Vitamin D Supplementation, Glycemic Control, and Insulin Resistance in Prediabetics

A Meta-Analysis

Naghmeh Mirhosseini; Hassanali Vatanparast; Mohsen Mazidi; Samantha M. Kimball


J Endo Soc. 2018;2(7):687-709. 

In This Article

Abstract and Introduction


Diabetes prevention is a public health priority. Vitamin D supplementation may help prevent the development of diabetes in persons at increased risk. We performed a meta-analysis of controlled clinical trials that assessed glycemic outcome measures among adults at risk for type 2 diabetes, including prediabetes, overweight, or obesity. We searched PUBMED/MEDLINE, CINAHL, and Google Scholar databases for trials published prior to April 2017. Placebo-controlled clinical trials with random allocation to vitamin D with or without calcium supplementation were selected. Data collection included country, study design, inclusion criteria, sample size, form, and dose of vitamin D, supplementation interval, control group, duration, participant characteristics, comorbidities, baseline and follow-up serum 25-hydroxyvitamin D [25(OH)D] concentration, and available outcome measures [glycosylated hemoglobin (HbA1c), fasting plasma glucose, plasma glucose after 2-hour oral glucose tolerance test, and homeostatic model assessment of insulin resistance (HOMA-IR)]. Data synthesis was conducted using random-effect models (PROSPERO registration no. CRD42017055326). Twenty-eight trials, representing 3848 participants, met the eligibility criteria. Compared with the control group, vitamin D supplementation significantly reduced HbA1c level by –0.48% (95% CI, −0.79 to –0.18), fasting plasma glucose level by –0.46 mmol/L (95% CI, −0.74 to –0.19), and HOMA-IR level by –0.39 (95% CI, −0.68 to –0.11). Subgroup analysis revealed that the effects of vitamin D supplementation on different glycemic measures were influenced by age, calcium coadministration, vitamin D deficiency, serum 25(OH)D level after supplementation, and duration of supplementation. Vitamin D supplementation and improved vitamin D status improved glycemic measures and insulin sensitivity and may be useful as part of a preventive strategy for type 2 diabetes.


Every 3 minutes, a Canadian is diagnosed with type 2 diabetes or prediabetes.[1] Currently, more than 5.7 million Canadians have prediabetes.[1] Prediabetes refers to impaired fasting glucose or impaired glucose tolerance, with fasting blood glucose levels above normal but not elevated enough to be diagnosed as type 2 diabetes mellitus.[2] People with prediabetes are at a 50% higher risk of developing type 2 diabetes.[3,4] Yet, even if these people at high risk do not progress to type 2 diabetes, prediabetics are still prone to some of the long-term complications associated with diabetes, such as heart disease, stroke, and nerve damage.[5] The pathogenesis of prediabetes involves the development of insulin resistance and later impaired insulin secretion,[6] often associated with chronic inflammation, an indicator in the development of type 2 diabetes.[7,8]

In parallel with the increased prevalence of prediabetes, there has been an increasing trend in the prevalence of vitamin D deficiency.[9,10] Individuals with prediabetes commonly have lower serum 25-hydroxyvitamin D [25(OH)D] concentrations than those with normal glucose control.[11–14] Further, the risk of developing diabetes is much greater for prediabetics who are vitamin D deficient.[15,16] Low vitamin D status in patients with prediabetes can predict future macrovascular complications by contributing to blood pressure dysregulation, renin-angiotensin activity impairments, endothelial dysfunction, and chronic inflammation.[17–19] Calcium might be beneficial for decreasing the risk of diabetes through its effect on insulin release and its indirect effect on weight loss.[20–24] Given this background, as well as its safety, reasonable price, and accessibility,[25] vitamin D supplementation during the prediabetic stage, either taken alone or in combination with calcium, has the potential to halt the progression to diabetes has been investigated.[21,26,27]

Several probable mechanisms of action may explain a possible role for vitamin D to help improve glucose metabolism, including its anti-inflammatory and immunomodulatory effects,[28] the induction of insulin secretion by pancreatic β-cells,[29] its indirect effect on regulating calcium concentration in pancreatic β-cells, and subsequent insulin secretion.[30] Further, vitamin D receptors are expressed on various insulin-dependent tissues (including the liver, skeletal muscle, and adipose tissue), suggesting a role for vitamin D in glucose utilization and insulin sensitivity.[31] The influence of vitamin D on genes regulating cellular proliferation, differentiation, and apoptosis in metabolic pathways may also play a role.[32,33] Moreover, in vitamin D–deficient individuals, moderate elevation of parathyroid hormone (PTH) may impair insulin release from pancreatic β-cells.[34,35]

Observational studies, several randomized controlled trials (RCTs), and meta-analyses[36,37] have been conducted to investigate the effect of vitamin D supplementation on glycemic measures and insulin sensitivity in prediabetes populations. However, no decisive conclusions can yet be drawn from these existing reports.[38,39] Some of the conflicting results from these studies are due to limitations, including studies not primarily designed for glycemic outcomes, relatively small sample sizes, limited reports on serum 25(OH)D concentrations, inappropriate or infrequent doses of vitamin D (monthly or large bolus doses), and relatively short duration of supplementation that does not account for physiology (i.e., shorter than the turnover of HbA1c).[40–43] To address these issues, we undertook a systematic review and meta-analysis of RCTs to delineate the impact of vitamin D supplementation on glycemic control and insulin resistance in prediabetic or overweight/obese adult populations. We restricted our analysis to clinical trials with daily or weekly supplementation, which provides a sustained serum 25(OH)D concentration over time, intervention periods of greater than 2 months or long enough for HbA1c turnover, a measurable impact of vitamin D supplementation on 25(OH)D concentrations, meaning the dose was high enough to impact vitamin D status, and the measurement of different parameters associated with prediabetes [HbA1c, FPG, HOMA-IR, and plasma glucose after 2-hour oral glucose tolerance test (2HPG)].