Sinapine Modulates Glycogen and Lipid Synthesis via IRS1-PI3K-AKT-GSK3β-GS Pathway in Insulin-Resistant Models - Original Article - Open Access

Sep 29, 2026

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This study investigates how sinapine affects glycogen synthesis and lipid metabolism in insulin-resistant HepG2 cell models and type 2 diabetes mellitus (T2DM) mice. Network pharmacology integrates 288 sinapine targets and 920 insulin-resistance targets to reveal 72 overlapping genes, enriched in an insulin-resistance pathway centered on the IRS1–PI3K–AKT–GSK3β–GS axis. Docking supports binding to pathway nuclear proteins (below −4.0 kcal/mol). Sinapine increases glucose uptake and glycogen synthesis, suppresses lipogenesis, lipid accumulation, and ROS, improves insulin sensitivity, lowers blood glucose, and improves liver histology and serum lipid profiles, outlining a mechanistic basis for nutritional intervention.

LanguageEnglish

CategoryResearch & Report

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Pages12

Reading Time30 min

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Introduction

Materials and Methods

Results

Discussion

Conclusion

Food Science & Nutrition | ORIGINAL ARTICLE OPEN ACCESS
Sinapine Modulates Glycogen and Lipid Synthesis via IRS1–PI3K–AKT–GSK3β–GS Pathway in
Insulin-Resistant Models
Tiancheng Xing1 | Yiling Bai1 | Weijie Wu1 | Ziqi Zhao1 | Hanyu Kong1 | Qianyi Zhang1 | Shuoqi Li1 | Yan Liu2 | Xiaohui Guo1 | Zengli Wang1
1College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China | 2Yingdong Intelligent Technology (Shandong)
Co. Ltd. , Jinan, China
Correspondence: Xiaohui Guo ([guoxiaohui@cau.edu.cn](guoxiaohui@cau.edu.cn)) | Zengli Wang ([wangzengli@cau.edu.cn](wangzengli@cau.edu.cn))
Received: 23 July 2025 | Revised: 21 October 2025 | Accepted: 13 November 2025
Keywords: glycogen synthesis | HepG2 cells | lipid synthesis | sinapine | T2DM | | | --- | --- | | ABSTRACT
This study investigates the effects of sinapine on glycogen synthesis and lipid metabolism in insulin-resistant HepG2 cell models and type 2 diabetes mellitus (T2DM) mice. Network pharmacology analysis integrated 288 potential sinapine targets and 920 insulin resistance-related targets, yielding 72 overlapping genes. KEGG enrichment of these genes identified one significantly enriched insulin resistance pathway, with target mapping concentrated on the IRS1–PI3K–AKT–GSK3β–GS axis, suggesting a key role in promoting hepatic glycogen synthesis. Molecular docking identified these key targets on this signaling pathway, with sinapine showing strong binding affinity to its nuclear proteins (below −4.0kcal/mol) . In vitro, sinapine treatment improved glucose uptake and glycogen synthesis, while reducing lipogenesis, lipid accumulation, and reactive oxygen species (ROS) levels. RT-qPCR and Western blot analyses confirmed that sinapine increases glycogen synthase activity. In T2DM mice, sinapine improved glucose and lipid metabolism, enhanced insulin sensitivity, and reduced blood glucose levels. Additionally, sinapine attenuated weight loss, improved liver index and histology, and regulated serum lipid profiles. Overall, this study reveals the molecular mechanism of sinapine in mitigating insulin resistance via modulation of the IRS1–PI3K–AKT–GSK3β–GS pathway, offering theoretical support for its potential application as a nutritional intervention to improve carbohydrate and lipid metabolism. | | | 1 | Introduction | number of serious complications (Bjornstad et al. 2023) . At the heart of IR is a dysregulation of the insulin signaling path- | | Patients with type 2 diabetes mellitus (T2DM) have meta- | way (Rohm et al. 2022) that impairs the sensitivity of target | | bolic abnormalities (Zheng et al. 2018) in glucose and lipid | organs of insulin, particularly the liver (Saini 2010) . Liver gly- | | homeostasis (Pereira et al. 2021) that are primarily caused | cogen is a highly branched glucose polymer consisting of α - | | by insulin resistance (IR) (Li et al. 2022) and can lead to a | particles formed by a series of interconnected β-particles (Ryu | | Abbreviations: AKT, protein kinase B; CCK-8, Cell Counting Kit-8; DMEM, Dulbecco's Modified Eagle Medium; ERK1/2, extracellular regulated protein kinases; G6Pase, glucose-6-phosphatase; GLUT2, glucose transporter type 2; GLUT4, glucose transporter type 4; GO, Gene Ontology; GS, glycogen synthase; GSK3, glycogen synthase kinase 3; GSK3β, glycogen synthase kinase 3β; HepG2, human hepatocellular carcinomas; INSR, insulin receptor; IR, insulin resistance; IRS, insulin receptor substrates; KEGG, Kyoto Encyclopedia of Genes and Genomes; mTOR, mammalian target of rapamycin; mTORC2, mammalian target of rapamycin complex 2; PDK1, 3-phosphoinositide-dependent protein kinase-1; PEPCK, phosphoenolpyruvate carboxykinase; PI3K, phosphoinositide 3 kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; RT-qPCR, real-time quantitative reverse transcription polymerase chain reaction; Ser, serine; T2DM, type 2 diabetes mellitus; Thr, threonine; Tyr, tyrosine.
Tiancheng Xing an

FAQs

What is the main purpose of this study on sinapine?

To evaluate how sinapine modulates glycogen synthesis and lipid metabolism in insulin-resistant HepG2 cell models and in T2DM mice, and to clarify the underlying molecular mechanism.

Which signaling pathway is highlighted as key in the study?

The IRS1–PI3K–AKT–GSK3β–GS axis is identified as central, supported by network pharmacology enrichment and molecular docking results.

What biological effects does sinapine produce in the models tested?

Sinapine enhances glucose uptake and glycogen synthesis, reduces lipogenesis, lipid accumulation, and ROS levels, increases glycogen synthase activity, and improves glucose and lipid metabolism and insulin sensitivity in T2DM mice.

Sep 29, 2026

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