Metformin modulates insulin receptor signaling in normal and cholesterol-treated human hepatoma cells (HepG2)
- PMID: 10456437
- DOI: 10.1016/s0014-2999(99)00386-6
Metformin modulates insulin receptor signaling in normal and cholesterol-treated human hepatoma cells (HepG2)
Abstract
The effects of the biguanide anti-hyperglycemic agent, metformin (N,N'-dimethyl-biguanide), on insulin signaling was studied in a human hepatoma cell line (HepG2). Cells were cultured in the absence (control cells) or in the presence of 100 microM of a cholesterol derivative, hemisuccinate of cholesterol. Cholesterol hemisuccinate-treatment alters cholesterol and lipid content of HepG2 and modulates membrane fluidity. Cholesterol hemisuccinate-treatment induces a decrease in insulin responsiveness and creates an 'insulin-resistant' state in these cells. Exposure to 100 microM of metformin resulted in a significant enhancement of insulin-stimulated lipogenesis in control and cholesterol hemisuccinate-treated cells. In control cells, metformin altered glycogenesis in a biphasic manner. In cholesterol hemisuccinate-treated cells, metformin inhibited basal glycogenesis but restored insulin-stimulated glycogenesis. Hence, to understand the mechanism of metformin action, we analyzed early steps in the insulin signaling pathway, including insulin receptor autophosphorylation, mitogen-activated-protein kinase and phosphatidylinositol 3-kinase activities, in both control and cholesterol hemisuccinate-treated cells. Overall, the results suggest that metformin may interact with the insulin receptor and/or a component involved in the early steps of insulin signal transduction.
Similar articles
-
Metformin modulates insulin post-receptor signaling transduction in chronically insulin-treated Hep G2 cells.Acta Pharmacol Sin. 2003 Jan;24(1):55-60. Acta Pharmacol Sin. 2003. PMID: 12511230
-
Incorporation of exogenous lipids modulates insulin signaling in the hepatoma cell line, HepG2.Biochim Biophys Acta. 1999 May 31;1454(1):38-48. doi: 10.1016/s0925-4439(99)00023-x. Biochim Biophys Acta. 1999. PMID: 10354513
-
Metformin enhances insulin signalling in insulin-dependent and-independent pathways in insulin resistant muscle cells.Br J Pharmacol. 2002 Oct;137(3):329-36. doi: 10.1038/sj.bjp.0704878. Br J Pharmacol. 2002. PMID: 12237252 Free PMC article.
-
Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes.Diabetes Metab. 1999 Jun;25(2):110-27. Diabetes Metab. 1999. PMID: 10443322 Review.
-
[Molecular action of insulin-sensitizing agents].Endokrynol Pol. 2005 May-Jun;56(3):308-13. Endokrynol Pol. 2005. PMID: 16350724 Review. Polish.
Cited by
-
Metformin inhibits cardiometabolic syndrome associated cognitive deficits in high fat diet rats.J Diabetes Metab Disord. 2022 Jul 18;21(2):1415-1426. doi: 10.1007/s40200-022-01074-4. eCollection 2022 Dec. J Diabetes Metab Disord. 2022. PMID: 36404813 Free PMC article.
-
Selection of Small Molecules that Bind to and Activate the Insulin Receptor from a DNA-Encoded Library of Natural Products.iScience. 2020 Jun 26;23(6):101197. doi: 10.1016/j.isci.2020.101197. Epub 2020 May 23. iScience. 2020. PMID: 32544667 Free PMC article.
-
Evidence-based prioritisation and enrichment of genes interacting with metformin in type 2 diabetes.Diabetologia. 2017 Nov;60(11):2231-2239. doi: 10.1007/s00125-017-4404-2. Epub 2017 Aug 25. Diabetologia. 2017. PMID: 28842730 Free PMC article.
-
Contextual inhibition of fatty acid synthesis by metformin involves glucose-derived acetyl-CoA and cholesterol in pancreatic tumor cells.Metabolomics. 2014;10(1):91-104. doi: 10.1007/s11306-013-0555-4. Epub 2013 Jun 26. Metabolomics. 2014. PMID: 24482631 Free PMC article.
-
Metformin regulates glucose transporter 4 (GLUT4) translocation through AMP-activated protein kinase (AMPK)-mediated Cbl/CAP signaling in 3T3-L1 preadipocyte cells.J Biol Chem. 2012 Dec 28;287(53):44121-9. doi: 10.1074/jbc.M112.361386. Epub 2012 Nov 7. J Biol Chem. 2012. PMID: 23135276 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical