Front. Endocrinol. Frontiers in Endocrinology Front. Endocrinol. 1664-2392 Frontiers Media S.A. 10.3389/fendo.2023.1216708 Endocrinology Review Effects of dietary polyphenol curcumin supplementation on metabolic, inflammatory, and oxidative stress indices in patients with metabolic syndrome: a systematic review and meta-analysis of randomized controlled trials Qiu Linjie 1 † Gao Chunyang 2 † Wang Haonan 1 Ren Yan 1 Li Jixin 1 Li Meijie 1 Du Xinlei 1 Li Wenjie 1 Zhang Jin 1 * 1 Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China 2 Department of Special Needs International Medical, Peking University International Hospital, Beijing, China

Edited by: Ying Xin, Jilin University, China

Reviewed by: Phiwayinkosi V. Dludla, South African Medical Research Council, South Africa; Vali Musazadeh, Tabriz University of Medical Sciences, Iran; Lakshmi Mundkur, Sami-Sabinsa Group limited, India

*Correspondence: Jin Zhang, zjmzy2000@hotmail.com

†These authors have contributed equally to this work and share first authorship

 14 07 2023 2023 14 1216708 04 05 2023 26 06 2023 Copyright © 2023 Qiu, Gao, Wang, Ren, Li, Li, Du, Li and Zhang 2023 Qiu, Gao, Wang, Ren, Li, Li, Du, Li and Zhang

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 Objective

The aim was to conduct a systematic review and meta-analysis for assessing the effectiveness and safety of dietary polyphenol curcumin supplement on metabolic, inflammatory, and oxidative stress indices in patients with metabolic syndrome (MetS).

 Methods

A comprehensive search for clinical trials was conducted in the following scientific databases: PubMed, SCOPUS, Cochrane Library, EMBASE, Web of Science, and China Biological Medicine. Randomized controlled trials (RCTs) evaluating the efficacy and safety of curcumin supplement for MetS were identified. A random-effects meta-analysis was performed using inverse variance, and efficacy was expressed as mean difference (MD) with 95% confidence interval (CI). The metabolic syndrome markers that were evaluated in the present study included waist circumference (WC), fasting blood sugar (FBS), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), C-reactive protein (CRP), ultrasensitive c-reactive protein (hsCRP), and malondialdehyde (MDA). By employing the Cochrane tool, RCTs were assessed for bias risk.

 Results

A total of 785 participants from 13 RCTs were included, with intervention durations ranging from 4 to 12 weeks. Compared with the control group, the curcumin group had positive effects on WC (MD = -2.16, 95% CI: -3.78 to -0.54, p = 0.009, seven studies), FBS (MD = -8.6, 95% CI: -15.45 to -1.75, p = 0.01, nine studies), DBP (MD = -2.8, 95% CI: -4.53 to - 1.06, p = 0.002, five studies), HDL-C (MD = 4.98, 95% CI: 2.58 to 7.38, p < 0.0001, eight studies), TNF-a (MD = -12.97, 95% CI: -18.37 to -7.57, p < 0.00001, two studies), CRP (MD = - 1.24, 95% CI: -1.71 to -0.77, p < 0.00001, two studies), and MDA (MD = -2.35, 95% CI: -4.47 to -0.24, p = 0.03, three studies). These improvements were statistically significant. Meanwhile, there was no significant improvement in SBP (MD = -4.82, 95% CI: -9.98 to 0.35, p = 0.07, six studies), TG (MD = 1.28, 95% CI: -3.75 to 6.30, p = 0.62, eight studies), IL-6 (MD = -1.5, 95% CI: -3.97 to 0.97, p = 0.23, two studies), or hsCRP (MD = -1.10, 95% CI: -4.35 to 2.16, p < 0.51, two studies). FBS, SBP, HDL-C, IL-6, CRP, hsCRP, and MDA had a relatively high heterogeneity.

 Conclusion

Curcumin exhibited promising potential in enhancing markers associated with metabolic syndrome, including inflammation. However, additional studies are required to confirm such findings since the included evidence is limited and has a relatively high heterogeneity.

 Systematic review registration

https://www.crd.york.ac.uk/prospero, identifier CRD42022362553.

 curcumin turmeric metabolic syndrome inflammation meta-analysis China Academy of Traditional Chinese Medicine10.13039/501100005893 section-in-acceptance Cardiovascular Endocrinology Introduction

Metabolic syndrome (MetS) is a metabolic disease. The National Cholesterol Education Program Adult Treatment Panel III (NCEP: ATPIII) and the International Diabetes Federation (IDF) are prominent organizations dedicated to addressing issues related to cholesterol and diabetes. At present, the two most extensively adopted definitions are those of the IDF and NCEP: ATP III (1). The criteria of both organizations for assessing MetS include waist circumference (WC), blood pressure (for assessing MetS BP), fasting blood sugar (FBS), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) (2). As a novel non-communicable disease, metabolic syndrome has emerged as a global problem. MetS, although challenging to measure epidemiologically, is estimated to be approximately three times more prevalent than diabetes. Therefore, it is believed to affect around one-fourth of the global population already (3). Moreover, MetS can lead to an increased risk of diabetes and coronary heart disease and is associated with a number of malignancies, including colon, liver, and pancreatic cancers (4, 5).

Abdominal adiposity is highly correlated to increased morbidity and mortality (6). Additionally, it serves as an indicator of “dysfunctional adipose tissue,” which is a key factor in the clinical diagnosis of MetS (7). MetS is a growing global public health concern. To effectively manage the condition, new and efficient treatments with minimal adverse effects are urgently needed.

Curcumin, a natural plant-based dietary polyphenol, is an active ingredient derived from turmeric from the ginger family. Curcumin has anti-inflammatory, anti-oxidant, anti-diabetic, and anti-atherosclerotic properties (8–10), which can improve the metabolic parameters and symptoms of polycystic ovarian syndrome, MetS, non-alcoholic fatty liver, and cardiovascular disease (11). As suggested by a recent study, curcumin is a potential drug for dealing with MetS (12).

In previous research, curcumin supplementation has been reported to improve obesity-related indices, fasting glucose, and lipids in metabolic diseases such as obesity, fatty liver, and MetS (13–18). A previous meta-analysis also revealed that curcumin supplementation improved certain components of MetS, including FBS, TG, diastolic blood pressure (DBP), and HDL-C, but there were no significant changes in systolic blood pressure (SBP) and WC (19). Another study reported similar results (20). However, four (21–24) newly randomized controlled trials on metabolic indices were missed in the aforementioned meta-analysis. Notably, pro-inflammatory state and oxidative stress are significant factors of MetS and play an important role in the development process of MetS (25, 26). In a previous meta-analysis, it was found that curcumin did not have a significant effect in reducing inflammatory markers associated with chronic inflammatory diseases (27). However, a randomized controlled trial demonstrated that curcumin supplementation improved the indicators of inflammation and oxidative stress in patients with critical sepsis (28). Furthermore, in one study, oxidative stress and inflammatory markers in conditions such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) were systematically reviewed (29). However, there has been no systematic review conducted specifically on inflammatory and oxidative stress markers in patients with metabolic syndrome (MetS). As such, the aim of the present study was to perform a meta-analysis of published randomized controlled clinical trials to further evaluate the effects of curcumin on metabolic, inflammatory, and oxidative stress markers in patients with MetS.

 Methods

The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 (30) standards were followed in the execution of the current meta-analysis, which was registered with PROSPERO under ID number CRD42022362553.

Literature search strategy

From the outset through June 2022, six electronic databases—PubMed, SCOPUS, Cochrane Library, EMBASE, Web of Science, and China Biological Medicine (CBM)—were thoroughly searched. The terms used included the following: “curcumin” or “turmeric yellow” or “yellow, turmeric” or “curcumin phytosome” or “curcuminoid” or “curcuma” or “curcuminoid supplement” or “curcumin extract” and “metabolic syndrome” or “metabolic syndromes” or “syndrome, metabolic” or “syndromes, metabolic” or “metabolic syndrome X” or “insulin resistance syndrome X” or “syndrome X, metabolic” or “syndrome X, insulin resistance” or “metabolic X syndrome” or “syndrome, metabolic X” or “X Syndrome, metabolic” or “dysmetabolic syndrome X” or “Reaven syndrome X” or “syndrome X, Reaven” or “metabolic cardiovascular syndrome” or “cardiovascular syndrome, metabolic” or “syndrome, metabolic cardiovascular” or “cardiometabolic syndrome” or “cardiometabolic syndromes” or “syndrome, cardiometabolic” or “insulin resistance syndrome x” or “insulin resistance” or “metabolic diseases” or “plurimetabolic syndrome” or “syndrome x plus”, and “randomized controlled trial” or “randomized” or “placebo” or “RCTs”. In order to include any relevant studies that may not have been captured in the initial database search, a thorough examination of the reference lists of potentially eligible literature was conducted.

 Research selection

The studies included in the present analysis met the following inclusion criteria (1): participants of both genders aged 18 years or older, (2) diagnosed with metabolic syndrome according to either NCEP-ATP III or IDF guidelines (31), (3) evaluated the effects of curcumin on at least one metabolic, inflammatory, or oxidative stress marker, and (4) provided data on the baseline and endpoint measurements for both intervention and control groups or reported changes within each group. When there were numerous reports regarding the identical population under study, the most comprehensive dataset was examined. There were no exclusions based on the individuals’ race or sexual orientation ( Table 1 ).

Eligibility criteria.

Inclusion criteria
Participants Patients with a diagnosis MetS
Interventions The intervention group was given curcumin supplementation (unlimited dose, dosage form, or duration)
Comparisons The control group was treated with placebo or blank
Outcomes WC, FBS, SBP, DBP, TG, HDL-C, TNF-a, IL-6, CRP, hsCRP, and MDA
Study type RCTs assessing the effects of curcumin supplementation on MetS

The following exclusion criteria were applied: (1) trials without specific restrictions, (2) studies with a duration of less than 4 weeks, (3) participants taking antihypertensive, antidyslipidemic, or antidiabetic medications, (4) insufficient data reported in the included studies, and (5) participants with malignancies or other systemic or chronic diseases unrelated to diabetes.

 Data extraction and quality assessment

After removing any duplicate entries, two reviewers individually evaluated the remaining records for qualification using the titles and abstracts. Subsequently, the reviewers individually selected potentially eligible literature in full text for inclusion in the present study. The title of the initial author, the publishing year, the location, the number of participants (in the intervention and placebo arms), the MetS diagnostic criteria, the participants’ ages and genders, the intervention dose, the length of the study, the reported side effects, and the results were all extracted by two reviewers.

Using the method suggested by the Cochrane Handbook V.5.1.0 (32), two writers independently evaluated the included randomized controlled trials’ (RCTs) risk of bias. Seven categories were considered during the evaluation, including the blinding of participants and staff, the blinding of the result evaluation, bad outcome data, selective reporting, and other biases. According to the recommendations in the Cochrane Handbook, each item was awarded a risk-of-bias score that ranged from moderate to high to unclear. In addition, STATA 15.1 software was used to plot funnel plots for determining the presence of publication bias.

 Statistical analysis

Review Manager was used for every analysis (RevMan 5.4; Cochrane Collaboration, Copenhagen, Denmark) (33). In comparison to the controls, curcumin’s effects on metabolic indices and inflammatory marker results were expressed as mean differences (MD) and reported with corresponding 95% confidence intervals (CI). For all data, a p-value less than 0.05 was regarded as statistically significant. The heterogeneity was assessed by inconsistency(I 2) and chi-square tests. High heterogeneity between studies was considered when the heterogeneity p <0.1 and I 2 ≥ 50%. Conversely, low heterogeneity was considered when these criteria were not met. By removing one study at a time and redoing the analysis, a sensitivity analysis was performed. Subgroup analyses were also conducted by sample size and intervention duration based on the features of the included studies.

 Results Selection of trials

The explicit research screening process is shown in Figure 1 . The preliminary database retrieval and the additional retrieval yielded a total of 691 records, with 434 articles being excluded for duplicated records. A total of 241 items were eliminated after reading the titles and abstracts in accordance with the inclusion and exclusion criteria. After reading the full texts of 16 studies, two studies were excluded due to non-compliant outcome indicators, and one study had missing data. This resulted in the inclusion of 13 randomized controlled studies with 785 patients (21–24, 34–42).

Flow diagram of the literature screening process and results.

 Research characteristics

Table 2 provides an overview of the trials that were taken into consideration. All 13 studies included in the analysis were parallel RCTs conducted between 2014 and 2022. Iran (n = 10) accounted for the majority of the trials, followed by Pakistan (n = 1), China (n = 1), and Italy (n = 1). The total sample size included 785 MetS participants (373/412, male/female). Two cohorts contained exclusively male (34, 36) participants, and two cohorts consisted of only female (24, 35) participants. The trials ranged in length from 4 to 12 weeks, with two lasting 4 weeks (21, 38), three lasting 6 weeks (24, 35, 41), four lasting 8 weeks (34, 36, 39, 40), and four lasting 12 weeks (22, 23, 37, 42).

Characteristics of the trials included in the meta‐analysis.

Author, year Location MetS diagnostic criteria Age (intervention/control) No. of participant (intervention/control) Sex (female/male) Type of intervention/placebo Dose of intervention (mg/day) Duration of study (weeks) Side effects Outcome
Salimi, 2017 Iran NCEP-ATP III Mean age, 48 10/10 20/0 Curcumin/placebo 20 mg/kg 8 None BMI, weight, WC, FBG, FAT%, BP, HDL-C, TG, TNF-α,
Alidadi, 2021 Iran IDF 42.84 ± 6.25/44.43 ± 5.92 32/28 29/31 Curcumin/placebo 500 12 None BMI, WC, NC, FM, VFA, weight, FPG, TC, TG, HDL-C, LDL-C, SBP, DBP
Amin, 2015 Pakistan NCEP-ATP III 42.4 ± 13.7/41.57 ± 12.8 56/52 108/0 Supplement of turmeric powder/spaghula husk capsule 2,400 8 Dyspepsia BMI, weight, WC, HC, SBP, DBP, FBG, LDL, HDL, TG, CRP
Bateni, 2021 Iran NCEP-ATP III 50 ± 9/54 ± 7 22/21 10/33 Nana-micelle curcumin/placebo 80 12 None BMI, weight, WC, total body fat%, total body muscle%, SBP, DBP, FBS, HbA1c, Insulin, TG, TC, LDL-C, HDL-C
Pierro, 2015 Italy NCEP-ATP III 39.10 ± 16.8/41.85 ± 15.91 22/22 17/27 Curcumin supplement/phosphatidylserine 800 4 None BMI, Weight, WC, HC, FAT%
Osali, 2020 Iran NCEP-ATP III Mean age, 62.3 ± 1.23 11/11 0/22 Nano-curcumin/placebo 80 6 None BMI, Weight, WC, Glucose, SBP, TG, HDL, body fat%, MDA, CRP, IL-6, IL-10
Panahi, 2015 Iran NCEP-ATP III 44.80 ± 8.67/43.46 ± 9.7 50/50 50/50 Curcuminoids–piperine/placebo 1,000 8 None hsCRP, MDA, SBP, DBP, FBS, HbA1c
Saberi-Karimian,2018 Iran IDF 37.52 ± 9.47/38.59 ± 10.28 36/36 11/61 Curcumin/placebo 1,000 6 None Weight, BMI, WC, FBG, hsCRP, FAT%, SBP, DBP, LDL-C, HDL-C, TC, TG, T-Chol, Apo A, Apo B
Yang, 2014 Iran NCEP-ATP III 59.03 ± 10.1/59.61 ± 14.09 30/29 23/36 Curcumin extract/placebo 1,890 12 Stomach pain, mild diarrhea, nausea Weight, BMI, TG, T-Chol, FPG, HDL-C, LDL-C, T-Chol, VLDL, HbA1c
Bateni, 2022 Iran NCEP-ATP III 50 ± 9/54 ± 7 22/21 10/33 Nana-micelle curcumin/placebo 80 12 None TAC, MDA, hsCRP, NF-kB
Panahi, 2016 Iran NCEP-ATP III 44.80 ± 8.67/43.46 ± 9.7 50/50 50/50 Curcuminoids–piperine/placebo 1,000 8 Gastrointestinal TNF-α, IL-6, TGF-β, MCP-1
Zhang, 2019 China NCEP-ATP III 66.9 ± 14.1/68.1 ± 12.3 46/46 45/47 Curcumin/control 1,500 4 None TC, TG, FPG, LDL-C, HDL-C
Osali, 2018 Iran NCEP-ATP III Mean age, 62.3 ± 1.23 11/11 0/22 Nano-curcumin/placebo 80 6 None TNF-α

MetS, metabolic syndrome; BMI, body mass index; WC, waist circumference; FBG, fasting blood glucose; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TNF, tumor necrosis factor; IL, interleukin; CRP, C-reactive protein; hsCRP, high-sensitivity C-reactive protein; Apo A, apolipoprotein A; Apo B, apolipoprotein B; VLDL, very-low-density lipoprotein; HbA1c, hemoglobin A1c; MDA, malondialdehyde; HC, hip circumference; NC, neck circumference; VFA, visceral fat area; TGF-β, transforming growth factor beta; MCP-1, chemoattractant protein-1.

 Risk of bias

Figure 2 demonstrates that three studies were assigned a low risk of bias due to extensive reporting of information on each item, while 10 trials were given an uncertain risk of bias due to insufficient reporting. Among the included studies, 10 RCTs had insufficient information regarding the random sequence generation method (21, 22, 24, 34, 35, 38–42), and 10 RCTs had imperfect allocation concealment information (21, 22, 24, 34, 35, 38–42). The design and blinding implementation of three RCTs were not clear (21, 34, 38).

Risk assessment of the included studies.

 Results of the meta-analysis Waist circumference

Seven trials (22–24, 34, 36, 38, 41) gave waist circumference data without heterogeneity (p = 0.97, I2 = 0%); hence, a fixed-effects model was used. The outcomes demonstrated that, as a consequence of reducing WC, the intervention group surpassed the control group (MD = -2.16, 95% CI: -3.78 to -0.54, p = 0.009) ( Figure 3 ).

Effect of curcumin supplement on waist circumference.

 Fasting blood sugar

Nine trials (21–24, 34, 36, 39, 41, 42) showed statistically significant heterogeneity in fasting glucose outcomes (p = 0.0005, I2 = 71%) and therefore used a random-effects model. The findings demonstrated that the experimental group fared better in decreasing the FBS than the placebo group (MD = -8.6, 95% CI: -15.45 to -1.75, p = 0.01) ( Figure 4 ).

Effect of curcumin supplement on fasting blood sugar.

 Blood pressure

A fixed-effects model was used to analyze the results, which revealed that the intervention group outperformed the control group in lowering the diastolic blood pressure (MD = -2.8, 95% CI: -4.53 to -1.06, p = 0.002) ( Figure 5 ). A total of five studies (22, 23, 36, 39, 41) reported diastolic blood pressure outcomes without statistically significant homogeneity (p = 0.16, I2 = 40%).

Effect of curcumin supplement on diastolic blood pressure.

A total of six studies (22–24, 36, 39, 41) reported statistically significant heterogeneity in SBP outcomes (p = 0.0004, I2 = 78%) and therefore used a random-effects model. According to the findings, curcumin had a negligible impact on SBP (MD = -4.82, 95% CI: -9.98 to 0.35, p = 0.07) ( Figure 6 ).

Effect of curcumin supplement on systolic blood pressure.

 Triglycerides

Eight studies (21–24, 34, 36, 41, 42) showed triglyceride outcomes with no statistically significant heterogeneity (p = 0.21, I2 = 27%). As such, the results of a fixed-effects model demonstrated that curcumin’s influence did not significantly lower the TG (MD = 1.28, 95% CI: -3.75 to 6.30, p = 0.62) ( Figure 7 ).

Effect of curcumin supplement on triglycerides.

 High-density lipoprotein cholesterol

Eight trials (21–24, 34, 36, 41, 42) demonstrated significant heterogeneity in the outcomes related to HDL cholesterol (p = 0.001, I2 = 71%). By employing a random-effects model, the data indicated that the intervention group had a more pronounced effect in increasing HDL cholesterol levels compared with the placebo group (MD = 4.98, 95% CI: 2.58 to 7.38, p < 0.0001) ( Figure 8 ).

Effect of curcumin supplement on high-density lipoprotein cholesterol.

 Inflammation indicators

Two studies (24, 40) reported statistically significant heterogeneity in the results for interleukin 6 (IL-6) (p = 0.02, I2 = 81%). Thus, the results of a model with random effects showed that curcumin had no discernible impact on IL-6 (MD = -1.5, 95% CI: -3.97 to 0.97, p = 0.23) ( Figure 9A ).

Effect of curcumin supplement on inflammation indicators: (A) IL-6, (B) TNF-a, (C) C-reactive protein, and (D) hsCRP.

The tumor necrosis factor-a (TNF-a) results from two trials (35, 40) reported high homogeneity (p = 0.004, I2 = 88%). After employing a model with random effects, the outcomes revealed that the intervention group surpassed the control group in lowering the TNF-a (MD = -12.97, 95% CI: -18.37 to -7.57, p < 0.00001) ( Figure 9B ).

Based on the results of two studies (24, 36), which did not show statistically significant heterogeneity for C-reactive protein (CRP) outcomes (p = 0.58, I2 = 0%), a fixed-effects model was used. The findings indicated that the intervention group exhibited a greater reduction in CRP levels compared with the control group (MD = -1.24, 95% CI: -1.71 to -0.77, p < 0.00001) ( Figure 9C ).

Two studies (37, 39) reported statistically significant homogeneity (p < 0.00001, I2 = 98%) in the results for ultrasensitive C-reactive protein (hsCRP). After employing a model with random effects, the findings revealed that the effect of curcumin did not significantly alter the hsCRP (MD = -1.10, 95% CI: -4.35 to 2.16, p = 0.51) ( Figure 9D ).

 Oxidative stress marker

Three studies (24, 37, 39) reported statistically significant heterogeneity (p < 0.00001, I2 = 92%) in the results for malondialdehyde (MDA). Using a random-effects model, the results showed that the intervention group was superior to the control group in reducing MDA (MD = -2.35, 95% CI: -4.47 to -0.24, p = 0.03) ( Figure 10 ).

Effect of curcumin supplement on malondialdehyde.

 Adverse events

A total of three studies (36, 40, 42) reported mild gastrointestinal and digestive adverse effects, mainly including diarrhea, nausea, and constipation, which could be attributed to the high daily dose of curcumin.

 Publication bias

Publication bias was assessed for WC as an outcome indicator using a funnel plot. The Begg’s test yielded a p-value of 0.548, and the Egger’s test yielded a p-value of 0.946. The results suggest that there was no substantial publication bias among the included studies. The funnel plot is shown in Figure 11 .

Publication bias.

 Sensitivity analysis

Significant heterogeneity was observed in studies reporting FBS, SBP, and HDL-C. As such, sensitivity analyses were performed to identify the potential causes. The sensitivity analysis indicated that the study by Osai et al. (2020) had a notable influence on the heterogeneity of the FBS and SBP outcomes. However, after removing the study from the analysis, the heterogeneity became non-significant ( Supplementary Figures S1, S2 ). For the heterogeneous results of HDL-C, no single study interfered with the results when any single study was excluded ( Supplementary Figure S3 ).

 Subgroup analysis

The results of the subgroup analyses by sample size or duration did not differ from those of the overall analyses of FBS, SBP, DBP, TG, and HDL-C. ( Supplementary Figures S4–S8 ). The only exception was a significant increase in HDL-C in trials with a duration less than or equal to 6 weeks compared with trials with a duration greater than 6 weeks ( Supplementary Figure S8A ). The subgroup analyses by duration or sample size showed differences from the overall analysis of WC, which did not change significantly in trials with durations greater than 6 weeks ( Supplementary Figure 9A ) or in trials with less than 60 patients ( Supplementary Figure 9B ).

 GRADE assessment

The GRADE tool was used to rate the evidence for the 11 outcome indicators (WC, FBS, DBP, SBP, TG, HDL-C, IL-6, TNF-a, CRP, hsCRP, and MDA). The evidence was categorized as “moderate”, “low”, or “very low” based on specific reasons for downgrading, such as a high risk of bias, inconsistency, and imprecision. The detailed ratings and reasons for downgrading can be found in Table 3 .

GRADE summary of outcomes for EG versus CG for patients with MetS.

Outcomes No. of participants(studies) Anticipated absolute effects(95% CI) Relative effect (95% CI) Certainty of the evidence (GRADE)
Risk with CG Risk difference with EG
WC 369 (7) The mean WC ranged from 95.9 to 107.85 The mean WC in the EG was 2.16 lower (3.78 to 0.54 lower) – ⊕⊕○○LOWa,b
FBS 576 (9) The mean FBS ranged from 96.28 to 182.1 The mean FBS in the EG was 8.6 lower (15.46 to 1.74 lower) – ⊕⊕○○LOWa,c
DBP 383 (5) The mean DBP ranged from 76.18 to 85.1 The mean DBP in the EG was 2.8 lower (4.53 to 1.06 lower) – ⊕⊕○○LOWa,b
SBP 405 (6) The mean SBP ranged from 108.11 to 152.7 The mean SBP in the EG was 4.82 lower (9.98 to 0.35 lower) – ⊕⊕○LOWa,c
TG 476 (8) The mean TG ranged from 26.28 to 224.09 The mean TG in the EG was 1.28 higher (3.75 lower to 6.3 higher) – ⊕⊕⊕○MODERATE a
HDL-C 476 (8) The mean HDL-C ranged from 25.74 to 49.42 The mean HDL-C in the EG was 1.28 higher (2.58 to 7.38 higher) – ⊕⊕○○LOWa,c
IL-6 122 (2) The mean IL-6 ranged from 1.81 to 18.68 The mean IL-6 in the EG was 1.50 lower (3.97 lower to 0.97 higher) – ⊕○○○VERY LOWa,b,c
TNF-a 122 (2) The mean TNF-a ranged from 36.52 to 78.9 The mean TNF-a in the EG was 12.97 lower (18.37 to 7.57 lower) – ⊕○○○ LOWa,b
CRP 130 (2) The mean CRP ranged from 2.31 to 2.8 The mean CRP in the EG was 1.24 lower (1.71 to 0.77 lower) – ⊕⊕○○LOWa,b
hsCRP 143 (2) The mean hsCRP ranged from 1.006 to 1.49 The mean hsCRP in the EG was 1.10 lower (4.35 lower to 2.16 higher) – ⊕○○○ VERY LOWa,b,c
MDA 165 (3) The mean MDA ranged from 2.81 to 19.78 The mean MDA in the EG was 2.35 lower (4.47 to 0.24 lower) – ⊕○○○ VERY LOWa,b,c

CG, control group; CI, confidence interval; EG, experimental group.

Poor methodology including the method of randomization, allocation concealment, and blinding.

Small sample sizes.

I2 ≥ 50% for heterogeneity.

⊕:Meets the quality of evidence rating. ○:Does not meet the quality of evidence rating.

 Discussion

The effects of curcumin supplementation on WC, FBS, BP, TG, and HDL levels and inflammatory markers (IL-6, TNF-a, CRP, and hsCRP) in MetS patients were assessed by analyzing 13 randomized controlled trials. The minimum duration of the studies was 4 weeks, and the maximum duration was 12 weeks. The results of the present study show significant improvements in WC, FBS, DBP, HDL, and inflammatory markers (TNF-a and CRP) levels. However, there were no significant changes observed in SBP, TG levels, IL-6, and hsCRP.

In comparison with a previous systematic evaluation (19), the present results differ in terms of waist circumference, and curcumin supplementation was found to significantly reduce waist circumference. The reason for such findings could be attributed to the inclusion of new studies to increase the sample size. As has been previously demonstrated, the pathophysiological mechanism of MetS involves systemic oxidative stress brought on by central obesity (43–45), and waist circumference is a significant indicator of abdominal obesity and a proxy for visceral adipose tissue (46). Waist circumference plays a crucial role in adult metabolic syndrome early detection and the prediction of insulin resistance (47). Studies have confirmed that WC, similar to body mass index (BMI), is associated with BP, insulin resistance, and blood lipids (48). According to epidemiological research, visceral adiposity is a substantial major risk for insulin resistance, cardiovascular disease, stroke, MetS, and mortality (49). Therefore, a reduction in waist circumference can help improve the metabolic index of metabolic syndrome and reduce mortality. Through inhibiting differentiation medium-induced β-catenin downregulation and downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer binding protein α(C/EBPα), the process may contribute to reducing lipid accumulation in 3T3-L1 adipocytes (50).

Furthermore, the impact of curcumin administration on MetS inflammatory and oxidative stress biomarkers was thoroughly examined. A previous systematic review found that curcumin supplementation improved the inflammation and oxidative stress in obesity, diabetes, and NAFLD (29). However, no studies have been conducted to independently perform a meta-analysis on the co-occurrence of metabolic syndrome, inflammation, and oxidative stress. Notably, curcumin supplementation was found to significantly improve TNF-a, but not hsCRP. The two studies included in the analysis of hsCRP were found to differ in the dose of curcumin used and the duration of the intervention, with Bateni et al. (37) using 80 mg of nanocurcumin per day for 12 weeks and Pahahi et al. (2015) using 1,000 mg of curcumin per day for 8 weeks. One study found that a 10-week intervention with 1,500 mg of curcumin daily in type 2 diabetes significantly improved the hsCRP level (51), and another study showed that a 12-week intervention with nano-curcumin in patients with NAFLD significantly improved the hsCRP level (52). Based on such findings, the present authors believe that metabolic syndrome, as a complex metabolic disorder, may require larger doses of curcumin supplementation to achieve a significant improvement in hsCRP. In the present study, there was a significant improvement in TNF-a and CRP inflammatory indexes with curcumin supplementation. The present study encompasses all available research on the association between curcumin supplementation and inflammation as well as oxidative stress in individuals with MetS. Moreover, a broader range of clinical outcome measures related to curcumin supplementation in patients with metabolic syndrome was evaluated, thereby offering additional evidence-based insights.

Curcumin is significant for the improvement of inflammatory and oxidative stress indicators. While the exact pathophysiology of metabolic syndrome remains unclear, there are widely acknowledged potential pathways that contribute to its development. Such pathways include insulin resistance and the presence of chronic low-grade inflammation, which are commonly associated with central obesity (53, 54). Chronic inflammation also interacts with oxidative stress (55). The majority of MetS patients are asymptomatic, but according to the Framingham Risk Score (56), they have a 16% to 18% chance of experiencing their first coronary event within a 10-year timeframe, which raises their risk of cardiovascular disease by fivefold and their risk of type 2 diabetes by twofold (57). Inflammation can also produce insulin resistance directly or indirectly; therefore, various inflammatory markers are considered as reliable MetS biomarkers. The administration of curcumin, which leads to improvements in inflammatory and oxidative stress markers, not only enhances the overall condition of patients with MetS but also reduces the likelihood of developing cardiovascular disease.

In the obese state, adipocyte hypertrophy and overcrowding lead to the hypoxic necrosis of cells, and necrotic adipocytes attract mononuclear macrophages to cluster, and the number of macrophages in adipose tissue increases from 10%–15% to 40%–50%, leading to the infiltration of macrophages. Such infiltration induces the macrophages to polarize to M1-type pro-inflammatory phenotype and generate and emit inflammatory substances such TNF-a, IL-1, and nitric oxide synthase (NOS2), among others, which, in turn, regulate local and systemic inflammation (58, 59). These inflammatory factors further activate the macrophages and impair insulin signaling in adipocytes, leading to systemic insulin resistance (60). According to epidemiology, patients with diabetes mellitus (DM), hypertension, atherosclerosis, and cardiovascular events had increased levels of IL-6 and TNF-a (45). Thus, an assumption could be made that the possible mechanism of curcumin treatment of MetS involves reducing chronic inflammation and oxidative stress by regulating macrophage polarization.

First, to our knowledge, the present research represents the first meta-analysis of curcumin’s impact on inflammatory and oxidative stress markers in MetS. Second, in the present study, the sample size was expanded by including new studies on the basis of previous meta-analyses. Third, bias was decreased to a certain extent because only randomized controlled clinical trials were included. Fourth, the robustness of the findings was demonstrated through sensitivity analyses in which each study was omitted one at a time, indicating that the conclusions were reliable. Fifth, to evaluate the potential research characteristics of the association between curcumin supplementation and metabolic syndrome, subgroup analyses of intervention duration and the sample size were conducted.

However, the present study also has several limitations. First, although the present study was not restricted to language and region, 12 of the 13 included studies were from Asian countries, including as many as 10 studies from Iran. The generalizability of the results needs to be further verified. Second, despite being the first meta-analysis conducted on the impact of curcumin on inflammatory and oxidative stress markers in individuals with MetS, the credibility of the results was somewhat compromised due to the limited number of publications included in the study. Third, there was a higher risk of bias in the research since two of the included studies had only male participants and two studies had only female participants. Fourth, the use of products that favorably enhance the bioavailability of curcumin (including piperine or alkaloids) was not excluded. Fifth, the limited amount of research available did not allow for a breakdown of the dosage of curcumin utilized in the smaller groups. Sixth, one of the studies included in the analysis used a combination of curcumin and black seed extract. Nigella sativa seed extract had a beneficial effect on MetS, which may have caused a bias in the analysis.

 Conclusion

The present meta-analysis demonstrates that curcumin supplementation has a positive impact on MetS patients. Future randomized controlled studies should focus on addressing the limitations identified in the present analysis. Future research should aim to include larger sample sizes that encompass diverse ethnic groups, consider gender differences, and explore various forms of curcumin supplements to ensure high bioavailability. In addition, more thorough research is required to determine how curcumin affects inflammatory and oxidative stress indicators in metabolic syndrome. Further exploration is needed to better understand the mechanisms by which curcumin may be effective in treating metabolic syndrome.

 Author contributions

LQ and JZ conceptualized the research question. CG and YR participated in drafting and writing the review. CG, HW, and YR participated in the formulation of retrieval strategies, data acquisition, data analysis, and quality assessment. JL and ML participated in the drawing of tables and figures. XD and WL participated in the critical revision of the manuscript. All authors contributed to the article and approved the submitted version.

 Funding

This study was funded by the Science and Technology Innovation Project of the Chinese Academy of Traditional Chinese Medicine (CI2021A03005).

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1216708/full#supplementary-material

References Kassi E Pervanidou P Kaltsas G Chrousos G . Metabolic syndrome: definitions and controversies. BMC Med (2011) 9:48. doi: 10.1186/1741-7015-9-48 Rezaianzadeh A Namayandeh Sm Fau - Sadr S-M Sadr SM . National cholesterol education program adult treatment panel III versus international diabetic federation definition of metabolic syndrome, which one is associated with diabetes mellitus and coronary artery disease? Int J Prev Med (2012) 3:552–8. doi: 10.1002/adsc.201800786 Saklayen MG . The global epidemic of the metabolic syndrome. Curr Hypertens Rep (2018) 20:12. doi: 10.1007/s11906-018-0812-z Sookoian S Pirola CJ . Metabolic syndrome: from the genetics to the pathophysiology. Curr Hypertens Rep (2011) 13:149–57. doi: 10.1007/s11906-010-0164-9 O'Neill S O'Driscoll L . Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev (2015) 16:1–12. doi: 10.1111/obr.12229 Cicero AFG Sahebkar A Fogacci F Bove M Giovannini M Borghi C . Effects of phytosomal curcumin on anthropometric parameters, insulin resistance, cortisolemia and non-alcoholic fatty liver disease indices: a double-blind, placebo-controlled clinical trial. Eur J Nutr (2020) 59:477–83. doi: 10.1007/s00394-019-01916-7 Després J-P Lemieux I . Abdominal obesity and metabolic syndrome. Nature (2006) 444:881–7. doi: 10.1038/nature05488 Kotha RR Luthria DL . Curcumin: biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules (2019) 24:2930. doi: 10.3390/molecules24162930 Shah M Murad W Mubin S Ullah O Rehman NU Rahman MH . Multiple health benefits of curcumin and its therapeutic potential. Environ Sci pollut Res Int (2022) 29:43732–44. doi: 10.1007/s11356-022-20137-w Vollono L Falconi M Gaziano R Iacovelli F Dika E Terracciano C . Potential of curcumin in skin disorders. Nutrients (2019) 11:2169. doi: 10.3390/nu11092169 Jabczyk M Nowak J Hudzik B Zubelewicz-Szkodzinska B . Curcumin in metabolic health and disease. Nutrients (2021) 13:4440. doi: 10.3390/nu13124440 Vafaeipour Z Razavi BM Hosseinzadeh H . Effects of turmeric (Curcuma longa) and its constituent (curcumin) on the metabolic syndrome: an updated review. J Integr Med (2022) 20:193–203. doi: 10.1016/j.joim.2022.02.008 Dehzad MJ Ghalandari H Nouri M Askarpour M . Effects of curcumin/turmeric supplementation on obesity indices and adipokines in adults: a grade-assessed systematic review and dose-response meta-analysis of randomized controlled trials. Phytother Res PTR (2023) 37:1703–28. doi: 10.1002/ptr.7800 Hosseini H Ghavidel F Panahi G Majeed M Sahebkar A . A systematic review and meta-analysis of randomized controlled trials investigating the effect of the curcumin and piperine combination on lipid profile in patients with metabolic syndrome and related disorders. Phytother research: PTR (2023) 37:1212–24. doi: 10.1002/ptr.7730 Lukkunaprasit T Tansawet A Boonmanunt S Sobhonslidsuk A McKay GJ Attia J . An updated meta-analysis of effects of curcumin on metabolic dysfunction-associated fatty liver disease based on available evidence from Iran and Thailand. Sci Rep (2023) 13:5824. doi: 10.1038/s41598-023-33023-3 Musazadeh V Golandam F Faghfouri AH Abdoli Shadbad M Keramati M Moridpour AH . Curcumin supplementation contributes to relieving anthropometric and glycemic indices, as an adjunct therapy: a meta-research review of meta-analyses. J Funct Foods (2022) 99:105357. doi: 10.1016/j.jff.2022.105357 Musazadeh V Roshanravan N Mohammadizadeh M Kavyani Z Dehghan P Mosharkesh E . Curcumin as a novel approach in improving lipid profile: an umbrella meta-analysis. Nutrition metabolism Cardiovasc diseases:NMCD (2022) 32:2493–504. doi: 10.1016/j.numecd.2022.07.021 Unhapipatpong C Polruang N Shantavasinkul PC Julanon N Numthavaj P Thakkinstian A . The effect of curcumin supplementation on weight loss and anthropometric indices: an umbrella review and updated meta-analyses of randomized controlled trials. Am J Clin Nutr (2023) 117:1005–16. doi: 10.1016/j.ajcnut.2023.03.006 Azhdari M Karandish M Mansoori A . Metabolic benefits of curcumin supplementation in patients with metabolic syndrome: a systematic review and meta-analysis of randomized controlled trials. Phytother research: PTR (2019) 33:1289–301. doi: 10.1002/ptr.6323 Nurcahyanti ADR Cokro F Wulanjati MP Mahmoud MF Wink M Sobeh M . Curcuminoids for metabolic syndrome: meta-analysis evidences toward personalized prevention and treatment management. Front Nutr (2022) 9:891339. doi: 10.3389/fnut.2022.891339 Zhang h . Study on the effect of curcumin on glucose and lipid metabolism in patients with metabolic syndrome. J Modern Integr Med (2019) 28(10):1103–1105. doi: 10.3969/j.issn.1008-8849.2019.10.019 Alidadi M Sahebkar A Eslami S Vakilian F Jarahi L Alinezhad-Namaghi M . The effect of curcumin supplementation on pulse wave velocity in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled trial. Advances in experimental medicine and biology (2021) 1308:1–11. doi: 10.1007/978-3-030-64872-5_1 Bateni Z Rahimi HR Hedayati M Afsharian S Goudarzi R Sohrab G . The effects of nano-curcumin supplementation on glycemic control, blood pressure, lipid profile, and insulin resistance in patients with the metabolic syndrome: a randomized, double-blind clinical trial. Phytother research: PTR (2021) 35:3945–53. doi: 10.1002/ptr.7109 Osali A . Aerobic exercise and nano-curcumin supplementation improve inflammation in elderly females with metabolic syndrome. Diabetol Metab Syndrome (2020) 12:26. doi: 10.1186/s13098-020-00532-4 Grandl G Wolfrum C . Hemostasis, endothelial stress, inflammation, and the metabolic syndrome. Semin Immunopathol (2018) 40:215–24. doi: 10.1007/s00281-017-0666-5 Wedell-Neergaard AS Krogh-Madsen R Petersen GL Hansen AM Pedersen BK Lund R . Cardiorespiratory fitness and the metabolic syndrome: roles of inflammation and abdominal obesity. PloS One (2018) 13:e0194991. doi: 10.1371/journal.pone.0194991 White CM Pasupuleti V Roman YM Li Y Hernandez AV . Oral turmeric/curcumin effects on inflammatory markers in chronic inflammatory diseases: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res (2019) 146:104280. doi: 10.1016/j.phrs.2019.104280 Karimi A Naeini F Niazkar HR Tutunchi H Musazadeh V Mahmoodpoor A . Nano-curcumin supplementation in critically ill patients with sepsis: a randomized clinical trial investigating the inflammatory biomarkers, oxidative stress indices, endothelial function, clinical outcomes and nutritional status. Food Funct (2022) 13:6596–612. doi: 10.1039/D1FO03746C Mokgalaboni K Ntamo Y Ziqubu K Nyambuya TM Nkambule BB Mazibuko-Mbeje SE . Curcumin supplementation improves biomarkers of oxidative stress and inflammation in conditions of obesity, type 2 diabetes and NAFLD: updating the status of clinical evidence. Food Funct (2021) 12:12235–49. doi: 10.1039/D1FO02696H Page MJ McKenzie JE Bossuyt PM Boutron I Hoffmann TC Mulrow CD . The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (2021) 372:n71. doi: 10.1016/j.jclinepi.2021.03.001 Alberti KGMM Zimmet P Shaw J . The metabolic syndrome–a new worldwide definition. Lancet (2005) 366:1059–62. doi: 10.1016/S0140-6736(05)67402-8 Higgins JP Altman DG Gotzsche PC Juni P Moher D Oxman AD . The cochrane collaboration's tool for assessing risk of bias in randomised trials. BMJ (2011) 343:d5928. doi: 10.1136/bmj.d5928 Nct . Effect of nutritional supplementation with turmeric on the cognitive performance of subjects with metabolic syndrome (2021). Available at: https://clinicaltrialsgov/show/NCT04705220. Salimi Avansar M . The effects of eight weeks interval training and curcumin consumption on TNF-α and BDNF levels in men with metabolic syndrome. J Ardabil Univ Med Sci (2017) 17(3):299–310. li Osali A . Effect of six-week aerobic exercise and consumption of nanocurcumin on TNF-α and memory in 60-65 years old women with metabolic syndrome. Journal of Semnan Univesity of Medical Sciences (2018) 20:503–9. Amin F Islam N Anila N Gilani AH . Clinical efficacy of the co-administration of turmeric and black seeds (Kalongi) in metabolic syndrome - a double blind randomized controlled trial - TAK-MetS trial. Complementary therapies Med (2015) 23:165–74. doi: 10.1016/j.ctim.2015.01.008 Bateni Z Behrouz V Rahim HR Hedayati M Afsharian S Sohrab G . Effects of nano-curcumin supplementation on oxidative stress, systemic inflammation, adiponectin, and NF-kappa b in patients with metabolic syndrome: a randomized, double-blind clinical trial. J Herbal Med (2022) 31:100531. doi: 10.1016/j.hermed.2021.100531 Di Pierro F Bressan A Ranaldi D Rapacioli G Giacomelli L Bertuccioli A . Potential role of bioavailable curcumin in weight loss and omental adipose tissue decrease: preliminary data of a randomized, controlled trial in overweight people with metabolic syndrome. preliminary study. Eur Rev Med Pharmacol Sci (2015) 19:195–202. Panahi Y Hosseini MS Khalili N Naimi E Majeed M Sahebkar A . Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: a randomized controlled trial and an updated meta-analysis. Clin Nutr (Edinburgh Scotland) (2015) 34:1101–8. doi: 10.1016/j.clnu.2014.12.019 Panahi Y Hosseini MS Khalili N Naimi E Simental-Mendia LE Majeed M . Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: a post-hoc analysis of a randomized controlled trial. Biomed Pharmacother (2016) 82:578–82. doi: 10.1016/j.biopha.2016.05.037 Saberi-Karimian M Parizadeh SMR Ghayour-Mobarhan M Salahshooh MM Dizaji BF Safarian H . Evaluation of the effects of curcumin in patients with metabolic syndrome. Comp Clin Pathol (2018) 27:555–63. doi: 10.1007/s00580-017-2624-y Yang YS Su YF Yang HW Lee YH Chou JI Ueng KC . Lipid-lowering effects of curcumin in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled trial. Phytother research: PTR (2014) 28:1770–7. doi: 10.1002/ptr.5197 Fruhbeck G Catalan V Rodriguez A Ramirez B Becerril S Salvador J . Involvement of the leptin-adiponectin axis in inflammation and oxidative stress in the metabolic syndrome. Sci Rep (2017) 7:6619. doi: 10.1038/s41598-017-06997-0 Furukawa S Fujita T Shimabukuro M Iwaki M Yamada Y Nakajima Y . Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest (2004) 114:1752–61. doi: 10.1172/JCI21625 McCracken E Monaghan M Sreenivasan S . Pathophysiology of the metabolic syndrome. Clin Dermatol (2018) 36:14–20. doi: 10.1016/j.clindermatol.2017.09.004 Armstrong A Jungbluth Rodriguez K Sabag A Mavros Y Parker HM Keating SE . Effect of aerobic exercise on waist circumference in adults with overweight or obesity: a systematic review and meta-analysis. Obes Rev (2022) 23:e13446. doi: 10.1111/obr.13446 Ramirez-Manent JI Jover AM Martinez CS Tomas-Gil P Marti-Lliteras P Lopez-Gonzalez AA . Waist circumference is an essential factor in predicting insulin resistance and early detection of metabolic syndrome in adults. Nutrients (2023) 15:257. doi: 10.3390/nu15020257 Lara M Bustos P Amigo H Silva C Rona RJ . Is waist circumference a better predictor of blood pressure, insulin resistance and blood lipids than body mass index in young Chilean adults? BMC Public Health (2012) 12:638. doi: 10.1186/1471-2458-12-638 Finelli C Sommella L Gioia S La Sala N Tarantino G . Should visceral fat be reduced to increase longevity? Ageing Res Rev (2013) 12:996–1004. doi: 10.1016/j.arr.2013.05.007 Wu L-Y Chen C-W Chen L-K Chou H-Y Chang C-L Juan C-C . Curcumin attenuates adipogenesis by inducing preadipocyte apoptosis and inhibiting adipocyte differentiation. Nutrients (2019) 11:2307. doi: 10.3390/nu11102307 Adibian M Hodaei H Nikpayam O Sohrab G Hekmatdoost A Hedayati M . The effects of curcumin supplementation on high-sensitivity c-reactive protein, serum adiponectin, and lipid profile in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Phytother research: PTR (2019) 33:1374–83. doi: 10.1002/ptr.6328 Jazayeri-Tehrani SA Rezayat SM Mansouri S Qorbani M Alavian SM Daneshi-Maskooni M . Nano-curcumin improves glucose indices, lipids, inflammation, and nesfatin in overweight and obese patients with non-alcoholic fatty liver disease (NAFLD): a double-blind randomized placebo-controlled clinical trial. Nutr Metab (2019) 16:8. doi: 10.1186/s12986-019-0331-1 Makki K Froguel P Wolowczuk I . Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflammation (2013) 2013:139239. doi: 10.1155/2013/139239 Son DH Ha HS Park HM Kim HY Lee YJ . New markers in metabolic syndrome. Adv Clin Chem (2022) 110:37–71. doi: 10.1016/bs.acc.2022.06.002 Bondia-Pons I Ryan L Martinez JA . Oxidative stress and inflammation interactions in human obesity. J Physiol Biochem (2012) 68:701–11. doi: 10.1007/s13105-012-0154-2 Sherling DH Perumareddi P Hennekens CH . Metabolic syndrome. J Cardiovasc Pharmacol Ther (2017) 22:365–7. doi: 10.1177/1074248416686187 Grundy SM . Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol (2008) 28:629–36. doi: 10.1161/ATVBAHA.107.151092 Scherer PE . The multifaceted roles of adipose tissue-therapeutic targets for diabetes and beyond: the 2015 banting lecture. Diabetes (2016) 65:1452–61. doi: 10.2337/db16-0339 Unamuno X Gomez-Ambrosi J Rodriguez A Becerril S Fruhbeck G Catalan V . Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur J Clin Invest (2018) 48:e12997. doi: 10.1111/eci.12997 Engin AB . Adipocyte-macrophage cross-talk in obesity. Adv Exp Med Biol (2017) 960:327–43. doi: 10.1007/978-3-319-48382-5_14