The pooled result of the current meta-analysis found that additional vitamin D treatment may improve insulin resistance, marked by decrease of HOMA-IR in patients with NAFLD. The route of vitamin D administration may vary, either intramuscular injection or oral. Its effect toward improvement of insulin resistance was further analyzed for changes in serum ALT and AST levels. A decrement in ALT levels was observed due to additional supplementation of vitamin D, but not for AST levels.
The occurrence of NAFLD closely related to insulin resistance. Increase free fatty acid (FFA), adipose tissue inflammation and decrease of adiponectin responsible to the development of insulin resistance in NAFLD.14 Patients with NAFLD possess significant elevation of serum FFA, subsequently converted to triacylglycerol by the glycerol-3‐phosphate pathway. The other product of this pathway is ceramides and diacylglycerols (DAGs). It has been known that DAG involved in activation of protein kinase C (PKC), which may inhibit insulin receptor threonine 1160, linked to reduced insulin resistance.15 Adipose tissue inflammation, along with increased of proinflammatory cytokines such as interleukin 6 (IL‐6) and tumor necrosis factor alpha (TNF‐α), also lead to insulin resistance. As for adiponectin, it may promotes fatty acid β‐oxidation (FAO), glucose utilization, and suppression of fatty acid synthesis. Its level decrease in NAFLD patients, hence promote the development of insulin resistance.14
Current evidence showed that vitamin D deficiency may related to pathogenesis of several diseases. This concept is true for linked between vitamin D deficiency and insulin resistance.16,17 Vitamin D exert its potential effect through its interaction with vitamin D receptor (VDR) and vitamin D-metabolizing enzymes. Those may be found in several cell types, including pancreatic β-cells and insulin-responsive cells such as adipocytes. Although the definite mechanism between vitamin D and insulin resistance still uncertain, it has been suggested that adipose tissue may be related to its mechanism. The major vitamin D storage in the body is adipose tissue, it also served as notable source of adipokine and cytokines, involved in the generation of systemic inflammation.18 Current evidence suggested that vitamin D regulate the events involved in insulin secretion of pancreatic β-cells.19
Given such evidences, it is rational for additional vitamin D to improve insulin resistance in NAFLD patients. Recent reports pointed out the beneficial effect of vitamin D addition for improvement in insulin resistance. Several RCTs provide conflicting results, lead to the necessity of further evaluation through meta-analysis. Recent meta-analysis by Guo et al to assess the effect of vitamin D on insulin resistance provide substantial evidence that vitamin D may have favorable effect on insulin sensitivity. They found reduction in HOMA-IR by -1.32; 95% CI: -2.30, -0.34. The studies included for the evaluation of HOMA-IR were six studies.20 However, conflicting evidence do exist. A systematic review and meta-analysis by Pramono et al, involving 18 RCTs, that evaluate the effect of vitamin D supplementation on insulin sensitivity in subjects with or at risk for insulin resistance showed that additional vitamin D treatment showed no effect of insulin sensitivity, with standardized mean difference of -0.01, 95% CI -0.12, 0.10; P = 0.87, I2 = 0%.21 However, it should be noted that the population evaluated in the meta-analysis was subjects with or at risk for insulin resistance (overweight, obesity, prediabetes, polycystic ovary syndrome [PCOS], and type 2 diabetes without complications), not NAFLD patients.21 Another meta-analysis by Wei et al also obtained similar finding. In the evaluation of vitamin D supplementation for HOMA-IR, which included four studies, vitamin D supplementation did not exert reduction in HOMA IR (WMD = 0.380, 95% CI: -0.162, 0.923; P = 0.169).22 Comparing all the data available, the current systematic review and meta-analysis provide more reports that vitamin D supplementation improve insulin resistance in NAFLD patients, similar to meta-analysis by Guo et al. Although similar meta-analysis had been conducted, the current meta-analysis provide updated literature with more RCTs involved, hence providing stronger evidence for the effect of vitamin D supplementation on insulin resistance.
The effect of vitamin D on insulin resistance may be explained by its effect as potential regulator of insulin secretion and Ca2+ levels. Calcitriol may directly trigger insulin secretion, since vitamin D responsive elements (VDRE) present in insulin gene promoter, located at β-cells of pancreas.23 Not only the transcription of insulin gene, VDRE also known to stimulate various genes related to cytoskeletal formation, intracellular junctions and cellular growth of pancreatic c β-cells.24 Vitamin D also showed effect to insulin resistance through its regulation in Ca2+ flux. As calcium is essential for several insulin-mediated intracellular processes in muscle an adipose tissue, hence vitamin D may be related to its effect on insulin resistance. Optimal intracellular level of Ca2+ is a mandatory for insulin action. Studies has found that vitamin D deficiency responsible for increase concentration of Ca2+, leading to decrease activity of GLUT-4, impacting in insulin resistance.25,26
The effect of improvement of insulin resistance due to vitamin D supplementation further analyzed towards its effect to liver function, reflected by changes in ALT and AST levels. A decrement in ALT levels was observed due to additional supplementation of vitamin D, but not for AST levels. A meta-analysis by Guo et al showed a borderline reduction in ALT levels and no effect toward AST levels, similar to this study.20 Another meta-analysis study by Wei et al in 2020 also found that serum alanine aminotransferase and aspartate aminotransferase levels were not different between vitamin D supplementation and placebo groups.22
The current systematic review and meta-analysis also objected to limitation. The heterogeneity of the current meta-analysis may affect the results obtained in the current study. The future perspective should be directed to the number of study and subjects involved in the evaluation of vitamin D supplementation toward insulin resistance, specified to NAFLD population, and its homogeneity of the studies. To conclude, vitamin D supplementation improve insulin resistance in NAFLD patients, marked by the decrease of HOMA-IR. It may serve as potential adjunctive treatment for NAFLD patients.