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. 2024 Nov 13:2024:1518080.
doi: 10.1155/2024/1518080. eCollection 2024.

Total Water-Soluble Flavonoids From Lithocarpus litseifolius (Hance) Chun (Sweet Tea) Improve Glucose Homeostasis Through Multitarget Signalling in GDM Mice

Junfei Xu  1 , Fenfang Zhang  1 , Huanhuan Li  1 , Pan Li  1 , Junying Zeng  1 , Xianjin Wu  1 , Rong Zhou  1 , Chunyan Yang  2 , Juzuo Zhang  1
Affiliations

Total Water-Soluble Flavonoids From Lithocarpus litseifolius (Hance) Chun (Sweet Tea) Improve Glucose Homeostasis Through Multitarget Signalling in GDM Mice

Junfei Xu et al. J Diabetes Res. .

Abstract

Background: The oral safety of Lithocarpus litseifolius (Hance) Chun (sweet tea) that has antihyperglycemic potential has been verified. However, its specific application and action mechanism in the treatment of gestational diabetes mellitus (GDM) are still unclear. Methods: Total water-soluble flavonoids extracted from L. litseifolius (Hance) Chun (sweet tea) were applied to GDM mice. The glucose tolerance, insulin sensitivity, and histopathology of the GDM mice were evaluated through an intraperitoneal glucose tolerance test (IPGTT), an intraperitoneal insulin tolerance test (IPITT), and histochemistry. The possible mechanism was analysed through network pharmacology. Results: Compared with those in GDM model mice (MD group), blood glucose levels indicating both glucose tolerance and insulin sensitivity were improved in GDM mice treated with total water-soluble flavonoids (LLHC group) but were greater than those in normal control mice (NC group). The number of apoptotic liver cells was significantly lower in the LLHC group than in the MD group, but greater than that in the NC group. Multiple targets and signalling pathways that were acted by eight main active ingredients were involved in the process by which total water-soluble flavonoids protect against GDM. The main mechanism involved quercetin (10 targets) and luteolin (8 targets), which acted on the effector target of GAA through six main signalling pathways around the AKT1 core axis. Conclusion: Oral administration of total water-soluble flavonoids can alleviate glucose intolerance and insulin resistance via the inhibition of liver cell apoptosis. The main active ingredients act on GAA through the signalling pathways of the AKT1 core axis.

Keywords: GDM; glucose homeostasis; multiple targets; total water–soluble flavonoids.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Oral administration of total water-soluble flavonoids alleviated glucose intolerance and insulin resistance in GDM mice. (a) Flow chart of the development and intervention of the GDM mouse model. (b) Changes in mouse body weight during pregnancy. (c) Blood glucose in the IPGTT before intervention with total water-soluble flavonoids (n = 5). (d) Blood glucose in the IPITT before intervention with total water-soluble flavonoids (n = 5). (e) Blood glucose in the IPGTT after intervention with total water-soluble flavonoids (n = 5). (f) Blood glucose in the IPITT after intervention with total water-soluble flavonoids (n = 5). (g) Litter sizes of fetuses at GD19 through dissection. (h) Placental efficiency (fetal weight/placental weight). (i) RBC count from routine blood tests. (j) WBC count from routine blood tests. (k) PLT count from routine blood tests. Different capital letters indicate highly significant differences (p < 0.01). Different lowercase letters indicate significant differences (p < 0.05). LLHC: Lithocarpus litseifolius (Hance) Chun; GDM: gestational diabetes mellitus; HFD: high-fat diet; STZ: induction and streptozocin; NC: normal control; MD: model; IPGTT: intraperitoneal glucose tolerance test; IPITT: intraperitoneal insulin tolerance test; RBC: red blood cell; WBC: white blood cell; PLT: platelet.
Figure 2
Figure 2
Oral administration of total water-soluble flavonoids inhibited liver cell apoptosis to improve glucose homeostasis in GDM mice. (a) Heart weight. (b) Liver weight. (c) Spleen weight. (d) Lung weight. (e) Kidney weight. (f) Liver indices (liver weight/body weight). (g) Number of inflammatory cells per 85908.44 μm2. (h) Ratios of the steatotic area of the liver sections. (i) Ratios of the ballooning area of the liver sections. (j) Ratio of apoptotic cells (%). (k) H&E and TUNEL staining of liver sections. Different capital letters indicate highly significant differences (p < 0.01). Different lowercase letters indicate significant differences (p < 0.05). LLHC: Lithocarpus litseifolius (Hance) Chun; GDM: gestational diabetes mellitus; NC: normal control; MD: model; H&E: hematoxylin–eosin; TUNEL: terminal deoxyribonucleotidyl transferase (TDT)–mediated dUTP–digoxigenin nick end labelling.
Figure 3
Figure 3
Multiple targets were involved in the process by which total water-soluble flavonoids protect against GDM. (a) The targets of GDM and the active ingredients identified in the GeneCards and OMIM databases, the Swiss Target Prediction System, and the communicative targets were screened through the Venny 2.1 platform. (b) The interaction network of GDM, active ingredients, and communicative targets was constructed with the Network Analyser of Cytoscape 3.10.1 software. (c) The interaction relationships of the targets were determined through the interaction database platform String 12.0. (d) The interaction relationships of the Top 20 scores (2.69e + 08) ranked by the MCC method.
Figure 4
Figure 4
The interactions between the core targets and active ingredients were confirmed by molecular docking and visualization. (a) Heatmap analysis of minimum binding energy of the molecular docking fraction. (b) Docking poses and interaction of INSR with luteolin-7-O-β-glucoside. (c) Docking poses and interactions of IGF1R with quercetin. (d) Docking poses and interactions of EGFR with quercetin. (e) Docking poses and interactions of AKT1 with luteolin-7-O-β-glucoside. (f) Docking poses and interactions of GSK3β with quercetin. (g) Docking poses and interactions of MMP2 with luteolin. (h) Docking poses and interactions of MMP9 with luteolin. (i) Docking poses and interactions of GAA with quercetin.
Figure 5
Figure 5
Total water-soluble flavonoids were deduced to improve glucose homeostasis in GDM through 6 main signalling pathways around the AKT1 core axis. (a) The signalling pathways associated with the main anti-GDM components were analysed and visualized by GO enrichment. (b) The signalling pathways of the main anti-GDM components were analysed and visualized via KEGG enrichment. (c) In the process of total water-soluble flavonoids improving GDM glucose homeostasis, quercetin affects AKT1, EGFR, SRC, MMP9, IGF1R, PARP1, GSK3B, MMP2, KDR, and ESRS. Luteolin affects AKT1, EGFR, SRC, ESR1, IGF1R, GSK3B, IGF1R, KDR, and ESR2.
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References

    1. Sudasinghe B. H., Wijeyaratne C. N., Ginige P. S. Long and short-term outcomes of gestational diabetes mellitus (GDM) among South Asian women - a community-based study. Diabetes Research and Clinical Practice . 2018;145:93–101. doi: 10.1016/j.diabres.2018.04.013. - DOI - PubMed
    1. Murray S. R., Reynolds R. M. Short- and long-term outcomes of gestational diabetes and its treatment on fetal development. Prenatal Diagnosis . 2020;40(9):1085–1091. doi: 10.1002/pd.5768. - DOI - PubMed
    1. 15. Management of diabetes in pregnancy:standards of care in diabetes-2024. Diabetes Care . 2024;47(Supplement_1):S282–S294. doi: 10.2337/dc24-S015. - DOI - PMC - PubMed
    1. Kuhl C. Insulin secretion and insulin resistance in pregnancy and GDM: implications for diagnosis and management. Diabetes . 1991;40(Supplement_2):18–24. doi: 10.2337/diab.40.2.S18. - DOI - PubMed
    1. Landi S. N., Radke S., Engel S. M., et al. Association of long-term child growth and developmental outcomes with metformin vs insulin treatment for gestational diabetes. JAMA Pediatrics . 2019;173(2):160–168. doi: 10.1001/jamapediatrics.2018.4214. - DOI - PMC - PubMed

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