Meta-analyses

The Effect of Vitamin D Supplementation on Insulin Sensitivity: A Systematic Review and Meta-analysis

  1. Adriyan Pramono1,2,
  2. Johan W.E. Jocken1,
  3. Ellen E. Blaak1⇑ and
  4. Marleen A. van Baak1
  1. 1Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
  2. 2Department of Nutrition, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
  1. Corresponding author: Ellen E. Blaak, e.blaak{at}maastrichtuniversity.nl
Diabetes Care 2020 Jul; 43(7): 1659-1669. https://doi.org/10.2337/dc19-2265

Abstract

BACKGROUND Vitamin D has been suggested to affect peripheral insulin sensitivity. Evidence regarding the effect of vitamin D supplementation on insulin sensitivity is still conflicting.

PURPOSE This meta-analysis aimed to assess the effect of vitamin D supplementation on insulin sensitivity in humans with or at risk for insulin resistance.

DATA SOURCES AND STUDY SELECTION PubMed, Web of Science, Embase, CINAHL, and Cochrane Library were systematically searched for randomized controlled trials (RCTs) from 1980 until 31 December 2018 reporting treatment effects of vitamin D supplementation on insulin sensitivity.

DATA EXTRACTION The main outcome of interest was the change in insulin sensitivity, derived from the gold standard hyperinsulinemic-euglycemic clamp or the Matsuda index derived from the oral glucose tolerance test and insulin sensitivity index from intravenous glucose tolerance test. We extracted data on the standardized mean difference between the vitamin D treatment and placebo groups in change from baseline insulin sensitivity.

DATA SYNTHESIS Eighteen RCTs were included in this meta-analysis comparing vitamin D supplementation (n = 612) with placebo (n = 608). Vitamin D supplementation had no effect on insulin sensitivity (standardized mean difference −0.01, 95% CI −0.12, 0.10; P = 0.87, I2 = 0%). Visual inspection of funnel plot symmetry did not suggest potential publication bias.

LIMITATIONS The number of individuals who participated in the included studies was relatively small, possibly due to the invasive character of the measurement (e.g., clamp).

CONCLUSIONS This meta-analysis provides no evidence that vitamin D supplementation has a beneficial effect on peripheral insulin sensitivity in people with or at risk for insulin resistance.

Introduction

The International Diabetes Federation (1) has reported that the worldwide diabetes prevalence in the adult population reached 8.8% (424.9 million people) in 2017. The majority (87%–91%) of these diabetes cases concerns type 2 diabetes. Type 2 diabetes has become a major public health concern due to its complications. It decreases quality of life and increases mortality risk (2). Additionally, ∼7.3% of the adult population (352.1 million people) suffers from prediabetes (1). Prediabetes is defined by increased fasting glucose or impaired glucose tolerance (postprandial hyperglycemia), which are both strongly associated with obesity (3). Moreover, postprandial hyperglycemia is a major risk factor for developing type 2 diabetes (4).

Obesity, prediabetes, and type 2 diabetes are often characterized by low circulating levels of vitamin D (vitamin D deficiency) (5). Indeed, based on cross sectional studies, vitamin D deficiency has been linked with impaired insulin sensitivity in humans (6). Furthermore, people with low vitamin D levels (7) may be at greater risk to develop type 2 diabetes. Of interest, the vitamin D receptor, which mediates the function of vitamin D, is also expressed in insulin-sensitive tissues (including adipose tissue, muscle, and pancreas) (8–10). Therefore, currently nonskeletal functions of vitamin D in insulin-sensitive organs are being investigated.

Several plausible mechanisms have been proposed to explain a potential role of vitamin D in improving insulin sensitivity (6,11). In adipose tissue, vitamin D may affect lipid metabolism (12) and may reduce inflammation (13). Vitamin D may affect pancreatic insulin secretion via protection of β-cells from local inflammation (14). Vitamin D may also affect insulin secretion, which is mediated by a calcium-dependent mechanism (15). In addition, it has been demonstrated that vitamin D affects skeletal muscle metabolism, insulin sensitivity, and lipid composition (16,17). Thus, increasing circulating vitamin D concentration might be expected to have beneficial effects on tissue energy and substrate metabolism, thereby contributing to an improvement of whole-body insulin sensitivity.

In recent years, several meta-analyses (18–23) have been conducted to investigate the effect of vitamin D supplementation on whole-body insulin sensitivity. However, the findings from these reports are inconsistent. From the six meta-analyses published between 2015 and 2018, four studies (18–21) indicated insufficient evidence/no effect on glycemic control and insulin resistance, whereas two studies (22,23) indicated sufficient evidence for an improvement of glycemic control and insulin sensitivity. Moreover, these meta-analyses have been focusing only on glucose homeostasis under fasting conditions by studying parameters such as HOMA of insulin resistance (HOMA-IR), fasting glucose, fasting insulin, and HbA1c as main outcome measures.

Of importance, the skeletal muscle is considered an important organ in peripheral insulin sensitivity, as it affects 70%–90% of total glucose disposal under postprandial conditions (nonfasting conditions) (24,25). Studies have shown that vitamin D may affect skeletal muscle substrate metabolism and insulin sensitivity (16,17). Thus, increasing circulating vitamin D concentration by means of supplementation might be expected to have beneficial effects during postprandial conditions by improving skeletal muscle glucose handling/insulin sensitivity. Therefore, we undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to delineate the impact of vitamin D supplementation on insulin sensitivity derived from the gold standard hyperinsulinemic-euglycemic clamp or from multisampled oral (OGTT) or intravenous (IVGTT) glucose tolerance tests as well as the postprandial glucose concentrations (OGTT) in humans with or at risk for insulin resistance.

Methods

Data Sources and Searches

We conducted our systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (26). The protocol for our systematic review was registered at the International Prospective Register of Systematic Reviews, PROSPERO (reg. no. CRD42018092961). The main outcome of interest was the change in insulin sensitivity, derived from a gold standard hyperinsulinemic-euglycemic clamp or in the form of the Matsuda index derived from OGTT and/or insulin sensitivity index derived from IVGTT, subsequent to vitamin D administration in individuals with or at risk for insulin resistance. The secondary outcome was the change in 2-h postprandial glucose concentration and/or area under the curve (AUC) for glucose during an OGTT.

A comprehensive literature search (PubMed/MEDLINE [Medical Literature Analyses and Retrieval System Online], Cochrane Library, Web of Science, Embase database [Ovid], and CINAHL [Cumulative Index to Nursing and Allied Health Literature]) was performed to identify articles from 1980 until 31 December 2018. The main keywords used were as follows: overweight, obesity, prediabetes, type 2 diabetes mellitus, vitamin D, insulin sensitivity, insulin resistance, blood glucose. These keywords were combined with Boolean operators (e.g., OR, AND, NOT), and all fields or MeSH (Medical Subject Heading) terms. This set of search terms was slightly modified when we searched in every database due to a different system and technical limitations (Supplementary Table 1).

Study Selection

Eligible studies met the PICOS (Patients/participants, Intervention, Comparison/control group, Outcome, and Study design) criteria: 1) study was an RCT; 2) study population consisted of individuals with elevated (risk for) insulin resistance (overweight, obesity, prediabetes, polycystic ovary syndrome [PCOS], and type 2 diabetes without complications); 3) interventions were vitamin D supplementation versus the appropriate placebo; 5) vitamin D supplementation dose was daily, weekly, or monthly; 6) trial length was ≥2 months; 7) serum 25-hydroxyvitamin D [25(OH)D] level was measured; 8) insulin sensitivity was measured by Matsuda index derived from an OGTT and/or insulin sensitivity index derived from IVGTT or by a hyperinsulinemic-euglycemic clamp at the beginning and at the end of the trial; and 9) study was published in English.

Exclusion criteria were as follows: 1) non–clinical trial studies; 2) studies without outcome of insulin sensitivity derived from multisampled OGTT or hyperinsulinemic-euglycemic clamp; 3) study populations with end-stage renal disease (kidney disease), cancers, gestational diabetes mellitus (GDM), nonalcoholic steatohepatitis, cardiovascular diseases complications, and infectious diseases; 4) intervention periods of <2 months; 5) vitamin D supplementation provided as a single dose; and 6) study performed in children or adolescents (<18 years old).

Following the search, duplicates were removed. Titles and abstracts were screened by two authors (A.P. and M.A.v.B.). Final study selection, based on the inclusion criteria, was done by two authors (A.P. and M.A.v.B.) and approved by another author (E.E.B.). Any disagreements between the authors were resolved through discussion with the fourth author (J.W.E.J.).

Data Extraction and Quality Assessment

Data were extracted by two authors (A.P. and M.A.v.B.). Data extracted from each study included the following items: first author, reference, year of publication, country of study, study design, inclusion criteria, sample size, form of vitamin D, dose and frequency of vitamin D supplementation, any cosupplementation (e.g., diet or calcium), treatment control group, duration of supplementation, participants’ characteristics (n, sex [% male], age, BMI, ethnicities), comorbidities, baseline and follow-up serum 25(OH)D levels, and outcome measures (e.g., M value or glucose infusion rate [GIR] or insulin-mediated glucose uptake derived from clamp, Matsuda index, insulin sensitivity index, 2-h glucose, or AUCglucose from an OGTT) (Table 1). The corresponding author of an eligible publication was contacted by e-mail for additional data when relevant.

View this table:
Table 1

Characteristics of randomized controlled trial studies included in the meta-analysis

Any further necessary calculations on study data, such as converting measurement units or calculating SD, were conducted by the first author (A.P.) and checked by another author (M.A.v.B.). Serum 25(OH)D levels were collated in nanomoles per liter; a multiplication factor of 2.456 was used to convert 25(OH)D levels from nanograms per milliliter to nanomoles per liter. Two-h glucose tolerance test glucose concentrations (2-h glucose) were collated in millimoles per liter; we used a multiplication factor of 0.0555 to convert glucose levels from milligrams per deciliter millimoles per liter as appropriate (27).

The quality of selected RCTs was assessed independently by two authors (A.P. and M.A.v.B.) using the risk-of-bias (RoB) checklist from the Cochrane Collaboration (28). The quality assessments of the checklist included 1) bias from randomization process (random sequence generation and allocation concealment), 2) bias due to deviations from intended interventions (blinding of participants and personnel), 3) bias due to missing outcome data, 4) bias from measurements of the outcome, 5) bias from selection of reported result, and other sources of bias. Each criterion could be answered in three ways: “low risk” (adequate information), “unclear risk” (if there was unclear information), and “high risk” (if there was high concern). Study quality and the risk of bias in the eligible RCTs were systematically assessed using software Review Manager 5.3 (the Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark, 2014).

Data Synthesis and Analysis

To calculate the effect size of each study, we used the mean change and SD of the outcome measures from baseline to the end of the intervention in the control and intervention groups (29). When the outcome measure was reported as mean and 95% CI or mean and SEM, values were estimated using Review Manager 5.3 software (30). If the outcome measures were reported in median, range, or 25th–75th percentiles, mean and SD values were estimated using formulas published by Wan et al. (31). If the outcome measures were only reported in figures, we used software to estimate the value. SDs of the mean difference were estimated using the following formula:Embedded ImageBecause the pretest-posttest correlation coefficients (r) were not reported in studies, an r value of 0.5 was assumed throughout this meta-analysis (30).

If a study included more than two intervention groups (e.g., two different doses of vitamin D), which were compared with one placebo (control) group, the number of subjects of the control group was divided by the number of comparisons. If the outcome measurement was performed at multiple time points after the intervention period, we only used first time point after the intervention (29).

The effect size is reported as standardized mean difference with its 95% CI (26,32). Standardized mean difference is used as a summary statistic in meta-analysis when the studies all assess the same outcome but measure it in a variety of ways (in this study, for example, all studies measured insulin sensitivity but use different methodology, i.e., clamp or Matsuda index or insulin sensitivity index). A random-effects model was used to estimate outcomes. Heterogeneity was assessed using the I2 statistic, indicating what proportion of the variation in observed effects across studies is due to the variation in true effects, with values >60% indicating substantial heterogeneity. A P value < 0.05 is considered statistically significant (29). The analysis was performed and generated using Review Manager 5.3 software. The PRISMA checklist was used as a guide for checking the quality of our systematic review (Supplementary Table 2).

Publication Bias

Publication bias was analyzed by visual inspection of the funnel plots.

Meta-Regression and Sensitivity Analysis

If the heterogeneity was >60%, additional analyses were conducted. Meta-regression analysis and sensitivity analysis using the leave-one-out method (removing one study each time and repeating the analysis) were applied to gain insight into the source of the heterogeneity (29).

Results

Study Characteristics

In total, 18 RCTs (33–50) published between 2011 and 2018 with 1,220 participants were included in the current meta-analysis (Fig. 1). Characteristics of the studies are summarized in Table 1. The studies were conducted in the U.S. (n = 5), Canada (n = 1), Iran (n = 1), India (n = 1), Malaysia (n = 1), Australia (n = 2), the Netherlands (n = 1), Denmark (n = 1), Norway (n = 1), Finland (n = 1), Sweden (n = 1), Austria (n = 1), and Italy (n = 1). Most studies included both men and women, except two studies that included only women (43,45) and two other studies that included only men (44,50). Among the 18 studies, 8 enrolled several ethnic populations (multiethnicity) (33,36–38,40,46–48), 2 enrolled individuals with African American ethnicity (34,44), 2 enrolled Asians (43,45), 1 enrolled participants from Middle Eastern countries (35), and 5 did not provide information about ethnicity (39,41,42,49,50). Sixteen trials were in participants with overweight, obesity, prediabetes, type 2 diabetes, or metabolic syndrome, and two of these trials also included apparently healthy participants (40,50), while participants in the two other trials had PCOS (45) or a history of GDM (43). Studies used different cutoffs for baseline vitamin D levels: nine studies (34,37–40,45–47) recruited individuals with vitamin D levels <50 nmol/L, and the others (33,35,36,41,42,44,48–50) included individuals with vitamin D levels <75 nmol/L at the beginning of trial (Table 1). Mean serum 25(OH)D concentrations at baseline varied from 19.2 nmol/L (45) to 59.9 nmol/L (33) in vitamin D–supplemented groups and 16.9 nmol/L (45) to 61.4 (33) in placebo groups. The mean oral dose of vitamin D was 4,608 IU per day (range 1,200 [37] to 12,695 [36] per day), with the majority of studies providing daily doses ≤4,000 IU (33,34,37–39,41,43,45,46,48–50). The duration of vitamin D supplementation ranged from 2 (42) to 12 (44) months.

Figure 1
Figure 1

Flowchart diagram for study selection of systematic review (based on PRISMA guideline). FPG, fasting plasma glucose.

The Effect of Vitamin D Supplementation on Insulin Sensitivity

There were 18 studies with sufficient data to be included in the meta-analysis to estimate the overall effect of vitamin D supplementation on insulin sensitivity derived from a clamp (39,42,46,47,49) or indices of insulin sensitivity derived from an OGTT or IVGTT (33–38,40,41,43–45,48,50). The total number of included individuals was 1,220; of these, 612 received vitamin D supplementation and 608 received placebo. From the 13 studies that used the Matsuda index derived from OGTT and/or insulin sensitivity index from IVGTT (33–38,40,41,43–45,48,50), none reported a significant change (increase or decrease) in insulin sensitivity after vitamin D supplementation compared with placebo. Furthermore, among those five studies in which the outcome of insulin sensitivity was derived from a clamp (39,42,46,47,49), only one study (Cefalo et al. [49]) reported a statistically significant improvement of insulin sensitivity.

Based on a random-effects meta-analysis, comparing the standardized mean difference of the change in insulin sensitivity from baseline between the vitamin D–supplemented and placebo groups, the overall effect on insulin sensitivity was not significant after vitamin D supplementation (standardized mean difference −0.01, 95% CI −0.12 to 0.10, P = 0.87; I2= 0%, P = 0.60) (Fig. 2).

Figure 2
Figure 2

Forest plot of the effect of vitamin D supplementation on insulin sensitivity. Horizontal lines span individual study 95% CIs. Diamonds represent the combined study standardized (Std.) mean value and the corresponding 95% CI values. df, degrees of freedom; ISI, insulin sensitivity index; IV, inverse variance. ‡Vitamin D3 1,600 IU/day (41). ¶Vitamin D3 3,200 IU/day (41).

The Effect of Vitamin D Supplementation on Postprandial Glucose Concentrations

There were 12 studies that reported 2-h glucose concentrations (6 studies) (33,34,36,41–43) or AUCglucose (6 studies) (35,37,45,48–50) as an outcome measure. A meta-analysis of these data including 745 individuals (n = 379 treated with vitamin D and n = 366 with placebo) was performed to compare the mean change in 2-h glucose and/or AUCglucose between the beginning and the end of study. Vitamin D supplementation had no effect on postprandial glucose, with a standardized mean difference of 0.09 (95% CI −0.08 to 0.25, P = 0.29; I2 = 18%, P = 0.26) (Fig. 3A).

Figure 3
Figure 3

Forest plots of the effect of vitamin D supplementation on postprandial glucose (A) and serum vitamin D level (B). Horizontal lines span individual study 95% CIs. Diamonds represent the combined study standardized mean value and the corresponding 95% CIs. 2OGTT, 2-h oral glucose tolerance test; df, degrees of freedom; IV, inverse variance. ‡Vitamin D3 1,600 IU/day (41). ¶Vitamin D3 3,200 IU/day (41).

The Effect of Vitamin D Supplementation on Serum Vitamin D Levels

All 18 trials (n = 1,223; 613 individuals treated with vitamin D and 610 individuals with placebo) reported the change in serum vitamin D level after the intervention. There was a significant increase in the serum vitamin D level in the vitamin D supplementation groups compared with the control groups (standardized mean difference 2.25, 95% CI 1.90–2.60, P < 0.001) (Fig. 3B) with considerable heterogeneity (I2 = 81%, P < 0.001).

Risk of Bias

Most included studies had a low risk of bias according to randomization process (random sequence generation and allocation concealment), blinding participants (comparability of intervention groups and placebo [control] groups), and incomplete outcome data (clear description of dropout/withdrawal/attrition rate). The blinding of outcome assessment was not clearly mentioned in some of the studies (34–36,41,44,45,48,49), which resulted in unclear risk of detection bias. The overall quality assessment of the included trials in this meta-analysis is shown in Supplementary Fig. 1.

Publication Bias

The visual inspection of funnel plots of changes in insulin sensitivity and postprandial glucose did not suggest potential publication bias. In addition, the funnel plot of serum vitamin D changes in this meta-analysis following vitamin D supplementation also did not indicate publication bias (Supplementary Fig. 2).

Meta-Regression and Sensitivity Analysis

Regarding the change in serum vitamin D levels following supplementation, there was a considerable heterogeneity (I2 = 81%). A meta-regression analysis of dose or duration with standardized mean difference of serum vitamin D levels showed that the dose of vitamin D supplementation may partly explain the heterogeneity (Supplementary Table 3). Further sensitivity analysis by leave-one-out analysis shows that no single study is responsible for the heterogeneity of changes in serum vitamin D levels.

Discussion

We conducted a systematic review and meta-analysis of 18 RCTs to determine the effect of vitamin D supplementation on insulin sensitivity in individuals with or at risk for insulin resistance. In this meta-analysis, vitamin D supplementation had no significant effect on insulin sensitivity derived from a hyperinsulinemic-euglycemic clamp or the Matsuda index derived from an OGTT and/or insulin sensitivity index from IVGTT. Additionally, no significant changes in 2-h glucose or AUCglucose during an OGTT were observed following vitamin D supplementation.

In our analysis, study populations were often characterized by the presence of overweight or obesity (33–39,41–44,46–49), accompanied by baseline serum concentrations of 25(OH)D <50 nmol/L (33–44,46–50) or <75 mmol (35,36,41,42,44,49,50). Indeed, it has been described that human obesity often coincides with low circulating 25(OH)D levels (5). Several mechanisms, such as uptake/sequestration of vitamin D within adipose tissue (51) and volumetric dilution due to increased body volume (52), may explain the link between obesity and low vitamin D levels. Furthermore, a comprehensive systematic review by Autier et al. (53) suggests that the low serum vitamin D levels could also be due to the chronic low-grade inflammation, which is an important characteristic of individuals with obesity and type 2 diabetes. Thus, vitamin D supplementation in human overweight/obesity could be expected to increase serum 25(OH)D levels.

In this meta-analysis, we showed that vitamin D supplementation increased the mean 25(OH)D level of treatment groups in all studies, although with considerable heterogeneity. Additional meta-regression analysis showed that some of the heterogeneity is explained by dose but not by treatment duration. Nevertheless, in our meta-analysis, improving 25(OH)D concentrations did not translate into an improvement in insulin sensitivity and glucose metabolism. In the present meta-analysis, we included only studies using standardized methodologies (nonfasting measures of insulin sensitivity), by multisampled OGTTs or IVGTTs (33–38,40,41,43–45,48,50) or the gold standard hyperinsulinemic-euglycemic clamp (39,42,46,47,49). Our meta-analysis, which shows no effect of vitamin D supplementation on peripheral insulin sensitivity and postprandial glucose handling, supports several other findings of studies that used fasting indices of insulin sensitivity (e.g., HOMA-IR) (18,19).

It has been shown that postprandial glycemia is strongly associated with obesity (3) and predicts cardiovascular events among insulin resistant individuals (4,54). Wood et al. (55) and Manson et al. (56). have shown that vitamin D supplementation did not result in the prevention of cardiovascular events. The most recent work by Pittas et al. (57) showed that vitamin D supplementation (4,000 IU) did not result in a significantly lower risk of diabetes, assessed by 2-h OGTT in 2,423 individuals. The skeletal muscle is a key organ for peripheral insulin sensitivity, as it is responsible for the majority of glucose disposal during postprandial conditions (24,58). Although effects of vitamin D on glucose responsiveness, insulin receptor substrate (59) and insulin sensitivity (17), and muscle mitochondria biogenesis (16) as well as lipid metabolism (17) have been documented at the transcriptional and posttranslational level in vitro, our analysis showing no effect on postprandial glucose concentrations suggests that these beneficial effects do not translate into beneficial effects at the functional level.

Studies have shown that vitamin D may affect insulin secretion (15,33) rather than insulin sensitivity per se. Vitamin D may contribute to normalization of extracellular calcium, ensuring normal calcium flux through cell membranes, and regulate the β-cell calcium pool (15). Nevertheless, whether there is sufficient evidence that vitamin D supplementation may improve insulin secretion in the postprandial condition (e.g., disposition index) needs further investigation.

Furthermore, there is only one trial included in this meta-analysis, by Cefalo et al. (49), that reported a significant increase of insulin sensitivity derived from a clamp after vitamin D supplementation. Of note, in that study vitamin D supplementation was combined with a low-calorie diet intervention, yet the sample size of this study was relatively small. Therefore, whether combining vitamin D supplementation with diet restriction may improve insulin sensitivity in humans with or at risk for insulin resistance needs further investigation in a well-controlled study.

In interpretation of the results, several factors should be taken into consideration. The optimal time of intervention and dose that are necessary to evaluate the effects of vitamin D supplementation on parameters related to glucose metabolism and insulin sensitivity are not well established. We showed that neither dose nor treatment duration was associated with changes in insulin sensitivity and postprandial glucose. It also should be noted that the results could be affected by other factors such as variation in age, season (19), and ethnicity (23) as well as tissue-specific metabolism and insulin resistance (60). A recent meta-analysis in populations with type 2 diabetes by Li et al. (23) has suggested that vitamin D supplementation may have more beneficial effects in individuals with Middle Eastern ethnicity as compared with other ethnicities, but some of the included studies on which this suggestion was based were of questionable quality. In this meta-analysis, we could not perform subgroup analysis based on ethnicity because 8 out of 18 trials (33,36–38,40,46–48) were conducted in multiethnic populations, whereas 5 other studies (39,41,42,49,50) did not report any information about ethnicity. In addition, the heterogeneity regarding the change in serum vitamin D levels may also be partly explained by compliance that was achieved during intervention, which we were unable to ascertain in more detail. Another limitation might be that the number of individuals who participated in the included studies was relatively small, possibly due to the invasive and expensive character of the measurement (e.g., clamp).

Despite the fact that the number of studies using clamps, the gold standard for the measurement of insulin sensitivity, was relatively small (only 5 studies), the outcome on insulin sensitivity derived from clamps was similar to the outcome based on the results from OGTTs and IVGTTs (13 studies). In addition, three studies that met our inclusion criteria and used a hyperinsulinemic-euglycemic clamp (61–63) were published in 2019—after the window for being included in the meta-analysis. After repeating of the meta-analysis with in total 21 studies (3 studies in 2019 and the original 18 studies), the outcome did not change (Supplementary Fig. 3A–C). In conclusion, this systematic review provides no evidence that supplementation with vitamin D has a beneficial effect on peripheral insulin sensitivity, as determined by hyperinsulinemic-euglycemic clamp, the Matsuda or insulin sensitivity index, and postprandial glucose concentrations after an OGTT in people with or at risk for insulin resistance.

Article Information

Funding. A.P. was supported by Indonesia Endowment Fund for Education (LPDP) during the preparation of the manuscript.

The funder had no role in the preparation, study design and analysis, or publication of the manuscript.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. A.P., E.E.B., J.W.E.J., and M.A.v.B designed the study. A.P. and M.A.v.B. searched databases and performed the selection of studies. A.P. analyzed the data. M.A.v.B checked the data analysis. A.P. wrote the manuscript. M.A.v.B., J.W.E.J., and E.E.B critically evaluated the review and meta-analysis, commented on it, and approved the last version. All authors reviewed and approved the final manuscript. E.E.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Footnotes

  • Received November 11, 2019.
  • Accepted March 2, 2020.
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References

  1. ↵
    1. International Diabetes Federation
    . IDF Diabetes Atlas. 8th ed. 2017
  2. ↵
    1. Zheng Y,
    2. Ley SH,
    3. Hu FB
    . Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018;14:88–98
    OpenUrlCrossRefPubMed
  3. ↵
    1. Blaak E,
    2. Antoine JM,
    3. Benton D, et al
    . Impact of postprandial glycaemia on health and prevention of disease. Obes Rev 2012;13:923–984
    OpenUrlCrossRefPubMed
  4. ↵
    1. American Diabetes Association
    . (5) Prevention or delay of type 2 diabetes. Diabetes Care 2015;38(Suppl.):S31–S32
    OpenUrlFREE Full Text
  5. ↵
    1. Kabadi SM,
    2. Lee BK,
    3. Liu L
    . Joint effects of obesity and vitamin D insufficiency on insulin resistance and type 2 diabetes: results from the NHANES 2001-2006. Diabetes Care 2012;35:2048–2054
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Pramono A,
    2. Jocken JWE,
    3. Blaak EE
    . Vitamin D deficiency in the aetiology of obesity-related insulin resistance. Diabetes Metab Res Rev 2019;35:e3146
    OpenUrl
  7. ↵
    1. Gagnon C,
    2. Lu ZX,
    3. Magliano DJ, et al
    . Serum 25-hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study). Diabetes Care 2011;34:1133–1138
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Wamberg L,
    2. Christiansen T,
    3. Paulsen SK, et al
    . Expression of vitamin D-metabolizing enzymes in human adipose tissue -- the effect of obesity and diet-induced weight loss. Int J Obes 2013;37:651–657
    OpenUrlCrossRef
    1. Girgis CM,
    2. Mokbel N,
    3. Cha KM, et al
    . The vitamin D receptor (VDR) is expressed in skeletal muscle of male mice and modulates 25-hydroxyvitamin D (25OHD) uptake in myofibers. Endocrinology 2014;155:3227–3237
    OpenUrlCrossRefPubMed
  10. ↵
    1. Sherman MH,
    2. Yu RT,
    3. Engle DD, et al
    . Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014;159:80–93
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    1. Alvarez JA,
    2. Ashraf A
    . Role of vitamin D in insulin secretion and insulin sensitivity for glucose homeostasis. Int J Endocrinol 2010;2010:351385
    OpenUrlPubMed
  12. ↵
    1. Larrick BM,
    2. Kim KH,
    3. Donkin SS,
    4. Teegarden D
    . 1,25-dihydroxyvitamin D regulates lipid metabolism and glucose utilization in differentiated 3T3-L1 adipocytes. Nutr Res 2018;58:72–83
    OpenUrl
  13. ↵
    1. Karkeni E,
    2. Bonnet L,
    3. Marcotorchino J, et al
    . Vitamin D limits inflammation-linked microRNA expression in adipocytes in vitro and in vivo: a new mechanism for the regulation of inflammation by vitamin D. Epigenetics 2018;13:156–162
    OpenUrl
  14. ↵
    1. Altieri B,
    2. Grant WB,
    3. Della Casa S, et al
    . Vitamin D and pancreas: the role of sunshine vitamin in the pathogenesis of diabetes mellitus and pancreatic cancer. Crit Rev Food Sci Nutr 2017;57:3472–3488
    OpenUrl
  15. ↵
    1. Pittas AG,
    2. Harris SS,
    3. Stark PC,
    4. Dawson-Hughes B
    . The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 2007;30:980–986
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Ryan ZC,
    2. Craig TA,
    3. Folmes CD, et al
    . 1α,25-dihydroxyvitamin D3 regulates mitochondrial oxygen consumption and dynamics in human skeletal muscle cells. J Biol Chem 2016;291:1514–1528
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Jefferson GE,
    2. Schnell DM,
    3. Thomas DT,
    4. Bollinger LM
    . Calcitriol concomitantly enhances insulin sensitivity and alters myocellular lipid partitioning in high fat-treated skeletal muscle cells. J Physiol Biochem 2017;73:613–621
    OpenUrl
  18. ↵
    1. Seida JC,
    2. Mitri J,
    3. Colmers IN, et al
    . Clinical review: effect of vitamin D3 supplementation on improving glucose homeostasis and preventing diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2014;99:3551–3560
    OpenUrlCrossRefPubMed
  19. ↵
    1. Jamka M,
    2. Woźniewicz M,
    3. Jeszka J,
    4. Mardas M,
    5. Bogdański P,
    6. Stelmach-Mardas M
    . The effect of vitamin D supplementation on insulin and glucose metabolism in overweight and obese individuals: systematic review with meta-analysis. Sci Rep 2015;5:16142
    OpenUrlCrossRefPubMed
    1. Poolsup N,
    2. Suksomboon N,
    3. Plordplong N
    . Effect of vitamin D supplementation on insulin resistance and glycaemic control in prediabetes: a systematic review and meta-analysis. Diabet Med 2016;33:290–299
    OpenUrl
  21. ↵
    1. Wu C,
    2. Qiu S,
    3. Zhu X,
    4. Li L
    . Vitamin D supplementation and glycemic control in type 2 diabetes patients: a systematic review and meta-analysis. Metabolism 2017;73:67–76
    OpenUrl
  22. ↵
    1. Mirhosseini N,
    2. Vatanparast H,
    3. Mazidi M,
    4. Kimball SM
    . The effect of improved serum 25-hydroxyvitamin D status on glycemic control in diabetic patients: a meta-analysis. J Clin Endocrinol Metab 2017;102:3097–3110
    OpenUrl
  23. ↵
    1. Li X,
    2. Liu Y,
    3. Zheng Y,
    4. Wang P,
    5. Zhang Y
    . The effect of vitamin D supplementation on glycemic control in type 2 diabetes patients: a systematic review and meta-analysis. Nutrients 2018;10:1–15
    OpenUrl
  24. ↵
    1. Baron AD,
    2. Brechtel G,
    3. Wallace P,
    4. Edelman SV
    . Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am J Physiol 1988;255:E769–E774
    OpenUrl
  25. ↵
    1. DeFronzo RA,
    2. Jacot E,
    3. Jequier E,
    4. Maeder E,
    5. Wahren J,
    6. Felber JP
    . The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981;30:1000–1007
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Moher D,
    2. Liberati A,
    3. Tetzlaff J,
    4. Altman DG; PRISMA Group
    . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097
    OpenUrlCrossRefPubMed
  27. ↵
    1. Makariou SE,
    2. Elisaf M,
    3. Challa A,
    4. Tentolouris N,
    5. Liberopoulos EN
    . No effect of vitamin D supplementation on cardiovascular risk factors in subjects with metabolic syndrome: a pilot randomised study. Arch Med Sci Atheroscler Dis 2017;2:e52–e60
    OpenUrl
  28. ↵
    1. Higgins JP,
    2. Altman DG,
    3. Gøtzsche PC, et al.; Cochrane Bias Methods Group; Cochrane Statistical Methods Group
    . The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928
    OpenUrlFREE Full Text
  29. ↵
    1. Higgins JPT,
    2. Green S
    . Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 [Internet], 2011. Available from https://handbook-5-1.cochrane.org. Accessed 18 December 2018
  30. ↵
    1. Higgins JPT,
    2. Green S
    . Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.2 [Internet], 2009. Available from https://handbook-5-1.cochrane.org/v5.0.2/. Accessed 17 April 2019
  31. ↵
    1. Wan X,
    2. Wang W,
    3. Liu J,
    4. Tong T
    . Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014;14:135
    OpenUrlCrossRefPubMed
  32. ↵
    1. Borenstein M,
    2. Hedges LV,
    3. Higgins JPT,
    4. Rothstein HR
    Introduction to Meta-analysis. John Wiley & Sons, 2009
  33. ↵
    1. Mitri J,
    2. Dawson-Hughes B,
    3. Hu FB,
    4. Pittas AG
    . Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the calcium and vitamin D for diabetes mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr 2011;94:486–494
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Harris SS,
    2. Pittas AG,
    3. Palermo NJ
    . A randomized, placebo-controlled trial of vitamin D supplementation to improve glycaemia in overweight and obese African Americans. Diabetes Obes Metab 2012;14:789–794
    OpenUrlCrossRefPubMed
  35. ↵
    1. Iraj B,
    2. Aminorroaya A,
    3. Amini M
    . Does the intramuscular injection of vitamin D increase insulin resistance? J Res Pharm Pract 2012;1:60–65
    OpenUrl
  36. ↵
    1. Davidson MB,
    2. Duran P,
    3. Lee ML,
    4. Friedman TC
    . High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care 2013;36:260–266
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Oosterwerff MM,
    2. Eekhoff EM,
    3. Van Schoor NM, et al
    . Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D-deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial. Am J Clin Nutr 2014;100:152–160
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Gagnon C,
    2. Daly RM,
    3. Carpentier A, et al
    . Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and β-cell function in multi-ethnic vitamin D-deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial. PLoS One 2014;9:e109607
    OpenUrlCrossRefPubMed
  39. ↵
    1. Kampmann U,
    2. Mosekilde L,
    3. Juhl C, et al
    . Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency - a double-blind, randomized, placebo-controlled trial. Metabolism 2014;63:1115–1124
    OpenUrlCrossRefPubMed
  40. ↵
    1. Mitchell DM,
    2. Leder BZ,
    3. Cagliero E, et al
    . Insulin secretion and sensitivity in healthy adults with low vitamin D are not affected by high-dose ergocalciferol administration: a randomized controlled trial. Am J Clin Nutr 2015;102:385–392
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Tuomainen T-P,
    2. Virtanen JK,
    3. Voutilainen S, et al
    . Glucose metabolism effects of vitamin D in prediabetes: the VitDmet randomized placebo-controlled supplementation study. J Diabetes Res 2015;2015:672653
    OpenUrl
  42. ↵
    1. Wagner H,
    2. Alvarsson M,
    3. Mannheimer B,
    4. Degerblad M,
    5. Östenson CG
    . No effect of high-dose vitamin D treatment on β-cell function, insulin sensitivity, or glucose homeostasis in subjects with abnormal glucose tolerance: a randomized clinical trial. Diabetes Care 2016;39:345–352
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Yeow TP,
    2. Lim SL,
    3. Hor CP,
    4. Khir AS,
    5. Wan Mohamud WN,
    6. Pacini G
    . Impact of vitamin D replacement on markers of glucose metabolism and cardio-metabolic risk in women with former gestational diabetes--a double-blind, randomized controlled trial. PLoS One 2015;10:e0129017
    OpenUrl
  44. ↵
    1. Barengolts E,
    2. Manickam B,
    3. Eisenberg Y,
    4. Akbar A,
    5. Kukreja S,
    6. Ciubotaru I
    . Effect of high-dose vitamin D repletion on glycemic control in African-American males with prediabetes and hypovitaminosis D. Endocr Pract 2015;21:604–612
    OpenUrl
  45. ↵
    1. Garg G,
    2. Kachhawa G,
    3. Ramot R, et al
    . Effect of vitamin D supplementation on insulin kinetics and cardiovascular risk factors in polycystic ovarian syndrome: a pilot study. Endocr Connect 2015;4:108–116
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Mousa A,
    2. Naderpoor N,
    3. de Courten MP, et al
    . Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults: a randomized placebo-controlled trial. Am J Clin Nutr 2017;105:1372–1381
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Gulseth HL,
    2. Wium C,
    3. Angel K,
    4. Eriksen EF,
    5. Birkeland KI
    . Effects of vitamin D supplementation on insulin sensitivity and insulin secretion in subjects with type 2 diabetes and vitamin D deficiency: a randomized controlled trial. Diabetes Care 2017;40:872–878
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Moreira-Lucas TS,
    2. Duncan AM,
    3. Rabasa-Lhoret R, et al
    . Effect of vitamin D supplementation on oral glucose tolerance in individuals with low vitamin D status and increased risk for developing type 2 diabetes (EVIDENCE): a double-blind, randomized, placebo-controlled clinical trial. Diabetes Obes Metab 2017;19:133–141
    OpenUrlPubMed
  49. ↵
    1. Cefalo CMA,
    2. Conte C,
    3. Sorice GP, et al
    . Effect of vitamin D supplementation on obesity-induced insulin resistance: a double-blind, randomized, placebo-controlled trial. Obesity (Silver Spring) 2018;26:651–657
    OpenUrl
  50. ↵
    1. Lerchbaum E,
    2. Pilz S,
    3. Trummer C, et al
    . Vitamin D and testosterone in healthy men: a randomized controlled trial. J Clin Endocrinol Metab 2017;102:4292–4302
    OpenUrl
  51. ↵
    1. Wortsman J,
    2. Matsuoka LY,
    3. Chen TC,
    4. Lu Z,
    5. Holick MF
    . Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000;72:690–693
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Drincic AT,
    2. Armas LA,
    3. Van Diest EE,
    4. Heaney RP
    . Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity. Obesity (Silver Spring) 2012;20:1444–1448
    OpenUrlCrossRefPubMed
  53. ↵
    1. Autier P,
    2. Mullie P,
    3. Macacu A, et al
    . Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol 2017;5:986–1004
    OpenUrl
  54. ↵
    1. Rizza RA
    . Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy. Diabetes 2010;59:2697–2707
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Wood AD,
    2. Secombes KR,
    3. Thies F, et al
    . Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. J Clin Endocrinol Metab 2012;97:3557–3568
    OpenUrlCrossRefPubMedWeb of Science
  56. ↵
    1. Manson JE,
    2. Cook NR,
    3. Lee I-M, et al.; VITAL Research Group
    . Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 2019;380:33–44
    OpenUrlCrossRefPubMed
  57. ↵
    1. Pittas AG,
    2. Dawson-Hughes B,
    3. Sheehan P, et al.; D2d Research Group
    . Vitamin D supplementation and prevention of type 2 diabetes. N Engl J Med 2019; 381:520–530
    OpenUrl
  58. ↵
    1. DeFronzo RA,
    2. Ferrannini E,
    3. Sato Y,
    4. Felig P,
    5. Wahren J
    . Synergistic interaction between exercise and insulin on peripheral glucose uptake. J Clin Invest 1981;68:1468–1474
    OpenUrlCrossRefPubMedWeb of Science
  59. ↵
    1. Maestro B,
    2. Campión J,
    3. Dávila N,
    4. Calle C
    . Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J 2000;47:383–391
    OpenUrlCrossRefPubMedWeb of Science
  60. ↵
    1. Trouwborst I,
    2. Bowser SM,
    3. Goossens GH,
    4. Blaak EE
    . Ectopic fat accumulation in distinct insulin resistant phenotypes; targets for personalized nutritional interventions. Front Nutr 2018;5:77
    OpenUrl
  61. ↵
    1. Scott D,
    2. Mousa A,
    3. Naderpoor N,
    4. de Courten MPJ,
    5. Scragg R,
    6. de Courten B
    . Vitamin D supplementation improves waist-to-hip ratio and fasting blood glucose in vitamin D deficient, overweight or obese Asians: a pilot secondary analysis of a randomised controlled trial. J Steroid Biochem Mol Biol 2019;186:136–141
    OpenUrl
    1. Wallace HJ,
    2. Holmes L,
    3. Ennis CN, et al
    . Effect of vitamin D3 supplementation on insulin resistance and β-cell function in prediabetes: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2019;110:1138–1147
    OpenUrl
  63. ↵
    1. Lemieux P,
    2. Weisnagel SJ,
    3. Caron AZ, et al
    . Effects of 6-month vitamin D supplementation on insulin sensitivity and secretion: a randomised, placebo-controlled trial. Eur J Endocrinol 2019;181:287–299
    OpenUrl
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The Effect of Vitamin D Supplementation on Insulin Sensitivity: A Systematic Review and Meta-analysis
Adriyan Pramono, Johan W.E. Jocken, Ellen E. Blaak, Marleen A. van Baak
Diabetes Care Jul 2020, 43 (7) 1659-1669; DOI: 10.2337/dc19-2265
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