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Background <p>Insulin resistance (IR) is a key component of type 2 diabetes mellitus and other metabolic disorders. Persistent hyperglycemia impairs insulin signaling and mitochondrial function, thereby contributing to IR progression. Ginsenoside Rf (G-Rf), a bioactive component of <i>Panax ginseng</i> (ginseng), possesses various pharmacological properties. However, its role in glucose metabolism under IR conditions remains largely unexplored.</p> Methods <p>High-glucose and insulin treatment was used to induce IR in AML12 hepatocytes. G-Rf cytotoxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays. Glucose metabolism was evaluated by measuring glucose consumption and Glut2 expression. Western blot analysis and real-time quantitative polymerase chain reaction were used to analyze the key proteins in the IRS1/PI3K/Akt and PPARα/PGC1α signaling pathways. Mitochondrial function was assessed through mitochondrial DNA (mtDNA) quantification and intracellular adenosine triphosphate (ATP) measurements. In parallel, liquid chromatography–mass spectrometry (LC–MS) analysis was conducted to quantify the G-Rf content in mature and sprouted ginseng.</p> Results <p>No cytotoxicity was observed at G-Rf concentrations up to 10&#xa0;µM. G-Rf treatment significantly improved glucose uptake and Glut2 expression in IR-AML12 cells and restored IRS1 phosphorylation, PI3K expression, and activation of downstream Akt/GSK-3β signaling, promoting glycogen synthesis. Moreover, it upregulated PPARα and PGC1α expression and increased mtDNA content and ATP production, indicating improved mitochondrial function. LC–MS/MS analysis revealed that mature and sprouted ginseng contained G-Rf, with higher concentrations in underground parts. Importantly, substantial G-Rf levels were found in the edible aerial parts of sprouted ginseng.</p> Conclusion <p>G-Rf improves glucose metabolism in IR hepatocytes by activating the IRS1/PI3K/Akt and PPARα/PGC1α signaling pathways and enhancing mitochondrial function. Thus, G-Rf is a promising candidate for the dietary or therapeutic management of IR. Furthermore, sprouted ginseng may serve as a sustainable source of G-Rf, supporting its application as a functional food.</p>

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Ginsenoside Rf improves glucose metabolism via the IRS/PI3K/Akt and PPARα/PGC1α signaling pathways in insulin-resistant AML12 cells

  • 期刊论文

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  • 发表日期：

    2025年9月30日

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  • Seulmin Hong,
  • Jangho Lee,
  • Sang Yoon Choi,
  • Jae-Ho Park,
  • Yu Geon Lee

摘要

Background

Insulin resistance (IR) is a key component of type 2 diabetes mellitus and other metabolic disorders. Persistent hyperglycemia impairs insulin signaling and mitochondrial function, thereby contributing to IR progression. Ginsenoside Rf (G-Rf), a bioactive component of Panax ginseng (ginseng), possesses various pharmacological properties. However, its role in glucose metabolism under IR conditions remains largely unexplored.

Methods

High-glucose and insulin treatment was used to induce IR in AML12 hepatocytes. G-Rf cytotoxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays. Glucose metabolism was evaluated by measuring glucose consumption and Glut2 expression. Western blot analysis and real-time quantitative polymerase chain reaction were used to analyze the key proteins in the IRS1/PI3K/Akt and PPARα/PGC1α signaling pathways. Mitochondrial function was assessed through mitochondrial DNA (mtDNA) quantification and intracellular adenosine triphosphate (ATP) measurements. In parallel, liquid chromatography–mass spectrometry (LC–MS) analysis was conducted to quantify the G-Rf content in mature and sprouted ginseng.

Results

No cytotoxicity was observed at G-Rf concentrations up to 10 µM. G-Rf treatment significantly improved glucose uptake and Glut2 expression in IR-AML12 cells and restored IRS1 phosphorylation, PI3K expression, and activation of downstream Akt/GSK-3β signaling, promoting glycogen synthesis. Moreover, it upregulated PPARα and PGC1α expression and increased mtDNA content and ATP production, indicating improved mitochondrial function. LC–MS/MS analysis revealed that mature and sprouted ginseng contained G-Rf, with higher concentrations in underground parts. Importantly, substantial G-Rf levels were found in the edible aerial parts of sprouted ginseng.

Conclusion

G-Rf improves glucose metabolism in IR hepatocytes by activating the IRS1/PI3K/Akt and PPARα/PGC1α signaling pathways and enhancing mitochondrial function. Thus, G-Rf is a promising candidate for the dietary or therapeutic management of IR. Furthermore, sprouted ginseng may serve as a sustainable source of G-Rf, supporting its application as a functional food.