J Clin Endocrinol Metab. 2017 Sep 1;102(9):3097-3110.

The Effect of Improved Serum 25-Hydroxyvitamin D Status on Glycemic Control in Diabetic Patients: A Meta-Analysis.

Mirhosseini N1, Vatanparast H2, Mazidi M3,4, Kimball SM1,5.
1 Pure North S’Energy Foundation, Calgary, Alberta T2R 0C5, Canada.
2 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A2, Canada.
3 Key State Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
4 Institute of Genetics and Developmental Biology, International College, University of Chinese Academy of Sciences, Beijing 100101, China.
5 St. Mary’s University, Calgary, Alberta T2X 1Z4, Canada.

Abstract

Background:

Type 2 diabetes is a global health concern, with an increased prevalence and high cost of treatment.

Objective:

The aim of this systematic review and meta-analysis was to determine the effect of vitamin D supplementation and improved vitamin D status on glycemia and insulin resistance in type 2 diabetic patients.

Data Source:

We searched PUBMED/Medline, Cumulative Index to Nursing and Allied Health, and Cochrane Library (until January 2017).

Study Selection:

Prospective clinical trials were selected evaluating the impact of vitamin D supplementation on glycosylated hemoglobin (HbA1c), serum fasting plasma glucose (FPG), and homeostatic model assessment of insulin resistance (HOMA-IR) in diabetic patients.

Data Extraction and Synthesis:

We used a random-effects model to synthesize quantitative data, followed by a leave-one-out method for sensitivity analysis. The systematic review registration was CRD42017059555. From a total of 844 entries identified via literature search, 24 controlled trials (1528 individuals diagnosed with type 2 diabetes) were included. The meta-analysis indicated a significant reduction in HbA1c [mean difference: -0.30%; 95% confidence interval (CI): -0.45 to -0.15, P < 0.001], FPG [mean difference: -4.9 mg/dL (-0.27 mmol/L); 95% CI: -8.1 to -1.6 (-0.45 to -0.09 mmol/L), P = 0.003], and HOMA-IR (mean difference: -0.66; 95% CI: -1.06 to -0.26, P = 0.001) following vitamin D supplementation and significant increase in serum 25-hydroxyvitamin D levels [overall increase of 17 ± 2.4 ng/mL (42 ± 6 nmol/L)].

Conclusions:

Vitamin D supplementation, a minimum dose of 100 µg/d (4000 IU/d), may significantly reduce serum FPG, HbA1c, and HOMA-IR index, and helps to control glycemic response and improve insulin sensitivity in type 2 diabetic patients.

PMID: 28957454

 

Summary:

Type 2 diabetes is a grave, chronic disease that develops when the body cannot produce enough insulin or cannot properly use the insulin it produces. Without insulin, glucose builds up in the bloodstream and leads to a variety of complications, particularly for the kidneys (leading to kidney failure), nerves (leading to peripheral neuropathy), heart (contributing to atherosclerosis), and eyes (leading to diabetic retinopathy and blindness).

The disease represents an enormous and growing public health problem. It is estimated that between 2010 and 2030 the worldwide number of adults with diabetes will increase by 54%, from 285 million to 439 million [1]. The epidemic of type 2 diabetes has major implications for healthcare spending. In Canada, for instance, where approximately 3.5 million individuals have diabetes and another 5.7 million are at risk of developing the disease, the cost of treatment was estimated to be $3.4 billion in 2016 with steady increases each year [2].

Type 2 diabetes can be prevented with the adoption of a healthy diet and lifestyle. In addition, nutrient supplementation may provide benefit through support of biochemical pathways. Vitamin D has been the focus of much interest in this regard.

Epidemiological studies consistently show that low blood concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with an increased risk of type 2 diabetes. In fact, vitamin D supplementation and even slight increases in 25(OH)D concentrations lead to significant risk reductions for developing type 2 diabetes [3].

There are several lines of evidence that support a role for vitamin D in pancreatic β-cell function, regulation of insulin secretion, and reduction in systemic inflammation. Vitamin D deficiency impairs insulin secretion, whereas vitamin D supplementation restores insulin secretion in pancreatic β-cells [4]. Vitamin D also regulates the calcium-binding protein calbindin in β-cells which controls the rate of insulin secretion via regulation of intracellular calcium [5]. Vitamin D may also enhance insulin sensitivity by stimulating the expression of insulin receptors by binding to elements in the human insulin receptor gene promoter [6]. The active form of vitamin D may also augment insulin sensitivity by activating receptors that help regulate fatty acid metabolism in insulin-responsive tissues [7]. Vitamin D has anti-inflammatory effects and appears to decrease the effects of systemic inflammation and protect against β-cell cytokine-induced apoptosis by directly modulating the expression and activity of cytokines [8].

Numerous randomized control trials have reported on the effect of vitamin D supplementation (with or without calcium) on glycemic control and insulin sensitivity in people with type 2 diabetes, but the outcomes of these trials have been somewhat inconclusive. Our objective was to investigate the overall effect of vitamin D supplementation on glycemic outcomes in a systematic review and meta-analysis. Outcomes included fasting plasma glucose (FPG), homeostatic model assessment of insulin resistance (HOMA-IR), and glycosylated hemoglobin (HbA1c) [9].

Twenty-four randomized controlled trials published between 2009 and 2016 and centered on vitamin D and glycemic measures in people with type 2 diabetes met our strict inclusion criteria. All of the included studies had a low risk of bias. Over 1,500 individuals diagnosed with type 2 diabetes were included in these trials. With the exception of two studies that included only women participants, all studies included both men and women. Mean age varied from 40 to 67 years. At the beginning of the trial, mean 25(OH)D concentrations varied from 17 nmol/L to 84 nmol/L in the intervention group. The average follow-up after baseline was seven months, and mean 25(OH)D concentrations varied from 19 nmol/L to 164 nmol/L in the intervention group.

Based on our random-effect meta-analysis, comparing the mean change in HbA1c from baseline between vitamin D supplemented groups and placebo groups, the overall effect was a significant reduction in HbA1c after vitamin D supplementation. There was also a significantly greater reduction in the mean change of HbA1c in the vitamin D with calcium group compared with vitamin D group. Detailed subgroup analyses revealed that a significantly greater mean reduction in HbA1c was observed in non-obese participants (˂25 kg/m2) compared with obese group (>25 kg/m2).

Vitamin D supplementation further resulted in a significant reduction of FPG with a standardized mean difference of -0.27 mmol/L. Co-administration of calcium significantly promoted the effect of vitamin D supplementation on FPG. Non-obese patients showed a greater reduction in FPG compared with obese group.

We found a significant lowering effect of vitamin D supplementation on HOMA-IR compared with controls. Co-administration of calcium with vitamin D had no significant effect on HOMA-IR changes. Obesity inversely influenced insulin resistance and the reduction in HOMA-IR was significant in non-obese but not in obese participants.

Serum 25(OH)D level at baseline (˂ 50 nmol/L vs >50 nmol/L) did not affect the changes in HbA1c and HOMA-IR after vitamin D supplementation, but did affect changes in FPG.

Overall, vitamin D supplementation appears to be efficacious as an adjuvant treatment of diabetes-related glucose metabolism disorders. The results of the meta-analysis suggest that a minimum dose of 4,000 international units each day, which is equivalent to the tolerable upper intake level of vitamin D for adults, to achieve a serum 25(OH)D concentration of 100 nmol/L is required to have a protective effect on glucose homeostasis in type 2 diabetic patients.

The strengths of our study are many and we carefully utilized data from good quality randomized clinical trials to perform a nuanced meta-analysis, determining the association between vitamin D supplementation and serum 25(OH)D concentrations with glycemic measures in type 2 diabetics. The large numbers of studies included in this analysis, high-dose supplementation in more than half of the included studies, and longer duration of trials added to the value of this meta-analysis.

 

 

Figure 1. Mean difference in the change of HbA1c (%) for vitamin D-supplemented and control groups. (Figure adapted from Mirhosseini et al. [9]). (Copyright © 2017 Endocrine Society).

 

 

Table 1. Meta-analysis and subgroup analysis of primary and secondary outcomes. (Table adapted from Mirhosseini et al. [9]). (Copyright © 2017 Endocrine Society).

 

References:

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[2] Canadian Diabetes Association. The Burden of Out-of-Pocket Costs for Canadians with Diabetes. Toronto, ON, Canada: Canadian Diabetes Association; 2016.

[3] Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr. 2011;65(9):1005–1015.

[4] Norman AW, Frankel JB, Heldt AM, et al. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science. 1980; 209:823–825.

[5] Johnson JA, Grande JP, Roche PC, et al. Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28k in human and rat pancreas. Am J Physiol. 1994; 267:E356–360

[6] Maestro B, Molero S, Bajo S, et al. Transcriptional activation of the human insulin receptor gene by 1,25-dihydroxyvitamin D(3). Cell Biochem Funct. 2002; 20:227–232.

[7] Dunlop TW, Vaisanen S, Frank C, et al. The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol. 2005; 349:248–260.

[8] Gysemans CA, Cardozo AK, Callewaert H, et al. 1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology. 2005; 146:1956–1964.

[9] Mirhosseini N, Vatanparast H, Mazidi M, Kimball SM. The effect of improved serum 25-hydroxyvitamin D on glycemic control in diabetic patients: a meta-analysis. J Clin Endocrinol Metab. 2017:102(9):3097-3110.