Insulin resistance plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).Several studies have evaluated the association of vitamin D supplementation with insulin resistance in patients with NAFLD.The results obtained still come with contradictory results.The aim of this study was to evaluate the effect of additional vitamin D therapy on improving insulin resistance in patients with NAFLD.Relevant literature was obtained from PubMed, Google Scholar, COCHRANE and Science Direct databases.The studies obtained were analyzed using fixed-effects or random-effects models.Seven eligible studies with a total of 735 participants were included.Vitamin D supplementation improved insulin resistance in patients with NAFLD, marked by a reduction in the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), with a pooled mean difference of -1.06 (p = 0.0006; 95% CI -1.66 to -0.45).Vitamin D supplementation increased serum vitamin D levels with a mean difference of 17.45 (p = 0.0002; 95% CI 8.33 to 26.56).Vitamin D supplementation reduced ALT levels with a pooled mean difference of -4.44 (p = 0.02; 95% CI -8.24 to -0.65).No effect was observed on AST levels.Vitamin D supplementation has beneficial effects on improving insulin resistance in NAFLD patients.This supplementation may reduce HOMA-IR in such patients.It can be used as a potential adjuvant therapy for NAFLD patients.
Nonalcoholic fatty liver disease (NAFLD) is a group of fat-related liver diseases1.It is characterized by a high accumulation of triglycerides in hepatocytes, often with necroinflammatory activity and fibrosis (steatohepatitis)2.It can progress to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis.NAFLD is considered a major cause of chronic liver disease and its prevalence is increasing, estimated at 25% to 30% of adults in developed countries3,4.Insulin resistance, inflammation, and oxidative stress are thought to be major factors in the development of NAFLD1.
The pathogenesis of NAFLD is closely related to insulin resistance.Based on the most prevalent “two-hit hypothesis” model, insulin resistance is involved in the “first-hit” process.In this initial mechanism, it involves the accumulation of lipids located in hepatocytes, where insulin resistance is thought to be a major causative factor in the development of hepatic steatosis.The “first hit” increases the vulnerability of the liver to the factors that make up the “second hit”.It can lead to liver damage, inflammation and fibrosis.Production of proinflammatory cytokines, mitochondrial dysfunction, oxidative stress, and lipid peroxidation are also factors that may contribute to the development of liver injury, constituted by adipokines.
Vitamin D is a fat-soluble vitamin that regulates bone homeostasis.Its role has been widely explored in a range of non-skeletal health conditions such as metabolic syndrome, insulin resistance, obesity, type 2 diabetes and cardiovascular-related diseases.Recently, a large body of scientific evidence has explored the relationship between vitamin D and NAFLD.Vitamin D is known to regulate insulin resistance, chronic inflammation and fibrosis.Therefore, vitamin D may help prevent the progression of NAFLD6.
Several randomized controlled trials (RCTs) have evaluated the effect of vitamin D supplementation on insulin resistance.However, the results obtained still vary; either showing a beneficial effect on insulin resistance or not showing any benefit7,8,9,10,11,12,13.Despite conflicting results, a meta-analysis is needed to assess the overall effect of vitamin D supplementation.Several meta-analyses have been performed previously14,15,16.A meta-analysis by Guo et al.Including six studies evaluating the effect of vitamin D on insulin resistance provides substantial evidence that vitamin D may have a beneficial effect on insulin sensitivity14.However, another meta-analysis yielded different results.Pramono et al15 found that additional vitamin D treatment had no effect on insulin sensitivity.The population included in the study were subjects with or at risk of insulin resistance, not those specifically targeted for NAFLD.Another study by Wei et al., including four studies, made similar findings.Vitamin D supplementation did not decrease HOMA IR16.Considering all previous meta-analyses on the use of vitamin D supplements for insulin resistance, an updated meta-analysis is needed along with additional updated literature.The purpose of this study was to evaluate the effect of vitamin D supplementation on insulin resistance.
By using the top search strategy, we found a total of 207 studies, and after deduplication, we obtained 199 articles.We excluded 182 articles by screening titles and abstracts, leaving a total of 17 relevant studies.Studies that did not provide all the information required for this meta-analysis or for which the full text was not available were excluded.After screening and qualitative assessment, we obtained seven articles for the current systematic review and meta-analysis.The flow chart of the PRISMA study is shown in Figure 1.
We included the full-text articles of seven randomized controlled trials (RCTs).The publication years of these articles ranged from 2012 to 2020, with a total of 423 samples in the intervention group and 312 in the placebo group.The experimental group received different doses and durations of vitamin D supplements, while the control group received a placebo.A summary of the study results and study characteristics is presented in Table 1.
Risk of bias was analysed using the Cochrane Collaboration’s risk of bias method.All seven articles included in this study passed the quality evaluation.Full results of risk of bias for all included articles are depicted in Figure 2.
Vitamin D supplementation improves insulin resistance in patients with NAFLD, characterized by decreased HOMA-IR.Based on a random effects model (I2 = 67%; χ2 = 18.46; p = 0.005), the pooled mean difference between vitamin D supplementation and no vitamin D supplementation was -1.06 (p = 0.0006; 95% CI -1.66 to -0.45) (image 3).
Based on a random-effects model (Figure 4), the pooled mean difference in vitamin D serum after vitamin D supplementation was 17.45 (p = 0.0002; 95% CI 8.33 to 26.56).According to the analysis, vitamin D supplementation can increase the serum vitamin D level by 17.5 ng/mL.Meanwhile, the effect of vitamin D supplementation on the liver enzymes ALT and AST showed different results.Vitamin D supplementation decreased ALT levels with a pooled mean difference of -4.44 (p = 0.02; 95% CI -8.24 to -0.65) (Figure 5).However, no effect was observed for AST levels, with a pooled mean difference of -5.28 (p = 0.14; 95% CI – 12.34 to 1.79) based on a random effects model (Figure 6).
Changes in HOMA-IR after vitamin D supplementation showed considerable heterogeneity (I2 = 67%).Meta-regression analyses of route of administration (oral or intramuscular), intake (daily or non-daily), or duration of vitamin D supplementation (≤12 weeks and >12 weeks) suggest that consumption frequency may explain heterogeneity (Table 2).All but one study by Sakpal et al. 11 used the oral route of administration.Daily intake of vitamin D supplements used in three studies7,8,13.Further sensitivity analysis by leave-one-out analysis of changes in HOMA-IR after vitamin D supplementation indicated that no study was responsible for the heterogeneity of changes in HOMA-IR (Fig. 7).
The pooled results of the current meta-analysis found that additional vitamin D treatment may improve insulin resistance, a hallmark of which is reduced HOMA-IR in patients with NAFLD.The route of administration of vitamin D may vary, by intramuscular injection or by mouth.Further analysis of its effect on improving insulin resistance to understand the changes in serum ALT and AST levels.A decrease in ALT levels, but not AST levels, was observed due to additional vitamin D supplementation.
The occurrence of NAFLD is closely related to insulin resistance.Increased free fatty acids (FFA), adipose tissue inflammation, and decreased adiponectin are responsible for the development of insulin resistance in NAFLD17.Serum FFA is significantly elevated in NAFLD patients, which is subsequently converted to triacylglycerols via the glycerol-3-phosphate pathway.Another product of this pathway is ceramide and diacylglycerol (DAG).DAG is known to be involved in the activation of protein kinase C (PKC), which may inhibit the insulin receptor threonine 1160, which is associated with reduced insulin resistance.Inflammation of adipose tissue and increases in proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) also contribute to insulin resistance.As for adiponectin, it can promote the inhibition of fatty acid beta-oxidation (FAO), glucose utilization and fatty acid synthesis.Its levels are reduced in NAFLD patients, thereby promoting the development of insulin resistance.Related to vitamin D, the vitamin D receptor (VDR) is present in liver cells and has been implicated in reducing inflammatory processes in chronic liver disease.The activity of VDR increases insulin sensitivity by modulating FFA.In addition, vitamin D has anti-inflammatory and anti-fibrotic properties in the liver19.
Current evidence suggests that vitamin D deficiency may be involved in the pathogenesis of several diseases.This concept holds true for the link between vitamin D deficiency and insulin resistance20,21.Vitamin D exerts its potential role through interaction with VDR and vitamin D metabolizing enzymes.These may be present in several cell types, including pancreatic beta cells and insulin-responsive cells such as adipocytes.Although the exact mechanism between vitamin D and insulin resistance remains uncertain, it has been suggested that adipose tissue may be involved in its mechanism.The main store of vitamin D in the body is adipose tissue.It also acts as an important source of adipokines and cytokines and is involved in the production of systemic inflammation.Current evidence suggests that vitamin D regulates events related to insulin secretion from pancreatic beta cells.
Given this evidence, vitamin D supplementation to improve insulin resistance in NAFLD patients is reasonable.Recent reports point to a beneficial effect of vitamin D supplementation on improving insulin resistance.Several RCTs have provided conflicting results, necessitating further evaluation by meta-analyses.A recent meta-analysis by Guo et al.Evaluating the effect of vitamin D on insulin resistance provides substantial evidence that vitamin D may have a beneficial effect on insulin sensitivity.They found a reduction in HOMA-IR of − 1.32; 95% CI – 2.30, – 0.34.The studies included to assess HOMA-IR were six studies14.However, conflicting evidence does exist.A systematic review and meta-analysis involving 18 RCTs by Pramono et al evaluating the effect of vitamin D supplementation on insulin sensitivity in subjects with insulin resistance or risk of insulin resistance showed that additional vitamin D Insulin sensitivity had no effect, standardized mean difference -0.01, 95% CI -0.12, 0.10; p = 0.87, I2 = 0%15.However, it should be noted that the population assessed in the meta-analysis were subjects with or at risk of insulin resistance (overweight, obesity, prediabetes, polycystic ovary syndrome [PCOS] and uncomplicated type 2 diabetes), rather than NAFLD patients15.Another meta-analysis by Wei et al.Similar findings were also obtained.In the evaluation of vitamin D supplementation in HOMA-IR, including four studies, vitamin D supplementation did not reduce HOMA IR (WMD = 0.380, 95% CI – 0.162, 0.923; p = 0.169)16.Comparing all available data, the current systematic review and meta-analysis provides more reports of vitamin D supplementation improving insulin resistance in NAFLD patients, similar to the meta-analysis by Guo et al.Although similar meta-analyses have been conducted, the current meta-analysis provides an updated literature involving more randomized controlled trials and thus provides stronger evidence for the effect of vitamin D supplementation on insulin resistance.
The effect of vitamin D on insulin resistance can be explained by its role as a potential regulator of insulin secretion and Ca2+ levels.Calcitriol may directly trigger insulin secretion because the vitamin D response element (VDRE) is present in the insulin gene promoter located in pancreatic beta cells.Not only the transcription of the insulin gene, but also VDRE is known to stimulate various genes related to cytoskeleton formation, intracellular junctions, and cell growth of pancreatic cβ cells.Vitamin D has also been shown to affect insulin resistance by modulating Ca2+ flux.Since calcium is essential for several insulin-mediated intracellular processes in muscle and adipose tissue, vitamin D may be involved in its effect on insulin resistance.Optimal intracellular Ca2+ levels are necessary for insulin action.Studies have found that vitamin D deficiency leads to increased Ca2+ concentrations, resulting in decreased GLUT-4 activity, which affects insulin resistance26,27.
The effect of vitamin D supplementation on improving insulin resistance was further analyzed to reflect its effect on liver function, which was reflected in changes in ALT and AST levels.A decrease in ALT levels, but not AST levels, was observed due to additional vitamin D supplementation.A meta-analysis by Guo et al.showed a borderline reduction in ALT levels, with no effect on AST levels, similar to this study14.Another meta-analysis study by Wei et al.2020 also found no difference in serum alanine aminotransferase and aspartate aminotransferase levels between vitamin D supplementation and placebo groups.
Current systematic reviews and meta-analyses also argue against limitations.The heterogeneity of the current meta-analysis may have influenced the results obtained in this study.Future perspectives should address the number of studies and subjects involved in evaluating vitamin D supplementation for insulin resistance, specifically targeting the NAFLD population, and the homogeneity of the studies.Another aspect to consider is to study other parameters in NAFLD, such as the effect of vitamin D supplementation in NAFLD patients on inflammatory parameters, NAFLD activity score (NAS) and liver stiffness.In conclusion, vitamin D supplementation improved insulin resistance in patients with NAFLD, a hallmark of which was reduced HOMA-IR.It can be used as a potential adjuvant therapy for NAFLD patients.
Eligibility criteria are determined by implementing the PICO concept.The framework described in Table 3.
The current systematic review and meta-analysis includes all studies up to March 28, 2021, and provides the full text, evaluating additional vitamin D administration in patients with NAFLD.Articles with case reports, qualitative and economic studies, reviews, cadavers and anatomy types were excluded from the current study.All articles that did not provide the data required to conduct the current meta-analysis were also excluded.To prevent sample duplication, the samples were evaluated for articles written by the same author within the same institution.
The review included studies of adult NAFLD patients receiving vitamin D administration.Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR).
The intervention under review was the administration of vitamin D.We included studies in which vitamin D was administered at any dose, by any method of administration, and for any duration.However, we recorded the dose and duration of vitamin D administered in each study.
The main outcome investigated in the current systematic review and meta-analysis was insulin resistance.In this regard, we used HOMA-IR to determine insulin resistance in patients.Secondary outcomes included serum vitamin D levels (ng/mL), alanine aminotransferase (ALT) (IU/l) and aspartate aminotransferase (AST) (IU/l) levels.
Extract Eligibility Criteria (PICO) into keywords using Boolean operators (eg OR, AND, NOT) and all fields or MeSH (Medical Subject Heading) terms.In this study, we used the PubMed database, Google Scholar, COCHRANE and Science Direct as search engines to find eligible journals.
The study selection process was carried out by three authors (DAS, IKM, GS) to minimize the possibility of removing potentially relevant studies.When disagreements arise, the decisions of the first, second and third authors are considered.Study selection begins with handling duplicate records.Title and abstract screening was performed to exclude irrelevant studies.Subsequently, studies that passed the first assessment were further evaluated to assess whether they met the inclusion and exclusion criteria for this review.All included studies underwent a thorough quality assessment before final inclusion.
All authors used electronic data collection forms to collect the required data from each article.The data was then assembled and managed using the software Review Manager 5.4.
Data items were author name, year of publication, study type, population, vitamin D dose, duration of vitamin D administration, sample size, age, baseline HOMA-IR, and baseline vitamin D levels.A meta-analysis of the mean differences in HOMA-IR before and after vitamin D administration was performed between treatment and control groups.
To ensure the quality of all articles meeting the eligibility criteria for this review, a standardized critical assessment tool was used.This process, designed to minimize the potential for bias in study selection, was performed independently by two authors (DAS and IKM).
The key assessment tool used in this review was the Cochrane Collaboration’s risk of bias method.
Pooling and analysis of mean differences in HOMA-IR with and without vitamin D in patients with NAFLD.According to Luo et al., if the data are presented as the median or range of Q1 and Q3, use a calculator to calculate the mean.and Wan et al. 28,29 Effect sizes are reported as mean differences with 95% confidence intervals (CI).Analyses were performed using fixed or random effects models.Heterogeneity was assessed using the I2 statistic, indicating that the proportion of variation in the observed effect across studies was due to variation in the true effect, with values >60% indicating significant heterogeneity.If heterogeneity was >60%, additional analyses were performed using meta-regression and sensitivity analyses.Sensitivity analyses were performed using the leave-one-out method (one study at a time was deleted and the analysis was repeated).p-values < 0.05 were considered significant.Meta-analyses were performed using the software Review Manager 5.4, sensitivity analyses were performed using the statistical software package (Stata 17.0 for Windows), and meta-regressions were performed using the Integrated Meta-Analysis Software Version 3.
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Post time: May-30-2022