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SYNOPSIS: Findings from a meta-analysis show vitamin D supplementation was associated with improved glycemic control in vitamin D-deficient or non-obese patients with type 2 diabetes.
SOURCE: Wu C, Qiu S, Zhu X, Li L. Vitamin D supplementation and glycemic control in type 2 diabetes patients: A systemic review and meta-analysis. Metabolism 2017;73:67-76.
SUMMARY POINTS
- Vitamin D supplementation reduced hemoglobin A1c (HbA1c) and fasting blood glucose in subjects with a vitamin D deficiency, defined as < 20 ng/mL (50 nmol/L).
- Vitamin D supplementation significantly reduced HbA1c in patients with diabetes who had a body mass index (BMI) < 30 kg/m2, but not in those with a BMI > 30 kg/m2.
- Vitamin D dosing and frequency varied widely from 1,000 IU oral per day to a single dose of 300,000 IU intramuscularly. Thus, optimal dosing has yet to be determined.
The subject of vitamin D supplementation and its effects on various aspects of health has been a popular topic. Previous studies have demonstrated the benefits of vitamin D extend past bone and parathyroid health to include metabolic diseases such as type 2 diabetes and obesity. Mechanisms of action on metabolism are elucidated further in the commentary. It has been found that lower vitamin D levels are relatively common in those with type 2 diabetes.1,2 However, the causal relationship between vitamin D and type 2 diabetes is unclear. Wu et al attempted to clarify this relationship through a careful meta-analysis and review of previous studies.
Currently, more than 400 million people worldwide suffer from diabetes.3 Improving glycemic control is the primary goal in diabetes management. There are many effective dietary and pharmacological agents used in diabetes management. However, diabetes continues to rise at epidemic proportions and having more tools in our clinical tool belts to address this problem is wise.
Other investigators have explored the use of vitamin D in glycemic control.4 Some of these studies have shown benefit, while others have shown no benefit. Previous studies have included dietary intake of vitamin D, patients who did not have diabetes, and patients with prediabetes. Wu et al conducted this review and meta-analysis to evaluate an association between vitamin D supplementation, specifically, and the reduction of fasting blood glucose (FBG) as well as glycosylated hemoglobin A1c (HbA1c) only in patients with type 2 diabetes. FBG reflects daily glycemic fluctuations. HbA1c indicates the average plasma glucose level over the previous eight to 12 weeks.
Wu et al started with 637 articles and narrowed their list to include just 26 in the final analysis. They searched PubMed, Web of Science, and the Cochrane Library for articles published through March 2017 and included international publications of any language. The authors’ numerous exclusions strengthened the final analysis. To be included in this review, studies had to be randomized, controlled trials of human subjects with type 2 diabetes that evaluated HbA1c and FBG. The studies used either vitamin D, vitamin D analogues, and/or vitamin D and calcium supplementation. The studies included also had to demonstrate some change in serum vitamin D and a difference between the intervention group and the control group. All 26 studies were printed in full-text articles. (See Table 1.)
Table 1: Inclusion Data |
|
Vitamin D deficiency was defined as serum 25(OH)D concentrations of < 20 ng/mL (50 nmol/L). Vitamin D insufficiency was defined as serum (OH)D concentrations of 20-30 ng/mL (50-75 nmol/L), and vitamin D sufficiency was defined as serum 25(OH)D concentrations of > 30 ng/mL (75 nmol/L). It has been suggested that serum concentrations > 30 ng/mL maximize the noncalcemic benefits of vitamin D.5
Wu et al conducted a further analysis in subgroups including baseline 25(OH)D, body mass index (BMI), dosage of vitamin D supplementation, length of intervention, and change of 25(OH)D concentration. In this evaluation of moderating factors, they found vitamin D supplementation had a significant benefit on FBG and HbA1c in those who were non-obese with a BMI < 30 kg/m2. BMI is an attempt to quantify the amount of tissue mass, including muscle, fat, and bone, in an individual to categorize them as underweight, normal weight, overweight, and obese. (See Table 2.)
Table 2: Vitamin D Supplementation and Effect on HbA1c and Fasting Blood Glucose |
|
Body mass index |
Significant effect on HbA1c and FBG? |
|
< 18.5 kg/m2 (underweight) |
Yes |
|
18.5-25 kg/m2 (normal) |
Yes |
|
25-30 kg/m2 (overweight) |
Yes |
|
> 30 kg/m2 (obese) |
No |
Another subgroup analysis showed that HbA1c and FBG levels both dropped significantly when changes in 25(OH)D serum levels were < 20 ng/mL or between 10-20 ng/mL. The connection between physiological parameters and serum vitamin D levels is important, demonstrating benefits even with small laboratory changes with vitamin D repletion.
The dosing of vitamin D also was highly variable, from as low as 1,000 IU per day to a single intramuscular injection of 300,000 IU. Additionally, the course of intervention ran from four to 48 weeks. Because of this high variability in dosing quantity and trial length, this analysis failed to yield specific clinical recommendations. However, in patients who have a serum 25(OH)D level < 20 ng/mL and are non-obese, vitamin D supplementation can lower their glycemic parameters. Unfortunately, the authors did not identify a specific dosing schedule that can reach a beneficial serum level.
Although Wu et al were careful to streamline the data included in this analysis by having many exclusions, there were some weaknesses in the methods to gather data. First, not all of the study authors reported hypoglycemic pharmacologic use. Authors of seven studies included in this analysis did not report diabetes pharmaceutical use; therefore, lower blood sugars could be attributed to pharmaceuticals rather than vitamin D supplementation. There was not a subgroup analysis conducted to eliminate this variable. Second, the numbers of participants in the included studies were relatively small. On average, the included studies had 30 to 40 participants. Third, most of the authors did not include the effects of sun exposure, dietary intake, or regular exercise, which all contribute to vitamin D synthesis. Despite these limitations, we can conclude that patients with diabetes who have deficient vitamin D levels would benefit from some amount of vitamin D supplementation. The exact amount and for how long has yet to be determined.
COMMENTARY
Previous studies regarding vitamin D and glycemic control have been conflicting and confusing. Some have demonstrated benefit, and others have found no benefit. No trials have shown a worsening of glycemic parameters with vitamin D supplementation. Most studies have confounding variables and interfering factors that weaken their arguments in favor of or against vitamin D. Wu et al tried to resolve this confusion by presenting data from a highly selective group of studies, breaking the collected data into subgroups, and analyzing the data using different statistical methods. They focused specifically on vitamin D supplementation in people with type 2 diabetes and evaluated HbA1c and FBG as their specific parameters.
Most of the body’s vitamin D is synthesized in the skin upon exposure to sunlight. Upon stimulation in the skin, vitamin D3 is produced from pro-hormone 7-dehydrocholesterol. Vitamin D3 (cholecalciferol) is the more bioactive form of vitamin D than vitamin D2 (ergocalciferol).6 Vitamin D2 does not bind as well to receptors in human tissue as vitamin D3 binds. Most experts agree vitamin D3 should be used in practice.7 In this meta-analysis, the authors did not distinguish between the use of vitamins D3 and D2, and this discrepancy may contribute to a decreased metabolic effect overall.
To understand the mechanism of vitamin D, it is best to think of it more as a hormone than a vitamin. Instead of being a cofactor and facilitator for metabolic processes like a vitamin, vitamin D regulates metabolic processes.8 The effect of vitamin D on glucose metabolism is not yet entirely clear. However, it is understood vitamin D deficiency impairs glucose-mediated insulin secretion in pancreatic beta cells,9 and data suggest that normalization of vitamin D stimulates insulin secretion in rats that are deficient in vitamin D.10 It is postulated vitamin D’s glucose regulation occurs in two ways: by regulating plasma calcium levels, which regulate insulin synthesis and secretion, and through a direct action on pancreatic beta-cell function.11
In this meta-analysis, some studies included patients receiving insulin treatments, and serum insulin was not measured as a parameter. The specific effect of vitamin D supplementation on serum insulin is an area of research to be explored. Non-obese patients with diabetes received the most glycemic benefit from vitamin D supplementation in this meta-analysis. Although obesity is a risk factor for vitamin D deficiency,12 these findings suggest improving vitamin D status in obese patients does not significantly improve their glycemic parameters. In one study, Hypponen et al reported that as BMI increased, serum 25(OH)D decreased and HbA1c increased,13 suggesting the association between vitamin D and glucose metabolism might depend on body habitus.
The most clinically relevant information in this analysis is to understand vitamin D as biologically active influence on metabolism. Further research on mechanism and specific clinical protocols has yet to be developed. However, in our non-obese patients with diabetes who are deficient in vitamin D, supplementing with vitamin D3 on a daily basis could yield glycemic benefits.
REFERENCES
- Cigolini M, Iagulli MP, Miconi V, et al. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care 2006;29:722-724.
- Scragg R, Holdaway I, Singh V, et al. Serum 25-hydroxyvitamin D3 levels decreased in impaired glucose tolerance and diabetes mellitus. Diabetes Res Clin Pract 1995;27:181-188.
- International Diabetes Federation. IDF diabetes atlas. Available at: http://www.diabetesatlas.org. Accessed May 31, 2018.
- Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systemic review and meta-analysis. J Clin Endocrinol Metab 2007;92:2017-2029.
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of Vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911-1930.
- Trang HM, Cole DE, Rubin LA, et al. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 1998;68:854-858.
- Wolpowitz D1, Gilchrest BA. The vitamin D questions: How much do you need and how should you get it? J Am Acad Dermatol 2006;54:301-317.
- Reichrath J, Lehmann B, Carlberg C, et al. Vitamins as hormones. Horm Metab Res 2007;39:71-84.
- Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science 1980;209:823-825.
- Cade C, Norman AW. Rapid normalization/stimulation by 1.25-dihydroxyvitamin D3 of insulin recreation and glucose tolerance in the vitamin D-deficient rat. Endocrinology 1987;120:1490-1497.
- Palomer X, Gonzalez-Clemente JM, Blanco-Vaca F, Mauricio D. Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Diabetes Obes Metab 2008;10:185-197.
- Wortsman J, Matsuoka LY, Chen TC, et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000;72:690-693.
- Hypponen E, Power C. Vitamin D status and glucose homeostasis in the 1958 British birth cohort: The role of obesity. Diabetes Care 2006;29:2244-2246.
Findings from a meta-analysis show vitamin D supplementation was associated with improved glycemic control in vitamin D-deficient or non-obese patients with type 2 diabetes.
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