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


Interest in the protective effects of vitamin D supplementation against the progression of diabetes has heightened in recent years, and the current analysis underscores some of these benefits. We evaluated 28 studies combined, including 11 centered on prediabetics and 16 on populations at high risk, and found significant effects of vitamin D supplementation on insulin resistance and hyperglycemia. Vitamin D supplementation and increased serum 25(OH)D concentrations improved insulin sensitivity (decreased HOMA-IR), glucose metabolism, and glycemic control (reduced HbA1c and FPG). Our findings suggest that a serum 25(OH)D concentration above 86 nmol/L can improve measures of glucose metabolism and response to insulin in prediabetics. Serum 25(OH)D concentrations above 86 nmol/L were achieved with an average vitamin D supplementation of 88 μg/d (3500 IU/d) or more, taking body weight into account; Ekwaru et al.[84] previously showed that obese individuals often require two to three times the dose of vitamin D that an individual with a normal BMI requires to achieve the same 25(OH)D response. The greatest benefits were found in populations most at risk for early disease. We also found improvements in those considered vitamin D sufficient when they started vitamin D supplementation.

Subgroup analyses further demonstrated that both FPG and 2-hour postprandial plasma glucose reductions were enhanced with vitamin D taken in combination with calcium supplements, as were insulin resistance and fasting HOMA-IR. Longer duration of supplementation seemed to be more effective at reducing HOMA-IR than those shorter than 6 months. We used fasting HOMA-IR, which detects liver insulin resistance and shows inability of insulin in liver to lower glucose concentration. This is different from the fed-state HOMA-IR representing peripheral insulin resistance or failure of glucose uptake in muscle tissues.[85] Other studies have similarly shown that the combination of vitamin D with calcium may help improve glucose metabolism and significantly lower the risk of diabetes[21,24,73] by facilitating glucose transportation into different organs and regulating insulin receptor genes and insulin secretion.[86,87] Subgroup analyses additionally found that individuals who are obese but not prediabetic and younger than 45 years and/or those considered to be vitamin D sufficient at baseline had the largest improvements. The duration of treatment did not influence the short-term measures of response.

These results are consistent with previous reports that have demonstrated that vitamin D supplementation and the highest quartile of serum 25(OH)D concentration, compared with the lowest quartile, reduced the risk of cardiometabolic disorders, including diabetes, metabolic syndrome, and cardiovascular diseases.[21,82,88] Moreover, our results support the findings that individuals whose 25(OH)D concentrations increased by at least 50 nmol/L had a 26% reduction in the risk of HbA1c elevation (≥5.8%).[89] The findings of the current study are not in agreement with all previous reviews;[36–38,90,91] however, it should be noted that our methodology properly accounted for the biology of vitamin D and glucose metabolism. For instance, only studies that were sufficiently long enough to detect changes in HbA1c, a 2- to 3-month measure of glucose control, and long enough for 25(OH)D concentrations to reach a plateau, for individuals across the range of BMIs, were included. We also included various blood measurements used in the diagnosis of diabetes.

There is growing biological and mechanistic evidence that support a role for low vitamin D status as a contributing factor in the development of type 2 diabetes. Reduction in insulin secretion, for instance, has been linked to vitamin D deficiency, and optimization of serum 25(OH)D concentrations following vitamin D supplementation has been shown to restore insulin secretion and improve glucose metabolism, glucose tolerance, and insulin sensitivity.[30,92,93] Also, vitamin D indirectly stimulates insulin secretion by altering calcium flux through cell membranes to normalize extracellular calcium.[21] Evidence suggests that elevated PTH may be associated with an increased risk of glucose intolerance and diabetes,[94,95] and the concomitant use of calcium with vitamin D decreases PTH levels significantly.[96] Other potential mechanisms demonstrated in vitro and in animal models include improving insulin action through stimulating the expression of the insulin receptor, enhancing insulin responsiveness for glucose transport, gene polymorphism, and the influence of vitamin D on gene expression of metabolic pathways,[31,33] and improving systemic inflammation by a direct effect on cytokines.[21]

The current study has several limitations. The trials included in this systematic review were heterogeneous with respect to the outcomes measured, supplemental vitamin D dose and whether it was given in combination with calcium, the length of the intervention, and the definition of a high-risk population. We used a random-effects model in a meta-analysis to overcome these limitations, but this model can have poor error estimations and, with heterogeneous data such as in the current meta-analysis, might default to an arithmetic mean (equal weights). Some of the studies had comparatively small populations (10 to 30 participants per intervention group) that in isolation are hard to extrapolate, but taken together lend support to the larger trials. Most studies did not describe dietary intake, latitude, season, or sun exposure contributing to vitamin D synthesis. Also, although it is difficult to interpret results based solely on vitamin D supplementation, we included only studies that measured serum 25(OH)D to account for outside factors as well as different doses provided and different responses to supplementation based on BMI. We examined the effect of serum 25(OH)D concentration in addition to vitamin D dose to overcome some of these limitations.

This review is based on a recent and up-to-date literature search representing the available data on the effect of vitamin D supplementation on glycemic control in prediabetics and a high-risk population. We included only placebo-controlled RCTs with appropriate methodological qualities and the least probable chance of bias or dropout and studies that measured several outcome measures of glucose control and insulin response: HbA1c, FPG, HOMA-IR, and 2HPG. We ensured that the studies included provided vitamin D supplements as daily or weekly doses to reduce variation introduced by the differences in response in vitamin D metabolism and only those that measured 25(OH)D concentrations. Most of the included studies had been designed for glycemic outcomes and covered a diverse population that supports the generalizability of the results.