Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state

Journal of Clinical Investigation

Volumn 120, Issue 7, 2010, Pages 2355-2369

  Foretz, Marc ^a   Hébrard, Sophie ^a   Leclerc, Jocelyne ^a   Zarrinpashneh, Elham ^b   Soty, Maud ^c,d,e   Mithieux, Gilles ^c,d,e   Sakamoto, Kei ^b   Andreelli, Fabrizio ^a,f   Viollet, Benoit ^a  

^a INSTITUT COCHIN   (France)

^b UNIVERSITY OF DUNDEE   (United Kingdom)

^c INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE   (France)

^d UNIVERSITÉ DE LYON   (France)

^e UNIVERSITÉ LYON 1   (France)

^f BICHAT HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; DRUG VEHICLE; GLUCOSE; GLUCOSE 6 PHOSPHATASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; LIVER ENZYME; METFORMIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PHOSPHOENOLPYRUVATE CARBOXYKINASE (GTP); PROTEIN KINASE LKB1; ANTIDIABETIC AGENT; PHOSPHOENOLPYRUVATE CARBOXYKINASE (ATP); PROTEIN SERINE THREONINE KINASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG MECHANISM; ENZYME ACTIVE SITE; GENE EXPRESSION; GENE OVEREXPRESSION; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; HYPERGLYCEMIA; HYPOGLYCEMIA; LIVER CELL; MALE; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; WILD TYPE; ANIMAL; BIOSYNTHESIS; C57BL MOUSE; DRUG EFFECT; GENETICS; LIVER; METABOLISM; MOUSE MUTANT; UPREGULATION;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; DIABETES MELLITUS, TYPE 2; GLUCONEOGENESIS; GLUCOSE; GLUCOSE-6-PHOSPHATASE; HEPATOCYTES; HYPERGLYCEMIA; HYPOGLYCEMIC AGENTS; LIVER; METFORMIN; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; PHOSPHOENOLPYRUVATE CARBOXYKINASE (ATP); PROTEIN-SERINE-THREONINE KINASES; UP-REGULATION;

EID: 77954933558     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI40671     Document Type: Article

References (66)

1. Rotella CM, Monami M, Mannucci E. Metformin beyond diabetes: new life for an old drug. Curr Diabetes Rev. 2006;2(3):307-315.
2. Crandall JP, et al. The prevention of type 2 diabetes. Nat Clin Pract Endocrinol Metab. 2008;4(7):382-393.
3. Klip A, Leiter LA. Cellular mechanism of action of metformin. Diabetes Care. 1990;13(6):696-704.
4. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574-579.
5. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137(1):25-33.
6. Hundal RS, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49(12):2063-2069.
7. Shu Y, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117(5):1422-1431.
8. Zhou G, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-1174.
9. Musi N, et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51(7):2074-2081.
10. Shaw RJ, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642-1646.
11. Hardie DG. AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol. 2007;47:185-210.
12. Viollet B, et al. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol (Oxf). 2009;196(1):81-98.
13. Hawley SA, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2(4):28.
14. Shaw RJ, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A. 2004;101(10):3329-3335.
15. Woods A, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13(22):2004-2008. (Pubitemid 37425212)
16. Hawley SA, et al. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005; 2(1):9-19.
17. Woods A, et al. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005; 2(1):21-33.
18. Koo SH, et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005;437(7062):1109-1111.
19. Dentin R, et al. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature. 2007; 449(7160):366-369.
20. Horike N, et al. AMP-activated protein kinase activation increases phosphorylation of glycogen synthase kinase 3beta and thereby reduces cAMP-responsive element transcriptional activity and phosphoenolpyruvate carboxykinase C gene expression in the liver. J Biol Chem. 2008;283(49):33902- 33910.
21. Jansson D, Ng AC, Fu A, Depatie C, Al Azzabi M, Screaton RA. Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. Proc Natl Acad Sci U S A. 2008;105(29):10161-10166.
22. He L, et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell. 2009;137(4):635-646.
23. Lizcano JM, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004;23(4):833-843.
24. Sakamoto K, Goransson O, Hardie DG, Alessi DR. Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am J Physiol Endocrinol Metab. 2004;287(2):E310-E317.
25. Sum CF, Webster JM, Johnson AB, Catalano C, Cooper BG, Taylor R. The effect of intravenous metformin on glucose metabolism during hyperglycaemia in type 2 diabetes. Diabet Med. 1992;9(1):61-65.
26. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24(1):49-57.
27. Wilcock C, Wyre ND, Bailey CJ. Subcellular distribution of metformin in rat liver. J Pharm Pharmacol. 1991;43(6):442-444.
28. Yin W, Mu J, Birnbaum MJ. Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis In 3T3-L1 adipocytes. J Biol Chem. 2003; 278(44):43074-43080.
29. Guigas B, et al. 5-Aminoimidazole-4-carboxamide- 1-{beta}-d- ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation. Diabetes. 2006;55(4):865-874.
30. Wilcock C, Bailey CJ. Sites of metformin-stimulated glucose metabolism. Biochem Pharmacol. 1990;39(11):1831-1834.
31. Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-aminoimidazole-4- carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem. 1995; 229(2):558-565.
32. Cool B, et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 2006;3(6):403-416.
33. Goransson O, et al. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem. 2007;282(45):32549- 32560.
34. Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J. 2007;403(1):139-148. (Pubitemid 46569875)
35. Scott JW, et al. Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes. Chem Biol. 2008; 15(11):1220-1230.
36. Guigas B, et al. Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators. IUBMB Life. 2009;61(1):18-26.
37. El-Mir MY, Nogueira V, Fontaine E, Averet 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(1):223-228.
38. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(pt 3):607-614.
39. Bryla J, Harris EJ, Plumb JA. The stimulatory effect of glucagon and dibutyryl cyclic AMP on ureogenesis and gluconeogenesis in relation to the mitochondrial ATP content. FEBS Lett. 1977;80(2):443-448.
40. Guigas B, et al. AMP-activated protein kinase-independent inhibition of hepatic mitochondrial oxidative phosphorylation by AICA riboside. Biochem J. 2007;404(3):499-507.
41. Sakamoto K, et al. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 2005;24(10):1810-1820.
42. Mithieux G, Guignot L, Bordet JC, Wiernsperger N. Intrahepatic mechanisms underlying the effect of metformin in decreasing basal glucose production in rats fed a high-fat diet. Diabetes. 2002;51(1):139-143.
43. Argaud D, Roth H, Wiernsperger N, Leverve XM. Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur J Biochem. 1993;213(3):1341-1348.
44. Zong H, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002;99(25):15983-15987.
45. Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337-342.
46. Owen MR, Halestrap AP. The mechanisms by which mild respiratory chain inhibitors inhibit hepatic gluconeogenesis. Biochim Biophys Acta. 1993; 1142(1-2):11-22.
47. Pryor HJ, Smyth JE, Quinlan PT, Halestrap AP. 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(2):449-457.
48. Burgess SC, et al. Diminished hepatic gluconeogenesis via defects in tricarboxylic acid cycle flux in peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)-deficient mice. J Biol Chem. 2006;281(28):19000-19008.
49. Bandsma RH, et al. Hepatic de novo synthesis of glucose 6-phosphate is not affected in peroxisome proliferator-activated receptor alpha-deficient mice but is preferentially directed toward hepatic glycogen stores after a short term fast. J Biol Chem. 2004; 279(10):8930-8937.
50. Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes. 1991;40(10):1259-1266.
51. Mukhtar MH, et al. Inhibition of glucokinase translocation by AMP-activated protein kinase is associated with phosphorylation of both GKRP and 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase. Am J Physiol Regul Integr Comp Physiol. 2008;294(3):R766-R774.
52. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000; 6(9):998-1003.
53. Raso GM, et al. Comparative therapeutic effects of metformin and vitamin E in a model of non-alcoholic steatohepatitis in the young rat. Eur J Pharmacol. 2009;604(1-3):125-131.
54. Zang M, et al. AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J Biol Chem. 2004;279(46):47898-47905.
55. Viollet B, et al. Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J Physiol. 2006;574(pt 1):41-53.
56. Qiu BY, et al. High-throughput assay for modulators of mitochondrial membrane potential identifies a novel compound with beneficial effects on db/db mice. Diabetes. 2010;59(1):256-265.
57. Turner N, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes. 2008;57(5):1414-1418.
58. Viollet B, et al. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J Clin Invest. 2003;111(1):91-98.
59. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A. 1998;95(5):2509-2514.
60. Benhamouche S, et al. Apc tumor suppressor gene is the "zonation-keeper" of mouse liver. Dev Cell. 2006;10(6):759-770.
61. Foretz M, Guichard C, Ferre P, Foufelle F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci U S A. 1999;96(22):12737-12742.
62. Berry MN, Friend DS. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol. 1969;43(3):506-520.
63. Foretz M, Carling D, Guichard C, Ferre P, Foufelle F. AMP-activated protein kinase inhibits the glucoseactivated expression of fatty acid synthase gene in rat hepatocytes. J Biol Chem. 1998;273(24):14767-14771.
64. Atkinson DE, Walton GM. Adenosine triphosphate conservation in metabolic regulation. Rat liver citrate cleavage enzyme. J Biol Chem. 1967; 242(13):3239-3241.
65. Rajas F, Jourdan-Pineau H, Stefanutti A, Mrad EA, Iynedjian PB, Mithieux G. Immunocytochemical localization of glucose 6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase in gluconeogenic tissues reveals unsuspected metabolic zonation. Histochem Cell Biol. 2007;127(5):555-565.
66. Sakamoto K, et al. Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha1. Am J Physiol Endocrinol Metab. 2006;290(5):E780-E788.