Beneficial effects of Huanglian Jiedu decoction (黄连解毒汤 ) on metabolic syndrome: a prospective randomized controlled clinical trial

Abstract

OBJECTIVE:

To evaluate the clinical efficacy of Huanglian Jiedu decoction (黄连解毒汤, HLJDD) in patients with metabolic syndrome (MS) and to elucidate its potential underlying mechanisms.

METHODS:

A total of 132 participants were enrolled and randomly divided into the HLJDD group and the control group. Participants in the HLJDD group received a 3-month HLJDD treatment in addition to lifestyle guidance, while the control group received only lifestyle guidance. Anthropometric indices, blood lipid profiles, liver function indices, glucose homeostasis, insulin sensitivity, inflammatory profiles, and the brown adipokine fibroblast growth factor 21 (FGF-21) were measured both at baseline and at the end of the trial.

RESULTS:

The study demonstrated that administering HLJDD for three months significantly reduces the body weight [8.91% (6.03%-10.22%) vs5.58% (3.31%-8.70%), P<0.01], body mass index [8.55% (6.08%-10.16%) vs5.37% (3.27%-8.54%), P<0.01], waist circumference [9.56% (6.63%-14.41%) vs 7.43% (3.11%-11.69%), P <0.01] as well as the metabolic profiles of patients with metabolic syndrome. Additionally, it was observed that the HLJDD regimen led to lower serum levels of inflammatory cytokines IL-6 (-45.03% vs-22.90%, P < 0.01), IL-17A (-23.34% vs -9.13%, P < 0.05), TNF-α (-33.78% vs-11.02%, P < 0.01) and FGF-21 (P < 0.05) when compared to the control group.

CONCLUSION:

It can be concluded that HLJDD contributes to ameliorating metabolic disorders in individuals suffering from metabolic syndrome. The data also imply that the beneficial effects of HLJDD on metabolism might be attributed to its role in enhancing FGF-21 secretion, which is otherwise compromised due to metabolic inflammation.

1. INTRODUCTION

Metabolic syndrome (MS), characterized by a variety of metabolic abnormalities including obesity, hypertension, hyperglycaemia, dyslipidaemia, and insulin resistance, is a multifaceted clinical syndrome. Its strong association with increased risks of type 2 diabetes (T2D) and cardiovascular disease (CVD) has been well-documented. Over recent years, the prevalence of MS has escalated, making it a critical concern in public health.^1-3

Huanglian Jiedu decoction (黄连解毒汤, HLJDD) is an ancient formula of Traditional Chinese Medicine, derived from Ge Hong's Zhou Hou Bei ji Fang.⁴ It consists of Huanglian (Rhizoma Coptidis), Huangqin (Radix Scutellariae Baicalensis), Huangbai (Cortex Phellodendri Amurensis), and Zhizi (Fructus Gardeniae) in a 3∶2∶2∶3 ratio, primarily aimed at alleviating ‘heat’ and aiding ‘detoxification’. In Traditional Chinese Medicine, ‘heat’ and ‘detoxification’ are considered common causes of metabolic disorders. HLJDD has been clinically shown to have therapeutic effects on various metabolic diseases.^5,6 Recent studies have indicated that treatment with HLJDD leads to significant reductions in various parameters, including body weight, fasting plasma glucose, total cholesterol (TC), triglyceride (TG), and low density lipoprotein (LDL-C) levels, in diabetic rats induced by a high-fat diet and streptozotocin (STZ). Simultaneously, there was an increase in high density lipoprotein (HDL-C) levels noted in these subjects.^7,8 However, there remains a significant gap in clinical research regarding the efficacy of HLJDD in treating MS and its various associated metabolic disorders, which consequently limits the use of HLJDD in MS treatment.

This study aims to investigate the clinical efficacy of HLJDD in the treatment of MS. Our findings indicate that HLJDD treatment enhances metabolic profiles in MS patients, potentially by ameliorating the impaired secretion of fibroblast growth factor 21 (FGF-21) induced by metabolic inflammation.

2. MATERIALS AND METHODS

2.1. Trial design

In this forward-looking, randomized, controlled clinical study, the therapeutic impact of HLJDD on MS was assessed. Once initiated, the methodologies of the trial remained consistent throughout.

2.2. Participants

All participants were recruited from the outpatient clinic of Changzhou Hospital of Traditional Chinese Medicine from February 2021 to January 2022. Eligible participants with MS were defined according to the International Diabetes Federation 2005 criteria.⁹ The exclusion criteria for participants in the study were specified as follows: (a) individuals younger than 18 years or older than 70 years were not included; (b) Acute diabetic complications in the preceding month; (c) Secondary obesity attributable to a well-defined etiology; (d) Patients undergoing insulin treatment; (e) Patients with concurrent acute infection; (f) Patients with severe cardiac, hepatic, or renal precursor diseases; (g) Pregnant or lactating women; (h) Patients experiencing acute coronary syndromes or strokes; (i) Patients who had used medications of the same class or with antagonistic effects to the study drug in the past two months; (j) Patients currently involved in other pharmaceutical clinical trials.

The detailed protocol, as well as the potential risks, and benefits were clarified to the participants. Written consents were signed at the time of enrolment.

2.3. Workflow of the trial

Participants were recruited and then randomly assigned to either the HLJDD group or the control group, with a 1∶1 allocation ratio. The study coordinator, PhD. ZHU, distributed sealed envelopes to an independent evaluator. Each envelope contained a unique, randomly generated assignment code. It is important to note that the independent evaluator played no part in the recruitment of participants or the administration of interventions. Instead, sole responsibility of the evaluator was to determine the group allocation for each participant based on the codes contained within the envelopes. During the initial two weeks, all participants received standard lifestyle guidance only (referred to as the adaptation period below). Starting from the third week, those in the HLJDD group were advised to consume 200 mL of HLJDD both in the morning and evening, while the control group continued with lifestyle guidance only; this phase lasted for three months. Participants with comorbidities were instructed to maintain their existing treatments, and all medications taken were documented throughout the trial.

The formula of HLJDD included 9 g Huanglian (Rhizoma Coptidis), 6 g Huangqin (Radix Scutellariae Baicalensis), 6 g Huangbai (Cortex Phellodendri Amurensis), and 9 g Zhizi (Fructus Gardenia). All ingredients of HLJDD were provided and decocted by the Chinese Medicine Pharmacy of Changzhou Hospital of Traditional Chinese Medicine. The above herbs were decocted with water into a 400 mL HLJDD solution. The entire process, from sourcing the ingredients to preparing the final decoction, was carried out in accordance with traditional Chinese medicine practices and modern regulatory standards, ensuring the safety and effectiveness of HLJDD for its intended use.

All measurements, including anthropometric indices, blood lipid profiles, liver function indices, glucose homeostasis, insulin sensitivity, inflammatory profiles, and brown adipokine FGF-21, were conducted at both the commencement and conclusion of the study. Bi-weekly telephone follow-ups were conducted with participants to monitor for adverse events. This study was registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR2100043387). The Ethics Committee of Changzhou Hospital of Traditional Chinese Medicine granted approval for this study [Reference number: 2020-LL-29(S)].

2.4. Anthropometric indices analysis and blood pressure

Measurements of standing height and weight were conducted using a wall-mounted stadiometer, with participants wearing minimal clothing. Waist circumference (WC) was determined by placing a tape measure midway between the lower rib margin and the upper iliac crest. Body mass index (BMI) was calculated as body weight in kilograms divided by the square of height in meters. Blood pressure (BP) measurements were taken thrice in a resting state using the same electronic sphygmomanometer, and the average of these three readings was recorded as the BP value.

2.5. Blood sample collection and biochemical analysis

At the outset and conclusion of the study, blood samples were obtained from participants who were in a fasting state. These freshly collected blood samples were left to stand at room temperature for a duration of 30 min before being centrifuged at 3000 revolutions per minute (rpm) for 10 min. The resulting supernatant was then gathered as serum samples and preserved at a temperature of -80 ℃ for subsequent analyses.

At Changzhou Hospital of Traditional Chinese Medicine, an automated clinical chemistry analyzer was employed for the assessment of various biomarkers. These included fasting blood-glucose (FBG), glycosylated hemoglobin (HbA1c), insulin, TC, TG, HDL-C, LDL-C, free fatty acid (FFA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltranspeptidase (γ-GT), blood urea nitrogen (BUN), creatinine (Cr). Homeostasis model of assessment for insulin resistance (HOMA-IR) = fasting glucose (mmol/L) × fasting insulin (mU/L) / 22.5.

2.6. Inflammatory cytokines detection

The preparation of serum samples was conducted according to the guidelines provided with the inflammatory cytokines detection kit (manufactured by Ruisikaier, Qingdao, China). This kit is specifically engineered to identify several inflammatory cytokines, namely interleukin (IL)-2 (IL-2), IL-4, IL-6, IL-10, IL-17A, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), utilizing the cytometric bead assay technique.

2.7. Serum FGF-21 measurement

The serum FGF-21 concentration was quantified using ELISA kits (model EK1151, provided by Multisciences Biotech, Hangzhou, China), in strict accordance with the provided procedural guidelines.

2.8. Statistical analysis

The primary efficacy analyses including anthropometric indices, blood pressure, the metabolic profiles and serum levels of inflammatory cytokines were based on the intention-to-treat principle. The mean imputation was used to deal with missing data. The analysis of FGF-21 was based on the per-protocol principle.

Data analysis was conducted using SPSS 26.0 software (IBM Corp., Armonk, NY, USA). Data presentations were in forms of mean ± standard deviation ($ \bar{x} \pm s$), median with interquartile range (IQR), or percentage as deemed fitting. For data deviating from a normal distribution, the Wilcoxon and Mann-Whitney tests were utilized for group comparisons. The χ² test was used for the analysis of categorical data. A P-value below 0.05 was considered to denote statistical significance.

3. RESULTS

3.1. Baseline characteristics of the participants

The initial plan aimed to recruit 101 individuals per group. However, due to the insufficient number of clinical patients during the special period, only 132 MS patients were successfully recruited from the outpatient clinic of Changzhou Hospital of Traditional Chinese Medicine for our clinical study. Following the adaptation period, 8 out of 132 participants experienced significant body weight fluctuations and subsequently withdrew from the trial. The remaining 124 participants were randomly assigned to either the control group or the HLJDD group. In the control group, 5 participants were excluded due to lack of motivation, blood draw difficulties, and unspecified reasons. In the HLJDD group, 7 participants were excluded owing to lack of motivation, pregnancy, and relocation to a different city. Ultimately, 112 participants completed the entire trial, with 59 in the control group and 53 in the HLJDD group (Figure 1).

Figure 1. Flow diagram of the study.

HLJDD: Huanglian Jiedu decoction.

At baseline, no significant differences were observed between the control group and the HLJDD group in terms of anthropometric indices (including body weight, BMI, and WC) and metabolic profiles (including TC, TG, HDL-C, and LDL-C), liver and kidney function markers (including γ-GT, BUN, Cr, UA), blood pressure (both diastolic and systolic), serum levels of inflammatory cytokines (including IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α), and serum FGF-21 levels. Furthermore, the medications used to treat comorbidities showed no significant differences between the control and HLJDD groups (supplementary Table 1).

3.2. HLJDD reduces the body weight of patients with MS

The comparison of anthropometric indices between the two groups before and after the intervention is presented in Table 1. Following a 3-month intervention, there was a reduction in body weight, BMI, and WC in both groups compared to baseline values (P < 0.01). The reduction of BMI in the HLJDD group is more than that in the control group (P = 0.009). Moreover, after adjusting these parameters for their baseline values in Per- protocol set, it was observed that the relative reductions in body weight [8.91% (6.03%-10.22%) vs 5.58% (3.31%-8.70%), P < 0.01], body mass index [8.55% (6.08%-10.16%) vs 5.37% (3.27%-8.54%), P < 0.01], waist circumference [9.56% (6.63%-14.41%) vs 7.43% (3.11% -11.69%), P < 0.01] were significantly greater in the HLJDD group compared to the control group.

Table 1.

Anthropometric indices before and after intervention

Item	HLJDD group (n = 60)					Control group (n = 64)				Differences between groups
	Baseline	After intervention		P value		Baseline	After intervention	P value		P value
Weight (kg)	85.75 (78.25-93.88)		80.00 (72.00-82.75)a	<0.0001		86.00 (77.30-95.00)	80.70 (72.41-88.38)c	<0.0001		0.189
BMI (kg/m2)	31.18 (28.55-32.99)		28.01 (25.79-30.12)ab	<0.0001		31.40 (29.40-34.10)	29.00 (27.33-31.60)c	<0.0001		-0.009
WC (cm)	105.50 (100.00-110.75)		93.50 (88.00-98.00)a	<0.0001		103.00 (96.50-109.75)	94.00 (88.25-99.75)c	<0.0001		0.317

Notes: HLJDD group: treated with standard lifestyle guidance and Huanglian Jiedu decoction (decocted to 400, 200 mL twice daily) for 3 months; Control group: treated only with standard lifestyle guidance for 3 months. HLJDD: Huanglian Jiedu decoction; BMI: body mass index; WC: waist circumference. Data are presented as median (interquartile range). Comparisons within groups were performed using paired samples Wilcoxon test. When comparable at baseline, differences after intervention between HLJDD and Control groups were compared using the Mann-Whitney test. Compared with the baseline of HLJDD group, ^aP < 0.05; compared with Control group after intervention, ^bP < 0.05; compared with the baseline of Control group, ^cP < 0.05.

3.3. HLJDD improves the metabolic profiles of patients with MS

As depicted in Table 2 the HLJDD treatment significantly decreased TC, LDL-C levels and increased the HDL-C level (P < 0.01), whereas the control treatment only reduced the TG and HDL-C levels of the patients. Both the control treatment and the HLJDD treatment significantly improved glucose homeostasis parameters (P < 0.01) in overweight/obese patients, including FBG, HbA1c, fasting insulin, and HOMA-IR, compared to their baselines. However, reductions in HbA1c% [5.89 (5.40-6.00) vs 5.90 (5.70-6.50), P = 0.025] was more pronounced in the HLJDD group than in the control group (Table 3).

Table 2.

Serum lipid levels before and after intervention ($ \bar{x} \pm s$)

Item	HLJDD group (n = 60)				Control group (n = 64)				Differences between groups
	Baseline	After intervention	P value		Baseline	After intervention	P value		P value
TC (mmol/L)	4.98±1.23	4.31±0.81ab	<0.0001		4.80±0.76	4.69±0.75	0.245		0.02
TG (mmol/L)	2.34±0.81	1.40±0.46a	<0.0001		1.98±0.83	1.41±0.62c	<0.0001		NA
HDL-C (mmol/L)	1.04±0.18	1.16±0.21a	<0.0001		1.06±0.20	1.11±0.20c	0.048		0.137
LDL-C (mmol/L)	2.92±0.88	2.43±0.62ab	<0.0001		2.96±0.68	2.83±0.63	0.100		<0.0001
FFA (μmol/L)	531.00±195.17	554.88±196.10	0.149		582.38±191.13	571.59±203.05	0.725		NA

Notes: HLJDD group: treated with standard lifestyle guidance and Huanglian Jiedu decoction (decocted to 400, 200 mL twice daily) for 3 months; Control group: treated only with standard lifestyle guidance for 3 months. HLJDD: Huanglian Jiedu decoction; TC: total cholesterol; TG: triglyceride; HDL-C: high density lipoprotein; LDL-C: low density lipoprotein; FFA: free fatty acid. Data are presented as mean ± standard deviation. NA: not available. When uncomparable at baseline, differences after intervention between HLJDD and Control groups were not available. Comparisons within groups were performed using the paired t-test. When comparable at baseline, differences after intervention between HLJDD and Control groups were compared using the unpaired t-test. Compared with the baseline of HLJDD group, ^aP < 0.05; compared with Control group after intervention, ^bP < 0.05; compared with the baseline of Control group, ^cP < 0.05.

Table 3.

Glucose homeostasis and insulin sensitivity before and after intervention

Item	HLJDD group (n = 60)				Control group (n = 64)				Differences between groups
	Baseline	After intervention	P value		Baseline	After intervention	P value		P value
FBG (mmol/L)	6.05 (5.53-6.44)	5.20 (5.10-5.60)a	<0.0001		5.28 (4.98-5.72)	5.03 (4.68-5.21)c	<0.0001		NA
HbA1c (%)	6.10 (5.73-6.58)	5.89 (5.40-6.00)ab	<0.0001		6.10 (5.90-6.90)	5.90 (5.70-6.50)c	<0.0001		0.025
Insulin (μU/mL)	28.63 (15.81-34.00)	11.25 (7.23-14.85)ab	<0.0001		24.65 (18.06-34.00)	16.18 (10.30-24.39)c	<0.0001		<0.0001
HOMA	4.03 (2.85-6.60)	2.59 (1.84-2.97)a	<0.0001		4.48 (2.92-6.22)	2.71 (1.68-3.74)c	<0.0001		0.227

Notes: HLJDD group: treated with standard lifestyle guidance and Huanglian Jiedu decoction (decocted to 400, 200 mL twice daily) for 3 months; Control group: treated only with standard lifestyle guidance for 3 months. HLJDD: Huanglian Jiedu decoction; FBG: fasting blood-glucose; HbA1c: glycosylated hemoglobin; HOMA: Homeostasis model of assessment for insulin resistance.Data are presented as median (interquartile range). NA: not available. When uncomparable at baseline, differences after intervention between HLJDD and Control groups were not available. Comparisons within groups were performed using paired samples Wilcoxon test. When comparable at baseline, differences after intervention between HLJDD and Control groups were compared using the Mann-Whitney test. Compared with the baseline of HLJDD group, ^aP < 0.05; compared with Control group after intervention, ^bP < 0.05; compared with the baseline of Control group, ^cP < 0.05.

As illustrated in Table 4, reductions in both diastolic and systolic blood pressure levels were observed in both groups (P < 0.01). However, the HLJDD group did not show a significant advantage in blood pressure reduction compared with the control group [SBP: 125.96 (120.25-130.00) vs 120.00 (120.00-130.00), P = 0.994; DBP: 76.72 (71.75-80.00) vs 76.72 (70.00-80.00), P = 0.334].

Table 4.

Blood pressure before and after intervention

Item	HLJDD group (n = 60)					Control group (n = 64)				Differences between groups
	Baseline	After intervention	P value		Baseline		After intervention	P value		P value
SBP (mm Hg)	130.00 (121.00-130.00)	125.96 (120.25-130.00)a	<0.0001		131.50 (121.25-137.60)		120.00 (120.00-130.00)b	<0.0001		0.994
DBP (mm Hg)	80.00 (72.00-85.00)	76.72 (71.75-80.00)a	<0.0001		78.00 (75.00-88.00)		76.72 (70.00-80.00)b	<0.0001		0.334

Notes: HLJDD group: treated with standard lifestyle guidance and Huanglian Jiedu decoction (decocted to 400, 200 mL twice daily) for 3 months; Control group: treated only with standard lifestyle guidance for 3 months. HLJDD: Huanglian Jiedu decoction; SBP: systolic blood pressure; DBP: diastolic blood pressure. Data are presented as median (interquartile range). Comparisons within groups were performed using paired samples Wilcoxon test. When comparable at baseline, differences after intervention between HLJDD and Control groups were compared using the Mann-Whitney test. Compared with the baseline of HLJDD group, ^aP < 0.05; compared with the baseline of Control group, ^bP < 0.05.

3.4. HLJDD inhibits the metabolic inflammation of patients with MS

Given the significant role of inflammation in the pathogenesis of metabolic disorders associated with obesity, we assessed the serum levels of common pro-inflammatory and anti-inflammatory cytokines in the patients.¹⁰

Upon concluding the trial, a reduction in the levels of pro-inflammatory factors, specifically IL-6, IL-17A, TNF-α, and γ-IFN, was observed in both study groups when compared to their initial levels, as detailed in Table 5. No marked changes were detected in the levels of anti-inflammatory agents IL-2 and IL-4 pre and post the HLJDD intervention. Notably, a trend of increased levels of IL-2 and IL-4 was observed post HLJDD treatment, whereas these levels tended to decrease in the control group. IL-10, predominantly an anti-inflammatory cytokine in obesity, exhibited a significant rise in the HLJDD group (P < 0.01) from the baseline, in contrast to the control group, which showed no substantial change (P = 0.495).

Table 5.

Serum cytokines before and after intervention (pg/mL)

Item	HLJDD group (n = 53)				Control group (n = 59)				Differences between groups
	Baseline	After intervention	P value		Baseline	After intervention	P value		P value
IL-2	0.94 (0.47-1.44)	1.03 (0.57-1.51)	0.105		1.04 (0.54-1.45)	0.99 (0.56-1.23)c	0.010		0.142
IL-4	1.12 (0.81-2.09)	1.34 (0.92-2.09)a	0.275		1.44 (0.98-1.74)	1.08 (0.86-1.42)c	<0.0001		0.008
IL-6	7.46±2.89	4.48±2.26ab	0.013		7.18±3.04	5.70±2.21c	<0.0001		0.003
IL-10	1.56 (1.09-1.98)	1.83 (1.47-2.22)ab	<0.0001		1.74 (1.26-1.98)	1.57 (1.20-1.88)	0.495		0.003
IL-17A	3.35 (1.40-8.53)	2.97 (1.35-4.88)b	0.001		3.82 (1.68-6.51)	3.73 (1.79-6.93)c	0.031		0.217
TNF-α	1.02 (0.77-1.73)	0.87 (0.55-1.03)b	<0.0001		0.93 (0.79-1.43)	0.99 (0.65-1.44)	0.093		0.13
γ- IFN	1.48 (0.83-2.59)	1.15 (0.66-1.52)b	<0.0001		0.85 (0.49-1.46)	0.96 (0.37-1.19)c	0.03		NA
FGF-21		79.87 (59.60-120.05)a				67.71 (51.48-85.52)			0.040

Notes: HLJDD group: treated with standard lifestyle guidance and Huanglian Jiedu decoction (decocted to 400, 200 mL twice daily) for 3 months; Control group: treated only with standard lifestyle guidance for 3 months. HLJDD: Huanglian Jiedu decoction; IL-2: interleukin-2; IL-4: interleukin-4; IL-6: interleukin-6; IL-10: interleukin-10; IL-17A: interleukin-17A; TNF-α: tumor necrosis factor-α; γ- IFN: interferon-γ. Data are presented as median (interquartile range) or mean ± standard deviation. NA: not available. When uncomparable at baseline, differences after intervention between HLJDD and Control groups were not available. Comparisons within groups were performed using paired samples Wilcoxon test or the paired t-test. When comparable at baseline, differences after intervention between HLJDD and Control groups were compared using the Mann-Whitney test or the unpaired t-test. Compared with Control group after intervention, ^aP < 0.05; compared with the baseline of HLJDD group, ^bP < 0.05; compared with the baseline of Control group, ^cP < 0.05.

Adjustments were made to the cytokine levels in relation to their baseline values. The treatment with HLJDD resulted in a notable improvement in the serum levels of anti-inflammatory agents IL-2 (-0.49% vs -6.94%, P < 0.01), IL-10 (10.62% vs -3.23%, P < 0.01), and IL-4 (-1.50% vs -8.85%, P < 0.01). This treatment also effectively reduced the levels of pro-inflammatory cytokines IL-6 (-45.03% vs -22.90%, P < 0.01), IL-17A (-23.34% vs -9.13%, P < 0.05), TNF-α (-33.78% vs -11.02%, P < 0.01) in comparison to the control treatment.

3.5. HLJDD elevates the serum level of FGF-21 of patients with MS

The association between peripheral blood FGF-21 levels and the evolution, progression, and outcomes of metabolic disorders is substantial. As depicted in Table5, the serum FGF-21 concentrations in patients receiving HLJDD were significantly elevated when compared to those in the control group (P < 0.05).

3.6. Safety index

Throughout the duration of the study, participants did not report any significant adverse effects. Several minor or temporary symptoms were noted, including gastrointestinal discomfort and increased frequency of defecation. The 3-month HLJDD treatment did not exhibit significant adverse effects on the patients’ liver or kidney functions (supplementary Table 2).

4. DISCUSSION

The findings of this study indicate that HLJDD treatment notably accelerates weight loss and enhances the metabolic profiles in patients with MS. Intriguingly, we also observed a marked decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines in the patients' serum following HLJDD treatment. This strongly suggests a potential immune-regulatory effect of HLJDD in MS patients, highlighting its significant potential in treating metabolic disorders through its anti-inflammatory action.

Inflammation is acknowledged as a pivotal factor in obesity and obesity-related metabolic disorders.¹¹ Chronic inflammation, stemming from obesity, is prevalent in various insulin-sensitive organs, ultimately impairing their physiological functions.^12,13 Both innate and adaptive immune cells partake in this process. For example, in adipose tissue, ATMs exhibit a phenotypic transition from anti-inflammatory (M2) to pro-inflammatory (M1) during obesity. M1 macrophages release pro-inflammatory cytokines like IL-6 and TNF-α, which interact with specific receptors on adipocytes, consequently disrupting glucose-lipid metabolism.¹⁴ Adaptive immune cells not only generate anti- or pro-inflammatory cytokines themselves but also modulate macrophage phenotypes.¹⁵ CD8+ T lymphocytes, Th1 cells, dendritic cells, and mast cells assist in sustaining the M1 phenotype of macrophages, whereas regulatory T cells, eosinophils, and Th2 cells activate the anti-inflammatory M2 macrophage phenotype.¹⁶

HLJDD is known for its widespread anti-inflammatory effects across various diseases. For instance, in coronary heart disease patients, HLJDD has been shown to lower peripheral serum levels of pro-inflammatory factors such as IL-1, IL-6, and TNF-α.¹⁷ Similarly, in type 2 diabetes patients, a decrease in serum hs-CRP and IL-6 levels has been observed following HLJDD treatment.¹⁸ The anti-inflammatory action of HLJDD might be attributed to the suppression of MyD88 and NF-κB in macrophages.¹⁹ In our study, we observed that HLJDD significantly diminished pro-inflammatory cytokines IL-6, IL-17A, TNF-α, and IFN-γ. These cytokines were well-documented disruptors of glucose-lipid metabolism and insulin sensitivity in insulin-sensitive organs, including adipose tissue, liver, and skeletal muscle. By reducing their concentrations, HLJDD facilitated an improvement in glucose-lipid metabolism and insulin sensitivity. Concurrently, HLJDD elevated the levels of anti-inflammatory cytokines, notably IL-2, IL-4 and IL-10. This delicate balance between pro-inflammatory and anti-inflammatory cytokines played a crucial role in mitigating metabolic inflammation. This suggests HLJDD's role in mitigating metabolic inflammation, thereby contributing to its metabolic enhancement effects.

Recently, an increasing number of studies have shifted focus to the metabolic-improvement effects of FGF-21 beyond enhancing insulin sensitivity, such as promoting adipose tissue thermogenesis, reducing food intake, and alleviating oxidative stress in metabolism-related tissues.^20,21 In our research, we further analyzed the serum levels of FGF-21 in patients with metabolic syndrome. FGF-21, a metabolic-protective signaling regulatory protein, is secreted by the liver, adipose tissue, skeletal muscle, and islets, thereby enhancing the insulin sensitivity of these organs.²² Moreover, inflammation was shown to hinder the secretion of FGF-21, a metabolic regulatory protein pivotal for enhancing insulin sensitivity and maintaining metabolic homeostasis. By its anti-inflammatory properties, HLJDD could indirectly stimulate the secretion of FGF-21, ultimately enhancing insulin sensitivity and further optimizing the metabolic profile of MS patients.²³ Our study reveals that HLJDD not only modulates immunity but also elevates serum FGF-21 levels in MS patients. This suggests that HLJDD may ameliorate target organ damage by promoting FGF-21 secretion, an effect potentially attributable to the anti-inflammatory properties of HLJDD.

In this study, we not only confirmed the effectiveness of HLJDD in improving metabolic profiles but also verified the safety of a 3-month HLJDD treatment in patients with metabolic syndrome. These findings provide robust support for the application of HLJDD as a therapeutic formula in the treatment of MS. However, our study establishes that HLJDD enhances both serum FGF-21 levels and the inflammatory state in MS patients, the relationship between the FGF-21 promoting effect and the anti-inflammatory effect of HLJDD warrants further investigation.

In conclusion, a 3-month treatment with HLJDD proves beneficial in enhancing the metabolic profiles of patients with metabolic syndrome. The potential mechanism may be attributed to the reduction of chronic inflammation and the consequent promotion of FGF-21 secretion.

5. SUPPORTING INFORMATION

Supporting data to this article can be found online at http://www.journaltcm.com.

Funding Statement

Supported by Subject of Academic Priority Discipline of Jiangsu Higher Education Institutions: Clinical and Basic Research on the Regulation of Glucose and Lipid Metabolism by Traditional Chinese Medicine (No. ZYX03KF058); Postgraduate Research & Practice Innovation Program of Jiangsu Province: Mechanism of Huanglian Jiedu Decoction in Promoting Adipose Tissue Browning to Improve Insulin Resistance (No. KYCX21_1659)