This Article Full Text Full Text (PDF) A correction has been published Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gunton, J. E. Articles by Baxter, R. C. Search for Related Content PubMed PubMed Citation Articles by Gunton, J. E. Articles by Baxter, R. C.

Metformin Rapidly Increases Insulin Receptor Activation in Human Liver and Signals Preferentially through Insulin-Receptor Substrate-2

Kolling Institute of Medical Research (J.E.G., P.J.D.D., R.C.B.), University of Sydney, Royal North Shore Hospital, St. Leonards, Sydney, New South Wales 2065 Australia; and Graduate School of Agriculture and Life Sciences (S.-I.T.), University of Tokyo, Tokyo 113-8657, Japan

Address all correspondence and requests for reprints to: Jenny E. Gunton, M.D., Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, Sydney, New South Wales 2065, Australia. E-mail: jennyeg{at}hotmail.com.

Metformin decreases endogenous glucose production by the liver. Few studies have examined the effect of metformin on the insulin-signaling pathway in liver models, and none have presented data on the effect in normal human liver. Huh7 human hepatoma cells and primary human hepatocytes were used. Insulin receptor (IR) and IR substrates (IRS)-1 and -2 were assessed by immunoprecipitation and immunoblot. Normal human liver was used to assay IR kinase activity (IR-KA). Tyrphostin AG1024 was used to inhibit IR-KA and examine effects on deoxyglucose uptake. Metformin (1 µg/ml) increased IR tyrosine phosphorylation by 78% (P = 0.0007) in 30 min in human hepatocytes and Huh7 cells and increased IRS-2 but not IRS-1 activation, and the downstream increase in deoxyglucose uptake was mediated via increased translocation of GLUT-1 to the plasma membrane. Metformin did not augment maximal or submaximal insulin-stimulated IR activation. Metformin increased basal IR-KA by 150% (P = 0.0001). AG1024 inhibited metformin-induced IR-ß phosphorylation in a concentration-dependent manner and abolished metformin-induced 2-deoxyglucose uptake. This study demonstrates that the mechanism of action of metformin in liver involves IR activation, followed by selective IRS-2 activation, and increased glucose uptake via increased GLUT-1 translocation. The effect of metformin was completely blocked by an IR inhibitor.

This work was supported by a Postgraduate Medical and Dental Scholarship from the National Health and Medical Research Council of Australia (Grant 008137; to J.E.G.).

Abbreviations: EGP, Endogenous glucose production; GLUT, glucose transporter; IR, insulin receptor; IRS, IR substrates; KA, kinase activity; WGA, wheat germ agglutinin agarose.

This article has been cited by other articles:

				F. Feng, L. Wang, N. Albanese, A. Holmes, and P. Xia Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Attenuates the Action of Insulin in Hepatocytes Endocrinology, April 1, 2008; 149(4): 1505 - 1513. [Abstract] [Full Text] [PDF]

				S.-K. Shields, C. Nicola, and C. Chakraborty Rho Guanosine 5'-Triphosphatases Differentially Regulate Insulin-Like Growth Factor I (IGF-I) Receptor-Dependent and -Independent Actions of IGF-II on Human Trophoblast Migration Endocrinology, October 1, 2007; 148(10): 4906 - 4917. [Abstract] [Full Text] [PDF]

				S. Srinivasan, G. R. Ambler, L. A. Baur, S. P. Garnett, M. Tepsa, F. Yap, G. M. Ward, and C. T. Cowell Randomized, Controlled Trial of Metformin for Obesity and Insulin Resistance in Children and Adolescents: Improvement in Body Composition and Fasting Insulin J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2074 - 2080. [Abstract] [Full Text] [PDF]

				S. S. Y. Chan, S. M. Twigg, S. M. Firth, and R. C. Baxter Insulin-Like Growth Factor Binding Protein-3 Leads to Insulin Resistance in Adipocytes J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6588 - 6595. [Abstract] [Full Text] [PDF]

				D. Ertunc, E.C. Tok, A. Aktas, E.M. Erdal, and S. Dilek The importance of IRS-1 Gly972Arg polymorphism in evaluating the response to metformin treatment in polycystic ovary syndrome Hum. Reprod., May 1, 2005; 20(5): 1207 - 1212. [Abstract] [Full Text] [PDF]

				M. E. Cleasby, N. Dzamko, B. D. Hegarty, G. J. Cooney, E. W. Kraegen, and J.-M. Ye Metformin Prevents the Development of Acute Lipid-Induced Insulin Resistance in the Rat Through Altered Hepatic Signaling Mechanisms Diabetes, December 1, 2004; 53(12): 3258 - 3266. [Abstract] [Full Text] [PDF]

				C. Wilson Hepatitis C Infection and Type 2 Diabetes in American-Indian Women Diabetes Care, September 1, 2004; 27(9): 2116 - 2119. [Abstract] [Full Text] [PDF]

				K. J. Nadeau, J. W. Leitner, I. Gurerich, and B. Draznin Insulin Regulation of Sterol Regulatory Element-binding Protein-1 Expression in L-6 Muscle Cells and 3T3 L1 Adipocytes J. Biol. Chem., August 13, 2004; 279(33): 34380 - 34387. [Abstract] [Full Text] [PDF]