The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective

Loranne Agius, Brian E Ford, Shruti S Chachra, Loranne Agius, Brian E Ford, Shruti S Chachra

Abstract

Metformin therapy lowers blood glucose in type 2 diabetes by targeting various pathways including hepatic gluconeogenesis. Despite widespread clinical use of metformin the molecular mechanisms by which it inhibits gluconeogenesis either acutely through allosteric and covalent mechanisms or chronically through changes in gene expression remain debated. Proposed mechanisms include: inhibition of Complex 1; activation of AMPK; and mechanisms independent of both Complex 1 inhibition and AMPK. The activation of AMPK by metformin could be consequent to Complex 1 inhibition and raised AMP through the canonical adenine nucleotide pathway or alternatively by activation of the lysosomal AMPK pool by other mechanisms involving the aldolase substrate fructose 1,6-bisphosphate or perturbations in the lysosomal membrane. Here we review current interpretations of the effects of metformin on hepatic intermediates of the gluconeogenic and glycolytic pathway and the candidate mechanistic links to regulation of gluconeogenesis. In conditions of either glucose excess or gluconeogenic substrate excess, metformin lowers hexose monophosphates by mechanisms that are independent of AMPK-activation and most likely mediated by allosteric activation of phosphofructokinase-1 and/or inhibition of fructose bisphosphatase-1. The metabolite changes caused by metformin may also have a prominent role in counteracting G6pc gene regulation in conditions of compromised intracellular homeostasis.

Keywords: AMPK; Liver metabolism; gluconeogenesis; metformin; phosphofructokinase-1.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Crossover plots of metabolites of gluconeogenesis and glycolysis in liver or isolated hepatocytes. (A) Effects of AICAR (500 μM) in hepatocytes incubated with 10 mM lactate + 1 mM pyruvate [61]. (B) Effects of mitochondrial inhibitors (DCMU, dichlorophenyl dimethylurea) [69] or phenformin [70], in rat hepatocytes incubated with 10 mM lactate + 1 mM pyruvate (red) or effects of metformin on rat liver in vivo [6] (blue).
Figure 1
Figure 1
Liver concentrations of intermediates of glycolysis and gluconeogenesis. (A) Metabolic intermediates of glycolysis and gluconeogenesis. (B) Concentrations of key metabolites in rat liver in the fed and fasted state; data from Bergmeyer, HU [52]). (C,D) Liver metabolites in fed and fasted rats treated with glucose (2 g/kg, 10 min) or glucagon (1 mg/kg, 2 min); data from [53,54]. (E) Effects of 1 mM oleate on metabolites in hepatocytes from fasted rats, data from [55]. (F) Rat liver metabolites in rested and exercised rats, data from [56]. * p < 0.05 fasted vs. fed
Figure 3
Figure 3
Metabolic pathways linked to glycerol 3-P formation in liver. G3P is generated from glycerol phosphorylation by glycerokinase or from DHAP, an intermediate of glycolysis and gluconeogenesis by cGPD, which catalyses the reversible NADH/NAD linked interconversion of DHAP and G3P; mGPD on the outer surface of the mitochondrial innermembrane catalyses irreversible oxidation of G3P coupled to the transfer of electrons to ubiquinone in the respiratory chain.

References

    1. Sanchez-Rangel E., Inzucchi S.E. Metformin: Clinical use in type 2 diabetes. Diabetologia. 2017;60:1586–1593. doi: 10.1007/s00125-017-4336-x.
    1. Natali A., Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: A systematic review. Diabetologia. 2006;49:434–441. doi: 10.1007/s00125-006-0141-7.
    1. Zhou G., Myers R., Li Y., Chen Y., Shen X., Fenyk-Melody J., Wu M., Ventre J., Doebber T., Fujii N., et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Investig. 2001;108:1167–1174. doi: 10.1172/JCI13505.
    1. He L., Wondisford F.E. Metformin action: Concentrations matter. Cell Metab. 2015;21:159–162. doi: 10.1016/j.cmet.2015.01.003.
    1. El-Mir M.Y., Nogueira V., Fontaine E., Avéret N., Rigoulet M., Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 2000;275:223–228. doi: 10.1074/jbc.275.1.223.
    1. Owen M.R., Doran E., Halestrap A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 2000;348:607–614. doi: 10.1042/bj3480607.
    1. Bridges H.R., Jones A.J., Pollak M.N., Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 2014;462:475–487. doi: 10.1042/BJ20140620.
    1. Hardie D.G., Schaffer B.E., Brunet A. AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs. Trends Cell Biol. 2016;26:190–201. doi: 10.1016/j.tcb.2015.10.013.
    1. Lin S.C., Hardie D.G. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab. 2018;27:299–313. doi: 10.1016/j.cmet.2017.10.009.
    1. Carling D., Clarke P.R., Zammit V.A., Hardie D.G. Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities. Eur. J. Biochem. 1989;186:129–136. doi: 10.1111/j.1432-1033.1989.tb15186.x.
    1. Foretz M., Hébrard S., Leclerc J., Zarrinpashneh E., Soty M., Mithieux G., Sakamoto K., Andreelli F., Viollet B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/ AMPK pathway via a decrease in hepatic energy state. J. Clin. Investig. 2010;120:2355–2369. doi: 10.1172/JCI40671.
    1. Zhang C.S., Hawley S.A., Zong Y., Li M., Wang Z., Gray A., Ma T., Cui J., Feng J.W., Zhu M., et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature. 2017;548:112–116. doi: 10.1038/nature23275.
    1. Li M., Zhang C.S., Zong Y., Feng J.W., Ma T., Hu M., Lin Z., Li X., Xie C., Wu Y., et al. Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK. Cell Metab. 2019;30:508–524. doi: 10.1016/j.cmet.2019.05.018.
    1. Zong Y., Zhang C.S., Li M., Wang W., Wang Z., Hawley S.A., Ma T., Feng J.W., Tian X., Qi Q., et al. Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress. Cell Res. 2019;29:460–473. doi: 10.1038/s41422-019-0163-6.
    1. Woods A., Johnstone S.R., Dickerson K., Leiper F.C., Fryer L.G., Neumann D., Schlattner U., Wallimann T., Carlson M., Carling D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 2003;13:2004–2008. doi: 10.1016/j.cub.2003.10.031.
    1. Hawley S.A., Pan D.A., Mustard K.J., Ross L., Bain J., Edelman A.M., Frenguelli B.G., Hardie D.G. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005;2:9–19. doi: 10.1016/j.cmet.2005.05.009.
    1. Woods A., Dickerson K., Heath R., Hong S.P., Momcilovic M., Johnstone S.R., Carlson M., Carling D. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005;2:21–33. doi: 10.1016/j.cmet.2005.06.005.
    1. Göransson O., McBride A., Hawley S.A., Ross F.A., Shpiro N., Foretz M., Viollet B., Hardie D.G., Sakamoto K. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J. Biol. Chem. 2007;282:32549–32560. doi: 10.1074/jbc.M706536200.
    1. Ubl J.J., Chen S., Stucki J.W. Anti-diabetic biguanides inhibit hormone-induced intracellular Ca2+ concentration oscillations in rat hepatocytes. Biochem. J. 1994;304:561–567. doi: 10.1042/bj3040561.
    1. Neumann D. Is TAK1 a Direct Upstream Kinase of AMPK? Int. J. Mol. Sci. 2018;19:2412. doi: 10.3390/ijms19082412.
    1. Jia J., Abudu Y.P., Claude-Taupin A., Gu Y., Kumar S., Choi S.W., Peters R., Mudd M.H., Allers L., Salemi M., et al. Galectins Control mTOR in Response to Endomembrane Damage. Mol. Cell. 2018;70:120–135. doi: 10.1016/j.molcel.2018.03.009.
    1. Jia J., Bissa B., Brecht L., Allers L., Choi S.W., Gu Y., Zbinden M., Burge M.R., Timmins G., Hallows K., et al. AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System. Mol. Cell. 2020;77:951–969. doi: 10.1016/j.molcel.2019.12.028.
    1. Inokuchi-Shimizu S., Park E.J., Roh Y.S., Yang L., Zhang B., Song J., Liang S., Pimienta M., Taniguchi K., Wu X., et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J. Clin. Investig. 2014;124:3566–3578. doi: 10.1172/JCI74068.
    1. Oakhill J.S., Steel R., Chen Z.P., Scott J.W., Ling N., Tam S., Kemp B.E. AMPK is a direct adenylate charge-regulated protein kinase. Science. 2011;332:1433–1435. doi: 10.1126/science.1200094.
    1. Ross F.A., Jensen T.E., Hardie D.G. Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem. J. 2016;473:189–199. doi: 10.1042/BJ20150910.
    1. Xiao B., Sanders M.J., Underwood E., Heath R., Mayer F.V., Carmena D., Jing C., Walker P.A., Eccleston J.F., Haire L.F., et al. Structure of mammalian AMPK and its regulation by ADP. Nature. 2011;472:230–233. doi: 10.1038/nature09932.
    1. Salt I., Celler J.W., Hawley S.A., Prescott A., Woods A., Carling D., Hardie D.G. AMP-activated protein kinase: Greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. Biochem. J. 1998;334:177–187. doi: 10.1042/bj3340177.
    1. Carroll B., Dunlop E.A. The lysosome: A crucial hub for AMPK and mTORC1 signalling. Biochem. J. 2017;474:1453–1466. doi: 10.1042/BCJ20160780.
    1. Herzig S., Shaw R.J. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 2018;19:121–135. doi: 10.1038/nrm.2017.95.
    1. Ford R.J., Fullerton M.D., Pinkosky S.L., Day E.A., Scott J.W., Oakhill J.S., Bujak A.L., Smith B.K., Crane J.D., Blümer R.M., et al. Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochem. J. 2015;468:125–132. doi: 10.1042/BJ20150125.
    1. Toyama E.Q., Herzig S., Courchet J., Lewis T.L., Jr., Losón O.C., Hellberg K., Young N.P., Chen H., Polleux F., Chan D.C., et al. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science. 2016;351:275–281. doi: 10.1126/science.aab4138.
    1. Assifi M.M., Suchankova G., Constant S., Prentki M., Saha A.K., Ruderman N.B. AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats. Am. J. Physiol. Endocrinol. Metab. 2005;289:E794–E800. doi: 10.1152/ajpendo.00144.2005.
    1. Huet C., Boudaba N., Guigas B., Viollet B., Foretz M. Glucose availability but not changes in pancreatic hormones sensitizes hepatic AMPK activity during nutritional transition in rodents. J. Biol. Chem. 2020 doi: 10.1074/jbc.RA119.010244.
    1. You M., Matsumoto M., Pacold C.M., Cho W.K., Crabb D.W. The role of AMP-activated protein kinase in the action of ethanol in the liver. Gastroenterology. 2004;127:1798–1808. doi: 10.1053/j.gastro.2004.09.049.
    1. Liangpunsakul S., Sozio M.S., Shin E., Zhao Z., Xu Y., Ross R.A., Zeng Y., Crabb D.W. Inhibitory effect of ethanol on AMPK phosphorylation is mediated in part through elevated ceramide levels. Am. J. Physiol. Gastrointest. Liver Physiol. 2010;298:G1004–G1012. doi: 10.1152/ajpgi.00482.2009.
    1. Agius L. Hormonal and Metabolite Regulation of Hepatic Glucokinase. Annu. Rev. Nutr. 2016;36:389–415. doi: 10.1146/annurev-nutr-071715-051145.
    1. Droppelmann C.A., Sáez D.E., Asenjo J.L., Yáñez A.J., García-Rocha M., Concha I.I., Grez M., Guinovart J.J., Slebe J.C. A new level of regulation in gluconeogenesis: Metabolic state modulates the intracellular localization of aldolase B and its interaction with liver fructose-1,6-bisphosphatase. Biochem. J. 2015;472:225–237. doi: 10.1042/BJ20150269.
    1. Stephenne X., Foretz M., Taleux N., van der Zon G.C., Sokal E., Hue L., Viollet B., Guigas B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia. 2011;54:3101–3110. doi: 10.1007/s00125-011-2311-5.
    1. Hou W.L., Yin J., Alimujiang M., Yu X.Y., Ai L.G., Bao Y.Q., Liu F., Jia W.P. Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPKactivation. J. Cell. Mol. Med. 2018;22:1316–1328.
    1. Ota S., Horigome K., Ishii T., Nakai M., Hayashi K., Kawamura T., Kishino A., Taiji M., Kimura T. Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. Biochem. Biophys. Res. Commun. 2009;388:311–316. doi: 10.1016/j.bbrc.2009.07.164.
    1. Bridges H.R., Sirviö V.A., Agip A.N., Hirst J. Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase. BMC Biol. 2016;14:65. doi: 10.1186/s12915-016-0287-9.
    1. Seo B.B., Wang J., Flotte T.R., Yagi T., Matsuno-Yagi A. Use of the NADH-quinone oxidoreductase (NDI1) gene of Saccharomyces cerevisiae as a possible cure for complex I defects in human cells. J. Biol. Chem. 2000;275:37774–37778. doi: 10.1074/jbc.M007033200.
    1. Zhang C.S., Li M., Ma T., Zong Y., Cui J., Feng J.W., Wu Y.Q., Lin S.Y., Lin S.C. Metformin Activates AMPK through the Lysosomal Pathway. Cell Metab. 2016;24:521–522. doi: 10.1016/j.cmet.2016.09.003.
    1. Wilcock C., Wyre N.D., Bailey C.J. Subcellular distribution of metformin in rat liver. J. Pharm. Pharmacol. 1991;43:442–444. doi: 10.1111/j.2042-7158.1991.tb03507.x.
    1. Sweeney D., Raymer M.L., Lockwood T.D. Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents. Biochem. Pharmacol. 2003;66:663–677. doi: 10.1016/S0006-2952(03)00338-1.
    1. Xiao B., Sanders M.J., Carmena D., Bright N.J., Haire L.F., Underwood E., Patel B.R., Heath R.B., Walker P.A., Hallen S., et al. Structural basis of AMPK regulation by small molecule activators. Nat. Commun. 2013;4:3017. doi: 10.1038/ncomms4017.
    1. Rajamohan F., Reyes A.R., Frisbie R.K., Hoth L.R., Sahasrabudhe P., Magyar R., Landro J.A., Withka J.M., Caspers N.L., Calabrese M.F., et al. Probing the enzyme kinetics, allosteric modulation and activation of α1- and α2-subunit-containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators. Biochem. J. 2016;473:581–592. doi: 10.1042/BJ20151051.
    1. Hunter R.W., Foretz M., Bultot L., Fullerton M.D., Deak M., Ross F.A., Hawley S.A., Shpiro N., Viollet B., Barron D., et al. Mechanism of action of compound-13: An α1-selective small molecule activator of AMPK. Chem. Biol. 2014;21:866–879. doi: 10.1016/j.chembiol.2014.05.014.
    1. Moonira T., Chachra S.S., Ford B.E., Marin S., Alshawi A., Adam-Primus N.S., Arden C., Al-Oanzi Z.H., Foretz M., Viollet B., et al. Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation. J Biol Chem. 2020;295:3330–3346. doi: 10.1074/jbc.RA120.012533.
    1. Alshawi A., Agius L. Low metformin causes a more oxidized mitochondrial NADH/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism. J. Biol. Chem. 2019;294:2839–2853. doi: 10.1074/jbc.RA118.006670.
    1. Agius L. Dietary carbohydrate and control of hepatic gene expression: Mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein. Proc. Nutr. Soc. 2016;75:10–18. doi: 10.1017/S0029665115002451.
    1. Bergmeyer H.U. Methods in Enzymatic Analysis, Concentrations of Metabolites in Animal Tissues. Volume 4. Verla Chemie; Weinheim, Germany: 1974. pp. 2267–2279.
    1. Van Schaftingen E., Hue L., Hers H.G. Study of the fructose 6-phosphate/fructose 1,6-bi-phosphate cycle in the liver in vivo. Biochem. J. 1980;192:263–271. doi: 10.1042/bj1920263.
    1. Bartrons R., Hue L., Van Schaftingen E., Hers H.G. Hormonal control of fructose 2,6-bisphosphate concentration in isolated rat hepatocytes. Biochem. J. 1983;214:829–837. doi: 10.1042/bj2140829.
    1. Ochs R.S., Harris R.A. Mechanism for the oleate stimulation of gluconeogenesis from dihydroxyacetone by hepatocytes from fasted rats. Biochim. Biophys. Acta. 1986;886:40–47. doi: 10.1016/0167-4889(86)90209-0.
    1. Jenkins C.M., Yang J., Sims H.F., Gross R.W. Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA: A mechanism integrating glycolytic flux with lipid metabolism. J. Biol. Chem. 2011;286:11937–11950. doi: 10.1074/jbc.M110.203661.
    1. Dohm G.L., Newsholme E.A. Metabolic control of hepatic gluconeogenesis during exercise. Biochem. J. 1983;212:633–639. doi: 10.1042/bj2120633.
    1. Hers H.G., Hue L. Gluconeogenesis and related aspects of glycolysis. Annu. Rev. Biochem. 1983;52:617–653. doi: 10.1146/annurev.bi.52.070183.003153.
    1. Hue L. Role of fructose 2,6-bisphosphate in the stimulation of glycolysis by anoxia in isolated hepatocytes. Biochem. J. 1982;206:359–365. doi: 10.1042/bj2060359.
    1. Al-Oanzi Z.H., Fountana S., Moonira T., Tudhope S.J., Petrie J.L., Alshawi A., Patman G., Arden C., Reeves H.L., Agius L. Opposite effects of a glucokinase activator and metformin on glucose-regulated gene expression in hepatocytes. Diabetes Obes. Metab. 2017;19:1078–1087. doi: 10.1111/dom.12910.
    1. Vincent M.F., Marangos P.J., Gruber H.E., Van den Berghe G. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes. 1991;40:1259–1266. doi: 10.2337/diab.40.10.1259.
    1. Hue L., Bartrons R. Role of fructose 2,6-bisphosphate in the control by glucagon of gluconeogenesis from various precursors in isolated rat hepatocytes. Biochem. J. 1984;218:165–170. doi: 10.1042/bj2180165.
    1. Vincent M.F., Bontemps F., Van den Berghe G. Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes. Biochem. J. 1992;281:267–272. doi: 10.1042/bj2810267.
    1. Javaux F., Vincent M.F., Wagner D.R., van den Berghe G. Cell-type specificity of inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside. Lack of effect in rabbit cardiomyocytes and human erythrocytes, and inhibition in FTO-2B rat hepatoma cells. Biochem. J. 1995;305:913–919. doi: 10.1042/bj3050913.
    1. Hasenour C.M., Ridley D.E., Hughey C.C., James F.D., Donahue E.P., Shearer J., Viollet B., Foretz M., Wasserman D.H. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J. Biol. Chem. 2014;289:5950–5959. doi: 10.1074/jbc.M113.528232.
    1. Chappell J.B. The effect of alkylguanidines on mitochondrial metabolism. J. Biol. Chem. 1963;238:410–417.
    1. Davidoff F. Effects of guanidine derivatives on mitochondrial function. 3. The mechanism of phenethylbiguanide accumulation and its relationship to in vitro respiratory inhibition. J. Biol. Chem. 1971;246:4017–4027.
    1. Pryor H.J., Smyth J.E., Quinlan P.T., Halestrap A.P. Evidence that the flux control coefficient of the respiratory chain is high during gluconeogenesis from lactate in hepatocytes from starved rats. Implications for the hormonal control of gluconeogenesis and action of hypoglycaemic agents. Biochem. J. 1987;247:449–457. doi: 10.1042/bj2470449.
    1. Owen M.R., Halestrap A.P. The mechanisms by which mild respiratory chain inhibitors inhibit hepatic gluconeogenesis. Biochim. Biophys. Acta. 1993;1142:11–22. doi: 10.1016/0005-2728(93)90079-U.
    1. Cook D.E., Blair J.B., Gilfillan C., Lardy H.A. Mode of action of hypoglycemic agents. IV. Control of the hypoglycemic activity of phenethylbiguanide in rats and guinea-pigs. Biochem. Pharmacol. 1973;22:2121–2128. doi: 10.1016/0006-2952(73)90111-1.
    1. Ballard F.J. The development of gluconeogenesis in rat liver. Controlling factors in the newborn. Biochem. J. 1971;124:265–274. doi: 10.1042/bj1240265.
    1. Hunter R.W., Hughey C.C., Lantier L., Sundelin E.I., Peggie M., Zeqiraj E., Sicheri F., Jessen N., Wasserman D.H., Sakamoto K. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat. Med. 2018;24:1395–1406. doi: 10.1038/s41591-018-0159-7.
    1. Williamson D.H., Lund P., Krebs H.A. The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem. J. 1967;103:514–527. doi: 10.1042/bj1030514.
    1. Fulgencio J.P., Kohl C., Girard J., Pégorier J.P. Effect of metformin on fatty acid and glucose metabolism in freshly isolated hepatocytes and on specific gene expression in cultured hepatocytes. Biochem. Pharmacol. 2001;62:439–446. doi: 10.1016/S0006-2952(01)00679-7.
    1. Gouaref I., Detaille D., Wiernsperger N., Khan N.A., Leverve X., Koceir E.A. The desert gerbil Psammomys obesus as a model for metformin-sensitive nutritional type 2 diabetes to protect hepatocellular metabolic damage: Impact of mitochondrial redox state. PLoS ONE. 2017;12:e0172053. doi: 10.1371/journal.pone.0172053.
    1. Wilcock C., Bailey C.J. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24:49–57. doi: 10.3109/00498259409043220.
    1. Wang Y., An H., Liu T., Qin C., Sesaki H., Guo S., Radovick S., Hussain M., Maheshwari A., Wondisford F.E., et al. Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK. Cell Rep. 2019;29:1511–1523. doi: 10.1016/j.celrep.2019.09.070.
    1. Kanamura S., Kanai K., Oka M., Watanabe J., Asada-Kubota M. Development of morphologic heterogeneity of hepatocyte mitochondria in the mouse. Anat. Rec. 1984;210:315–325. doi: 10.1002/ar.1092100206.
    1. Madiraju A.K., Erion D.M., Rahimi Y., Zhang X.M., Braddock D.T., Albright R.A., Prigaro B.J., Wood J.L., Bhanot S., MacDonald M.J., et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510:542–546. doi: 10.1038/nature13270.
    1. Madiraju A.K., Qiu Y., Perry R.J., Rahimi Y., Zhang X.M., Zhang D., Camporez J.G., Cline G.W., Butrico G.M., Kemp B.E., et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat. Med. 2018;24:1384–1394. doi: 10.1038/s41591-018-0125-4.
    1. Qi H., Nielsen P.M., Schroeder M., Bertelsen L.B., Palm F., Laustsen C. Acute renal metabolic effect of metformin assessed with hyperpolarised MRI in rats. Diabetologia. 2018;61:445–454. doi: 10.1007/s00125-017-4445-6.
    1. von Morze C., Ohliger M.A., Marco-Rius I., Wilson D.M., Flavell R.R., Pearce D., Vigneron D.B., Kurhanewicz J., Wang Z.J. Direct assessment of renal mitochondrial redox state using hyperpolarized (13) C-acetoacetate. Magn. Reson. Med. 2018;79:1862–1869. doi: 10.1002/mrm.27054.
    1. Mráček T., Drahota Z., Houštěk J. The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues. Biochim. Biophys. Acta. 2013;1827:401–410. doi: 10.1016/j.bbabio.2012.11.014.
    1. Pecinova A., Drahota Z., Kovalcikova J., Kovarova N., Pecina P., Alan L., Zima M., Houstek J., Mracek T. Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production. Oxid. Med. Cell. Longev. 2017;2017:7038603. doi: 10.1155/2017/7038603.
    1. Macdonald M.J., Israr-ul A., Longacre M., Stoker S. If Metformin Inhibited the Mitochondrial Glycerol Phosphate Dehydrogenase It Might Not Benefit Diabetes. BioRxiv. 2020 doi: 10.1101/2020.03.28.013334.
    1. Cameron A.R., Logie L., Patel K., Erhardt S., Bacon S., Middleton P., Harthill J., Forteath C., Coats J.T., Kerr C., et al. Metformin selectively targets redox control of complex I energy transduction. Redox Biol. 2018;14:187–197. doi: 10.1016/j.redox.2017.08.018.
    1. Batandier C., Guigas B., Detaille D., El-Mir M.Y., Fontaine E., Rigoulet M., Leverve X.M. The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J. Bioenerg. Biomembr. 2006;38:33–42. doi: 10.1007/s10863-006-9003-8.
    1. Kane D.A., Anderson E.J., Price J.W., 3rd, Woodlief T.L., Lin C.T., Bikman B.T., Cortright R.N., Neufer P.D. Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic. Biol. Med. 2010;49:1082–1087. doi: 10.1016/j.freeradbiomed.2010.06.022.
    1. Robb E.L., Hall A.R., Prime T.A., Eaton S., Szibor M., Viscomi C., James A.M., Murphy M.P. Control of mitochondrial superoxide production by reverse electron transport at complex I. J. Biol. Chem. 2018;293:9869–9879. doi: 10.1074/jbc.RA118.003647.
    1. Lewis A.J., Miller J.J., McCallum C., Rider O.J., Neubauer S., Heather L.C., Tyler D.J. Assessment of Metformin-Induced Changes in Cardiac and Hepatic Redox State Using Hyperpolarized[1-13C]Pyruvate. Diabetes. 2016;65:3544–3551. doi: 10.2337/db16-0804.
    1. Baur J.A., Birnbaum M.J. Control of gluconeogenesis by metformin: Does redox trump energy charge? Cell Metab. 2014;20:197–199. doi: 10.1016/j.cmet.2014.07.013.
    1. Saheki T., Iijima M., Li M.X., Kobayashi K., Horiuchi M., Ushikai M., Okumura F., Meng X.J., Inoue I., Tajima A., et al. Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency. J. Biol. Chem. 2007;282:25041–25052. doi: 10.1074/jbc.M702031200.
    1. Davis E.J., Bremer J., Akerman K.E. Thermodynamic aspects of translocation of reducing equivalents by mitochondria. J. Biol. Chem. 1980;255:2277–2283.
    1. Sibille B., Keriel C., Fontaine E., Catelloni F., Rigoulet M., Leverve X.M. Octanoate affects 2,4-dinitrophenol uncoupling in intact isolated rat hepatocytes. Eur. J. Biochem. 1995;231:498–502. doi: 10.1111/j.1432-1033.1995.tb20724.x.
    1. Dykens J.A., Jamieson J., Marroquin L., Nadanaciva S., Billis P.A., Will Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharmacol. 2008;233:203–210. doi: 10.1016/j.taap.2008.08.013.
    1. Argaud D., Roth H., Wiernsperger N., Leverve X.M. Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur. J. Biochem. 1993;213:1341–1348. doi: 10.1111/j.1432-1033.1993.tb17886.x.
    1. Van Schaftingen E., Bartrons R., Hers H.G. The mechanism by which ethanol decreases the concentration of fructose 2,6-bisphosphate in the liver. Biochem. J. 1984;222:511–518. doi: 10.1042/bj2220511.
    1. Woods H.F., Eggleston L.V., Krebs H.A. The cause of hepatic accumulation of fructose 1-phosphate on fructose loading. Biochem. J. 1970;119:501–510. doi: 10.1042/bj1190501.
    1. Woods H.F., Krebs H.A. Xylitol metabolism in the isolated perfused rat liver. Biochem. J. 1973;134:437–443. doi: 10.1042/bj1340437.
    1. Calza G., Nyberg E., Mäkinen M., Soliymani R., Cascone A., Lindholm D., Barborini E., Baumann M., Lalowski M., Eriksson O. Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration—A Mass Spectrometry Imaging Study of the Perfused Rat Liver. Front. Pharmacol. 2018;9:141. doi: 10.3389/fphar.2018.00141.
    1. Glossmann H.H., Lutz O.M.D. Commentary: Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration-A Mass Spectrometry Imaging Study of the Perfused Rat Liver. Front. Pharmacol. 2019;10:90. doi: 10.3389/fphar.2019.00090.
    1. Miller R.A., Chu Q., Xie J., Foretz M., Viollet B., Birnbaum M.J. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494:256–260. doi: 10.1038/nature11808.
    1. Sum C.F., Webster J.M., Johnson A.B., Catalano C., Cooper B.G., Taylor R. The effect of intravenous metformin on glucose metabolism during hyperglycaemia in type 2 diabetes. Diabet. Med. 1992;9:61–65. doi: 10.1111/j.1464-5491.1992.tb01716.x.
    1. Heishi M., Ichihara J., Teramoto R., Itakura Y., Hayashi K., Ishikawa H., Gomi H., Sakai J., Kanaoka M., Taiji M., et al. Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin. Diabetologia. 2006;49:1647–1655. doi: 10.1007/s00125-006-0271-y.
    1. Cao J., Meng S., Chang E., Beckwith-Fickas K., Xiong L., Cole R.N., Radovick S., Wondisford F.E., He L. Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activatedprotein kinase (AMPK) J. Biol. Chem. 2014;289:20435–20446. doi: 10.1074/jbc.M114.567271.
    1. Rada P., Mosquera A., Muntané J., Ferrandiz F., Rodriguez-Mañas L., de Pablo F., González-Canudas J., Valverde Á.M. Differential effects of metformin glycinate and hydrochloride in glucose production, AMPK phosphorylation and insulin sensitivity in hepatocytes from non-diabetic and diabetic mice. Food Chem. Toxicol. 2019;123:470–480. doi: 10.1016/j.fct.2018.11.019.
    1. Woods A., Williams J.R., Muckett P.J., Mayer F.V., Liljevald M., Bohlooly-Y M., Carling D. Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet. Cell Rep. 2017;18:3043–3051. doi: 10.1016/j.celrep.2017.03.011.
    1. Johanns M., Lai Y.C., Hsu M.F., Jacobs R., Vertommen D., Van Sande J., Dumont J.E., Woods A., Carling D., Hue L., et al. AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B. Nat. Commun. 2016;7:10856. doi: 10.1038/ncomms10856.
    1. Ma L., Robinson L.N., Towle H.C. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J. Biol. Chem. 2006;281:28721–28730. doi: 10.1074/jbc.M601576200.
    1. Arden C., Petrie J.L., Tudhope S.J., Al-Oanzi Z., Claydon A.J., Beynon R.J., Towle H.C., Agius L. Elevated glucose represses liver glucokinase and induces its regulatory protein to safeguard hepatic phosphate homeostasis. Diabetes. 2011;60:3110–3120. doi: 10.2337/db11-0061.
    1. Arden C., Tudhope S.J., Petrie J.L., Al-Oanzi Z.H., Cullen K.S., Lange A.J., Towle H.C., Agius L. Fructose 2,6-bisphosphate is essential for glucose-regulated gene transcription of glucose-6-phosphatase and other ChREBP target genes in hepatocytes. Biochem. J. 2012;443:111–123. doi: 10.1042/BJ20111280.
    1. Mattila J., Havula E., Suominen E., Teesalu M., Surakka I., Hynynen R., Kilpinen H., Väänänen J., Hovatta I., Käkelä R., et al. Mondo-Mlx Mediates Organismal Sugar Sensing through the Gli-Similar Transcription Factor Sugarbabe. Cell Rep. 2015;13:350–364. doi: 10.1016/j.celrep.2015.08.081.
    1. Sato S., Jung H., Nakagawa T., Pawlosky R., Takeshima T., Lee W.R., Sakiyama H., Laxman S., Wynn R.M., Tu B.P., et al. Metabolite Regulation of Nuclear Localization of Carbohydrate-responseElement-binding Protein (ChREBP): ROLE OF AMP AS AN ALLOSTERIC INHIBITOR. J. Biol. Chem. 2016;291:10515–10527. doi: 10.1074/jbc.M115.708982.
    1. Grefhorst A., Schreurs M., Oosterveer M.H., Cortés V.A., Havinga R., Herling A.W., Reijngoud D.J., Groen A.K., Kuipers F. Carbohydrate-response-element-binding protein (ChREBP) and not the liver X receptor α (LXRα) mediates elevated hepatic lipogenic gene expression in a mouse model of glycogen storage disease type 1. Biochem. J. 2010;432:249–254. doi: 10.1042/BJ20101225.
    1. Kalemba K.M., Wang Y., Xu H., Chiles E., McMillin S.M., Kwon H., Su X., Wondisford F.E. Glycerol induces G6pc in primary mouse hepatocytes and is the preferred substrate for gluconeogenesis both in vitro and in vivo. J. Biol. Chem. 2019;294:18017–18028. doi: 10.1074/jbc.RA119.011033.
    1. McCreight L.J., Mari A., Coppin L., Jackson N., Umpleby A.M., Pearson E.R. Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals. Diabetologia. 2020;63:444–447. doi: 10.1007/s00125-019-05042-1.
    1. Gormsen L.C., Søndergaard E., Christensen N.L., Brøsen K., Jessen N., Nielsen S. Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes. Diabetologia. 2019;62:1251–1256. doi: 10.1007/s00125-019-4872-7.

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