune system and inflammatory markers. In type 1 diabetes, seasonal variability and geographic differences in prevalence of the disease have led to interest about the role of vitamin D deficiency as a risk factor for type 1 diabetes.
Data from animal, epidemiologic and observational studies seem to show a link between low vitamin D levels and risk for type 1 diabetes. The activated form of vitamin D (1,25-dihydroxy-vitamin D) inhibits certain T cells and suppresses proinflammatory cytokines. In this way, vitamin D deficiency coupled with genetic susceptibility could increase the risk for autoimmune pancreatic destruction and type 1 diabetes. Some intervention trials in type 1 diabetes have shown dramatic benefits for children given vitamin D supplements, with reduced rates of type 1 diabetes later in life.
What is the connection between vitamin D and heart disease?
Becker: Most observational and epidemiologic studies show that vitamin D deficiency is correlated with heart disease and, conversely, that adequate levels of 25-(OH)D are protective against heart disease. However, we do not have large, adequately powered, randomized controlled clinical trials to support these findings or to guide us in clinical decision-making.
In terms of the mechanism of this correlation, vitamin D has beneficial effects on blood pressure, vascular smooth muscle, vascular tone, endothelial function and suppression of inflammatory cytokines. It may also modulate the renin-angiotensin-aldosterone system. The net result of this should be lower rates of heart disease in patients with adequate vitamin D levels.
Is vitamin D supplementation a reasonable course to take for preventing diabetes or heart disease?
Becker: We need large randomized intervention trials to determine if vitamin D supplementation should be recommended as a means of preventing (or improving) heart disease. Except for the results in children showing that vitamin D supplementation could reduce the risk for type 1 diabetes, the current studies do not tell us whether this approach is effective. For now, we should probably focus on the preventive measures that have been shown to make a difference, such as weight loss and exercise for prevention of diabetes, and smoking cessation, lipid-lowering, BP control, healthy diet and exercise for preventing heart disease.
Do we know the optimal levels of vitamin D for good glucose metabolism and lowering heart disease risk? Would these be the same as those recommended for bone health?
Becker: No, because we are not even sure that vitamin D is effective in lowering these risks. Until we have more data, it seems reasonable to keep 25-(OH)D levels above 20 ng/mL and close to 30 ng/mL, the same as we recommend for bone health. Although reference ranges vary, most experts feel that 25-(OH)D levels between 30 ng/mL and 50 ng/mL (75-125 nmol/L) are ideal for bone health. Levels that are too high may be associated with arterial calcification and excess mortality so that “more is not always better.”
What studies are underway investigating the role of vitamin D in diabetes and heart disease?
Becker: There are currently four large randomized clinical trials looking at the effect of vitamin D or placebo on glycemic control or incidence of type 2 diabetes as the primary outcomes, and three of the four will also look at cardiovascular outcomes. These trials — VITAL (NCT01169259), FIND (NCT01463813), D-HEALTH (NCT01537809) and D2D (NCT01942694) — are considered “megatrials” and include between 2,000 and almost 30,000 participants. Doses of vitamin D range from 1,600 IU per day to 4,000 IU per day or the equivalent dose once a week or once a month. These trials will take place over the next several years and will provide more conclusive information on whether vitamin D can improve glycemic control and prevent progression to type 2 diabetes. We should have many more answers to these questions over the next few years. – Compiled by Jennifer Byrne
References:
Holick MF, et al. J Clin Endocrinol Metab. 2011;doi:10.1210/jc.2011-0385.
Lips P, et al. J Steroid Biochem Mol Biol. 2017;doi:10.1016/j.jsbmb.2016.11.021.
For more information:
Carolyn B. Becker, MD, can be reached at 221 Longwood Avenue, RFB-2, Boston MA 02115; email: cbbecker@partners.org
Disclosure: Becker reports no relevant financial disclosures.