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Cited by 92Natural Antidiabetic Agents StudiesMetabolism, Diabetes, and CancerBioactive natural compounds

Carpachromene Ameliorates Insulin Resistance in HepG2 Cells via Modulating IR/IRS1/PI3k/Akt/GSK3/FoxO1 Pathway

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Alaaeldin, Rania, Abdel-Rahman, Iman A. M., Hassan, Heba Ali, Youssef, Nancy, Allam, Ahmed E., Abdelwahab, Sayed F., Zhao, Qing-Li, Fathy, Moustafa·2021·Molecules
DOI 10.3390/molecules26247629PMC PMC8708443
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Abstract

Insulin resistance contributes to several disorders including type 2 diabetes and cardiovascular diseases. Carpachromene is a natural active compound that inhibits α-glucosidase enzyme. The aim of the present study is to investigate the potential activity of carpachromene on glucose consumption, metabolism and insulin signalling in a HepG2 cells insulin resistant model. A HepG2 insulin resistant cell model (HepG2/IRM) was established. Cell viability assay of HepG2/IRM cells was performed after carpachromene/metformin treatment. Glucose concentration and glycogen content were determined. Western blot analysis of insulin receptor, IRS1, IRS2, PI3k, Akt, GSK3, FoxO1 proteins after carpachromene treatment was performed. Phosphoenolpyruvate carboxykinase (PEPCK) and hexokinase (HK) enzymes activity was also estimated. Viability of HepG2/IRM cells was over 90% after carpachromene treatment at concentrations 6.3, 10, and 20 µg/mL. Treatment of HepG2/IRM cells with carpachromene decreased glucose concentration in a concentration- and time-dependant manner. In addition, carpachromene increased glycogen content of HepG2/IRM cells. Moreover, carpachromene treatment of HepG2/IRM cells significantly increased the expression of phosphorylated/total ratios of IR, IRS1, PI3K, Akt, GSK3, and FoxO1 proteins. Furthermore, PEPCK enzyme activity was significantly decreased, and HK enzyme activity was significantly increased after carpachromene treatment. The present study examined, for the first time, the potential antidiabetic activity of carpachromene on a biochemical and molecular basis. It increased the expression ratio of insulin receptor and IRS1 which further phosphorylated/activated PI3K/Akt pathway and phosphorylated/inhibited GSK3 and FoxO1 proteins. Our findings revealed that carpachromene showed central molecular regulation of glucose metabolism and insulin signalling via IR/IRS1/ PI3K/Akt/GSK3/FoxO1 pathway.

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  • HepG2 cells are characterized by reduced sensitivity to insulin (insulin resistance) under TNFα, high glucose, or prolonged insulin stimulation, with reduced phosphorylation of IR, IRS-1, and Akt, leading to impaired insulin-stimulated glucose uptake and glycogen synthesis.

    “HepG2 cells are characterized by reduced sensitivity to insulin (insulin resistance), which has been demonstrated in numerous studies using models induced by tumor necrosis factor-α (TNFα), high glucose concentrations, or prolonged insulin stimulation [119,120,121].”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [120]

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References 48 · Cited by 92

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Authors
Alaaeldin, R., Abdel-Rahman, I. A. M., Hassan, H. A., Youssef, N., Allam, A. E., Abdelwahab, S. F., Zhao, Q.-L., & Fathy, M.
Affiliations
  • Deraya University (EG)
  • South Valley University (EG)
  • Sohag University (EG)
  • Minia University (EG)
  • Al-Azhar University (EG)
  • Taif University (SA)
  • University of Toyama (JP)
Corresponding author
  • Zhao, Qing-Li
  • Fathy, Moustafa
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2021-12-16
Volume
26
Issue
24
Pages
7629
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules26247629
PMC
PMC8708443
OpenAlex
W4200259742
Cited by
92
References
48
Citations by year
2026: 9 · 2025: 23 · 2024: 32 · 2023: 19 · 2022: 9
FWCI
11.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • JSPS KAKENHI Grant Number ((JP21K07614))
  • Taif University Researchers Supporting Project Number ((TURSP-2020/51))
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioactive natural compounds
Keywords
insulin resistance, HepG2 cells, insulin receptor, IRS-1, glucose metabolism, glycogen, phosphoenolpyruvate carboxykinase, hexokinase, antidiabetic activity, type 2 diabetes
MeSH terms
Forkhead Box Protein O1, Benzopyrans, Humans, Insulin Resistance, Signal Transduction, Phosphatidylinositol 3-Kinases, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Insulin Receptor Substrate Proteins, Hep G2 Cells

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