Efficacy of Xiaokeqing granules and lifestyle intervention in treating prediabetes mellitus considering metabolomic biomarkers: A randomised controlled trial

doi:10.4239/wjd.v16.i7.105219

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World Journal of Diabetes

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World J Diabetes. Jul 15, 2025; 16(7): 105219
Published online Jul 15, 2025. doi: 10.4239/wjd.v16.i7.105219

Table 1 Comparison of the baseline characteristics, mean ± SD

Variables	Con group (n = 20, ITT analysis)	Con group (n = 17, PP analysis)	XQG group (n = 20, ITT or PP analysis)
Sex (male/female)	8/12	7/10	5/15
Age (year)	51.10 ± 10.88	52.65 ± 10.52	51.65 ± 12.56
DD (month)	52.25 ± 53.32	56.18 ± 56.39	33.55 ± 33.35
BMI (kg/m²)	23.15 ± 3.09	23.06 ± 3.24	23.64 ± 4.08
SBP (mmHg)	120.85 ± 12.71	120.18 ± 13.50	119.30 ± 15.20
DBP (mmHg)	77.50 ± 8.68	76.65 ± 8.93	79.05 ± 8.74
FPG (mmol/L)	6.48 ± 0.47	6.48 ± 0.49	6.26 ± 0.47
2hPG (mmol/L)	10.20 ± 3.34	10.42 ± 3.51	9.71 ± 2.03
HbA1c (%)	5.97 ± 0.48	5.95 ± 0.31	5.92 ± 0.33
FINS (μIU/mL)	9.23 ± 4.90	9.52 ± 5.27	15.07 ± 12.46
HOMA-IR	2.67 ± 1.47	2.76 ± 1.59	4.15 ± 3.28
ALT (TU/L)	22.15 ± 9.90	23.22 ± 10.22	26.76 ± 17.52
AST (U/L)	21.83 ± 4.43	22.29 ± 4.62	24.99 ± 7.44
BUN (mg/dL)	5.03 ± 1.20	5.19 ± 1.22	5.61 ± 0.96
Cr (mg/dL)	61.50 ± 10.60	61.14 ± 10.85	64.46 ± 15.71

BMI: Body mass index; DD: Disease duration; 2hPG: 2-hour postprandial glucose; HbA1c: Glycated haemoglobin A1c; FINS: Fasting insulin; HOMA-IR: Homeostasis model assessment-insulin resistance; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; Cr: Creatinine; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; Con: Control; XQG: Xiaokeqing granule; ITT: Intention-to-treat; PP: Per-protocol; FPG: Fasting plasma glucose.

Table 2 Comparison of blood glucose and related indicators, mean ± SD

Variables	Con group (ITT analysis)			Con group (PP analysis)			XQG group (ITT or PP analysis)
Variables	Baseline (n = 20)	Follow-up 1 (n = 20)	Follow-up 2 (n = 20)	Baseline (n = 17)	Follow-up 1 (n = 17)	Follow-up 2 (n = 17)	Baseline (n = 20)	Follow-up 1 (n = 20)	Follow-up 2 (n = 20)
FPG (mmol/L)	6.48 ± 0.47	6.61 ± 0.66	6.47 ± 0.74	6.48 ± 0.49	6.63 ± 0.69	6.46 ± 0.78	6.26 ± 0.47	6.25 ± 0.73	6.09 ± 0.64
2hPG (mmol/L)	10.20 ± 3.34	9.69 ± 2.54	9.77 ± 2.71	10.42 ± 3.51	9.83 ± 2.45	9.93 ± 2.65	9.71 ± 2.03	9.68 ± 2.73	7.98 ± 2.17^a^,¹^,²
HbA1c (%)	5.97 ± 0.48	NA	6.14 ± 0.64	5.95 ± 0.31	NA	6.15 ± 0.56	5.92 ± 0.33	NA	5.84 ± 0.29^a^,²
FINS (μIU/mL)	9.23 ± 4.90	NA	9.97 ± 7.80	9.52 ± 5.27	NA	10.40 ± 8.41	15.07 ± 12.46	NA	14.05 ± 14.49
HOMA-IR	2.67 ± 1.47	NA	2.86 ± 2.27	2.76 ± 1.59	NA	2.98 ± 2.45	4.15 ± 3.28	NA	3.78 ± 3.88
BMI (kg/m²)	23.15 ± 3.09	NA	23.01 ± 3.20	23.06 ± 3.24	NA	22.89 ± 3.35	23.64 ± 4.08	NA	23.16 ± 3.83
SBP (mmHg)	120.85 ± 12.71	NA	119.80 ± 9.65	120.18 ± 13.50	NA	119.47 ± 10.43	119.30 ± 15.20	NA	120.40 ± 12.05
DBP (mmHg)	77.50 ± 8.68	NA	78.95 ± 9.77	76.65 ± 8.93	NA	79.29 ± 10.35	79.05 ± 8.74	NA	77.65 ± 7.20

^aP < 0.05.

¹P vs control group (intention-to-treat analysis).

²P vs control group (per-protocol analysis).

Con: Control; XQG: Xiaokeqing granule; ITT: Intention-to-treat; PP: Per-protocol; FPG: Fasting plasma glucose; 2hPG: 2-hour postprandial glucose; HbA1c: Glycated haemoglobin A1c; FINS: Fasting insulin; HOMA-IR: Homeostasis model assessment-insulin resistance; BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; NA: Not analyzed.

Table 3 Adverse events comparison, n (%)

Group	Number of participants number (ITT or PP analysis)	Number of AE
Con group	20/17	0 (0)
XQG group	20/20	2 (10.0)

Con: Control; XQG: Xiaokeqing granule; ITT: Intention-to-treat; PP: Per-protocol; AE: Adverse events.

Table 4 Comparison of liver and renal function, mean ± SD

Variables	Con group (ITT analysis)		Con group (PP analysis)		XQG group (ITT or PP analysis)
Variables	Baseline (n = 20)	Follow-up 2 (n = 20)	Baseline (n = 17)	Follow-up 2 (n = 17)	Baseline (n = 20)	Follow-up 2 (n = 20)
ALT (U/L)	22.15 ± 9.90	23.61 ± 18.73	23.22 ± 10.22	24.94 ± 20.01	26.76 ± 17.52	26.65 ± 18.95
AST (U/L)	21.83 ± 4.43	23.01 ± 8.30	22.29 ± 4.62	23.68 ± 8.85	24.99 ± 7.44	26.94 ± 14.01
BUN (mmol/L)	5.03 ± 1.20	5.18 ± 1.49	5.19 ± 1.22	5.37 ± 1.54	5.61 ± 0.96	5.66 ± 1.32
Cr (μmol/L)	61.50 ± 10.60	59.70 ± 9.81	61.14 ± 10.85	59.02 ± 9.80	64.46 ± 15.71	63.84 ± 15.24

Con: Control; XQG: Xiaokeqing granule; ITT: Intention-to-treat; PP: Per-protocol; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; Cr: Creatinine.

Table 5 Comparison of the dropout rates, n (%)

Group	Participants (n)	Dropped out
Con group	20	3 (15.0)
XQG group	20	0 (0)

Con: Control; XQG: Xiaokeqing granule.

Table 6 Metabolite and Kyoto Encyclopedia of Genes and Genomes pathways

Metabolite	KEGG pathway description
5-Hydroxy-L-Tryptophan	Tryptophan metabolism
L-Formyl kynurenine	Tryptophan metabolism, Biosynthesis of cofactors
2,3,4,5-tetrahydro-2-pyridinecarboxylic acid	Lysine degradation
N6-Acetyl-L-Lysine	Lysine degradation
Phenethylamine glucuronide	Biosynthesis of cofactors
3-Methyl-2-oxobutanoic acid	Pantothenate and CoA biosynthesis, Biosynthesis of cofactors
3-Methylindole	Tryptophan metabolism
4’-Phosphopantothenoylcysteine	Pantothenate and CoA biosynthesis, Biosynthesis of cofactors

KEGG: Kyoto Encyclopedia of Genes and Genomes; CoA: Certificate of analysis.

Table 7 Evaluation index table of the total feature model

Method	Kappa	F1	Precision	Recall	Accuracy
Random forest	0.7843	0.8889	0.8421	0.9412	0.8919
LASSO	0.6667	0.8333	0.8333	0.8333	0.8333

LASSO: Least absolute shrinkage and selection operator.

Table 8 Metabolite features of least absolute shrinkage and selection operator regression analysis

Feature	Coefficient
Dimethylformamide	-0.36107
5-Hydroxy-L-Tryptophan	10.6295
Lanthionine ketimine	0.750093
5-Nitro-2-phenylpropylaminobenzoic acid	0.214502
Tyr Leu	0.242158
N-Nervonoyl methionine	12.02622
Calcitroic acid	4.998331
Valylasparagine	1.677792
4-Epitetracycline	0.702722
Naringenin 7-sulfate	0.512388
Stearoyllactic acid	-1.58267
N-Oleoyl glutamine	2.505959
1-Nitro-7-glutathionyl-8-hydroxy-7,8-dihydronaphthalene	0.374231
2-(5-carboxypentanoylamino) benzoic acid	0.332139
Flurenol	0.023748

Table 9 Common targets of Xiaokeqing granule constituents and core metabolomic biomarkers

Targets	Targets	Targets
HTR2B	EGFR	MTNR1A
HTR1A	GRIA1	MTNR1B
HTR2C	ADORA3	MMP3
IDO1	SLC6A3	ITGB1
SLC6A4	MIF	PTPN1
DRD3	FAAH	SIRT2
HTR5A	TRPV1	BACE1

Citation: Zhao JD, Guo MZ, Zhang Y, Zhu SH, Wang YT, Zhang YP, Liu X, Cheng S, Wang F, Xu Q, Ruan NB, Fang ZH. Efficacy of Xiaokeqing granules and lifestyle intervention in treating prediabetes mellitus considering metabolomic biomarkers: A randomised controlled trial. World J Diabetes 2025; 16(7): 105219
URL: https://www.wjgnet.com/1948-9358/full/v16/i7/105219.htm
DOI: https://dx.doi.org/10.4239/wjd.v16.i7.105219