Current understanding of metformin effect on the control of hyperglycemia in diabetes

Journal of Endocrinology

Volumn 228, Issue 3, 2016, Pages R97-R106

  An, Hongying ^a   He, Ling ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Glucose metabolism; Insulin action; Liver; Metabolism

Indexed keywords

ADENOSINE MONOPHOSPHATE DEAMINASE; ADENYLATE KINASE; GLYCEROL 3 PHOSPHATE DEHYDROGENASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; METFORMIN; ANTIDIABETIC AGENT; ENZYME INHIBITOR; GLUCOSE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; INSULIN;

DISEASE CONTROL; DRUG EFFECT; DRUG MECHANISM; ENZYME ACTIVATION; GLUCONEOGENESIS; GLUCOSE METABOLISM; HOMEOSTASIS; HUMAN; HYPERGLYCEMIA; INTESTINE FLORA; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; RESPIRATORY CHAIN; REVIEW; SIGNAL TRANSDUCTION; ANTAGONISTS AND INHIBITORS; DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; LIVER; METABOLISM; PHYSIOLOGY;

AMP-ACTIVATED PROTEIN KINASES; DIABETES MELLITUS, TYPE 2; ENZYME ACTIVATION; ENZYME INHIBITORS; GASTROINTESTINAL MICROBIOME; GLUCONEOGENESIS; GLUCOSE; GLYCEROLPHOSPHATE DEHYDROGENASE; HUMANS; HYPERGLYCEMIA; HYPOGLYCEMIC AGENTS; INSULIN; LIVER; METFORMIN; SIGNAL TRANSDUCTION;

EID: 84975744759     PISSN: 00220795     EISSN: 14796805     Source Type: Journal    
DOI: 10.1530/JOE-15-0447     Document Type: Review

References (74)

1. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J & Karin M 2005 IKK-b links inflammation to obesity-induced insulin resistance. Nature Medicine 11 191-198. (doi:10.1038/nm1185)
2. Backhed F, Manchester JK, Semenkovich CF & Gordon JI 2007 Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. PNAS 104 979-984. (doi:10.1073/pnas.0605374104)
3. Brown MS, Brunschede GY & Goldstein JL 1975 Inactivation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in vitro. An adenine nucleotide-dependent reaction catalyzed by a factor in human fibroblasts. Journal of Biological Chemistry 250 2502-2509.
4. Cacicedo JM, Yagihashi N, Keaney JF, Rudermann NB & Ido Y 2004 AMPK inhibits fatty acid-induced increases in NF-k B transactivation in cultured human umbilical vein endothelial cells. Biochemical and Biophysical Research Communications 324 1204-1209. (doi:10.1016/j.bbrc.2004.09.177)
5. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C et al. 2007 Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56 1761-1772. (doi:10.2337/db06-1491)
6. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM & Burcelin R 2008 Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57 1470-1481. (doi:10.2337/db07-1403)
7. Cao J, Meng SM, Chang E, Beckwith-Fickas K, Xiong LS, Cole RN, Radovick S, Wondisford FE & He L 2014 Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK). Journal of Biological Chemistry 289 20435-20446. (doi:10.1074/jbc.M114.567271)
8. Centers for Disease Control and Prevention 2011 In Diabetes: Successes and Opportunities for Population-Based Prevention and Control At A Glance 2011. Atlanta, GA, USA: Centers for Disease Control and Prevention. (available at: http://www.cdc.gov/nccdphp/publications/aag/pdf/diabetes.pdf)
9. Chen L, Jiao ZH, Zheng LS, Zhang YY, Xie ST, Wang ZX & Wu JW 2009 Structural insight into the autoinhibitionmechanism of AMP-activated protein kinase. Nature 459 1146-U1139. (doi:10.1038/nature08075)
10. Cheng JT, Huang CC, Liu IM, Tzeng TF & Chang CJ 2006 Novel mechanism for plasma glucose-lowering action of metformin in streptozotocininduced diabetic rats. Diabetes 55 819-825. (doi:10.2337/diabetes.55. 03.06.db05-0934)
11. Corton JM, Gillespie JG & Hardie DG 1994 Role of the AMP-activated protein-kinase in the cellular stress-response. Current Biology 4 315-324. (doi:10.1016/S0960-9822(00)00070-1)
12. Creely SJ, McTernan PG, Kusminski CM, Fisher fM, Da Silva NF, Khanolkar M, Evans M, Harte AL & Kumar S 2007 Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. American Journal of Physiology. Endocrinology and Metabolism 292 E740-E747. (doi:10.1152/ajpendo. 00302.2006)
13. Davies SP, Hawley SA, Woods A, Carling D, Haystead TA & Hardie DG 1994 Purification of the AMP-activated protein-kinase on ATP-g-sepharose and analysis of its subunit structure. European Journal of Biochemistry 223 351-357. (doi:10.1111/j.1432-1033.1994.tb19001.x)
14. Duca FA, Cote CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM & Lam TK 2015 Metformin activates a duodenal AMPK-dependent pathway to lower hepatic glucose production in rats. Nature Medicine 21 506-511. (doi:10.1038/nm.3787)
15. Elamin EE, Masclee AA, Dekker J, Pieters HJ & JonkersDM2013 Short-chain fatty acids activate AMP-activated protein kinase and ameliorate ethanol-induced intestinal barrier dysfunction in Caco-2 cell monolayers. Journal of Nutrition 143 1872-1881. (doi:10.3945/jn.113.179549)
16. El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M& Leverve X 2000 Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. Journal of Biological Chemistry 275 223-228. (doi:10.1074/jbc.275.1.223)
17. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR & Morris AD 2005 Metformin and reduced risk of cancer in diabetic patients. British Medical Journal 330 1304-1305. (doi:10.1136/bmj.38415.708634.F7)
18. Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F & Viollet B 2010 Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. Journal of Clinical Investigation 120 2355-2369. (doi:10.1172/JCI40671)
19. Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, O'Neill HM, Ford RJ, Palanivel R, O'Brien M et al. 2013 Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine 19 1649-1654. (doi:10.1038/nm.3372)
20. Gao ZG, Yin J, Zhang J, He Q, McGuinness OP & Ye JP 2009 Inactivation of NF-k B p50 leads to insulin sensitization in liver through posttranslational inhibition of p70S6K. Journal of Biological Chemistry 284 18368-18376. (doi:10.1074/jbc.M109.007260)
21. Gowans GJ, Hawley SA, Ross FA & Hardie DG 2013 AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metabolism 18 556-566. (doi:10.1016/j.cmet.2013.08.019)
22. Hardie DG, Carling D & Sim AT 1989 The AMP-activated protein-kinase-a multisubstrate regulator of lipid-metabolism. Trends in Biochemical Sciences 14 20-23. (doi:10.1016/0968-0004(89)90084-4)
23. Hardie DG, Ross FA & Hawley SA 2012 AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Reviews. Molecular Cell Biology 13 251-262. (doi:10.1038/nrm3311)
24. Hattori Y, Suzuki K, Hattori S & Kasai K 2006 Metformin inhibits cytokineinduced nuclear factor k B activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 47 1183-1188. (doi:10.1161/01.HYP.0000221429.94591.72)
25. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG & Hardie DG 2005 Calmodulin-dependent protein kinase kinase-b is an alternative upstream kinase for AMP-activated protein kinase. Cell Metabolism 2 9-19. (doi:10.1016/j.cmet.2005.05.009)
26. Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM et al. 2010 Use of cells expressing g subunit variants to identify diverse mechanisms of AMPK activation. Cell Metabolism 11 554-565. (doi:10.1016/j.cmet.2010.04.001)
27. He L & Wondisford FE 2015 Metformin action: concentrations matter. Cell Metabolism 21 159-162. (doi:10.1016/j.cmet.2015.01.003)
28. He L, Sabet A, Djedjos S, Miller R, Sun XJ, Hussain MA, Radovick S & Wondisford FE 2009 Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137 635-646. (doi:10.1016/j.cell.2009.03.016)
29. He L, Meng SM, Germain-Lee EL, Radovick S & Wondisford FE 2014 Potential biomarker of metformin action. Journal of Endocrinology 221 363-369. (doi:10.1530/JOE-14-0084)
30. Heishi M, Hayashi K, Ichihara J, Ishikawa H, Kawamura T, Kanaoka M, Taiji M & Kimura T 2008 Comparison of gene expression changes induced by biguanides in db/db mice liver. Journal of Toxicological Sciences 33 339-347. (doi:10.2131/jts.33.339)
31. Hollunger G 1955 Guanidines and oxidative phosphorylations. Acta Pharmacologica et Toxicologica 11 1-84. (doi:10.1111/j.1600-0773.1955. tb02972.x)
32. Huang NL, Chiang SH, Hsueh CH, Liang YJ, Chen YJ & Lai LP 2009 Metformin inhibits TNF-a-induced I k B kinase phosphorylation, I k B-a degradation and IL-6 production in endothelial cells through PI3Kdependent AMPK phosphorylation. International Journal of Cardiology 134 169-175. (doi:10.1016/j.ijcard.2008.04.010)
33. Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR et al. 2000 Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49 2063-2069. (doi:10.2337/diabetes.49.12.2063)
34. Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V & Shulman GI 1998 Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. New England Journal of Medicine 338 867-872. (doi:10.1056/NEJM199803263381303)
35. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R & Matthews DR 2012 Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 55 1577-1596. (doi:10.1007/s00125-012-2534-0)
36. Kim JE, Lee MH, Nam DH, Song HK, Kang YS, Lee JE, Kim HW, Cha JJ, Hyun YY, Han SY et al. 2013 Celastrol, an NF-k B inhibitor, improves insulin resistance and attenuates renal injury in db/db mice. PloS ONE 8 e62068. (doi:10.1371/journal.pone.0062068)
37. Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO & Bilo HJ 2010 Metformin associated with lower cancer mortality in type 2 diabetes-ZODIAC-16. Diabetes Care 33 322-326. (doi:10.2337/dc09-1380)
38. Laugerette F, Vors C, Geloen A, Chauvin MA, Soulage C, Lambert-Porcheron S, Peretti N, Alligier M, Burcelin R, Laville M et al. 2011 Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation. Journal of Nutritional Biochemistry 22 53-59. (doi:10.1016/j.jnutbio.2009.11.011)
39. Lee SK, Lee JO, Kim JH, Kim SJ, You GY, Moon JW, Jung JH, Park SH, Uhm KO, Park JM et al. 2011 Metformin sensitizes insulin signaling through AMPK-mediated PTEN down-regulation in preadipocyte 3T3-L1 cells. Journal of Cellular Biochemistry 112 1259-1267. (doi:10.1002/jcb.23000)
40. Lee YJ, Jeschke GR, Roelants FM, Thorner J & Turk BE 2012 Reciprocal phosphorylation of yeast glycerol-3-phosphate dehydrogenases in adaptation to distinct types of stress. Molecular and Cellular Biology 32 4705-4717. (doi:10.1128/MCB.00897-12)
41. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD & Gordon JI 2005 Obesity alters gut microbial ecology. PNAS 102 11070-11075. (doi:10.1073/pnas.0504978102)
42. Ley RE, Turnbaugh PJ, Klein S & Gordon JI 2006 Microbial ecology-human gut microbes associated with obesity. Nature 444 1022-1023. (doi:10.1038/4441022a)
43. Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Makela TP, Hardie DG et al. 2004 LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO Journal 23 833-843. (doi:10.1038/sj.emboj. 7600110)
44. Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ et al. 2014 Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510 542-546. (doi:10.1038/nature13270)
45. Magnusson I, Rothman DL, Katz LD, Shulman RG & Shulman GI 1992 Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. Journal of Clinical Investigation 90 1323-1327. (doi:10.1172/JCI115997)
46. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ et al. 2013 Metformin improves healthspan and lifespan in mice. Nature Communications 4 2192. (doi:10.1038/ncomms3192)
47. Meng S, Cao J, He Q, Xiong L, Chang E, Radovick S, Wondisford FE & He L 2015 Metformin activates AMP-activated protein kinase by promoting formation of the αβγ heterotrimeric complex. Journal of Biological Chemistry 290 3793-3802. (doi:10.1074/jbc.M114.604421)
48. Miller RA, Chu QW, Xie JX, Foretz M, Viollet B & Birnbaum MJ 2013 Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494 256-260. (doi:10.1038/nature11808)
49. Mitchelhill KI, Stapleton D, Gao G, House C, Michell B, Katsis F, Witters LA & Kemp BE 1994 Mammalian AMP-activated protein-kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein-kinase. Journal of Biological Chemistry 269 2361-2364.
50. Momcilovic M, Hong SP & Carlson M 2006 Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. Journal of Biological Chemistry 281 25336-25343. (doi:10.1074/jbc.M604399200)
51. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP & Tonks NK 1998 The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. PNAS 95 13513-13518. (doi:10.1073/pnas.95.23.13513)
52. Neumann D, Woods A, Carling D, Wallimann T & Schlattner U 2003 Mammalian AMP-activated protein kinase: functional, heterotrimeric complexes by co-expression of subunits in Escherichia coli. Protein Expression and Purification 30 230-237. (doi:10.1016/S1046-5928(03)00126-8)
53. Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N, Tam S & Kemp BE 2011 AMPK is a direct adenylate charge-regulated protein kinase. Science 332 1433-1435. (doi:10.1126/science.1200094)
54. Okamura H, Yoshida K, Sasaki E, Qiu LH, Amorim BR, Morimoto H & Haneji T 2007 Expression of PTEN and Akt phosphorylation in lipopolysaccharide-treated NIH3T3 cells. Cell Biology International 31 119-125. (doi:10.1016/j.cellbi.2006.09.014)
55. Oliveira AG, Carvalho BM, Tobar N, Ropelle ER, Pauli JR, Bagarolli RA, Guadagnini D, Carvalheira JB & SaadMJ 2011 Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats. Diabetes 60 784-796. (doi:10.2337/db09-1907)
56. Ouyang JY, Parakhia RA & Ochs RS 2011 Metformin activates AMP kinase through inhibition of AMP deaminase. Journal of Biological Chemistry 286 1-11. (doi:10.1074/jbc.M110.121806)
57. Owen MR, Doran E & Halestrap AP 2000 Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochemical Journal 348 607-614. (doi:10.1042/bj3480607)
58. Peng L, Li ZR, Green RS, Holzman IR & Lin J 2009 Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. Journal of Nutrition 139 1619-1625. (doi:10.3945/jn.109.104638)
59. Ridaura VK, Faith JJ, Rey FE, Cheng JY, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR et al. 2013 Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341 1079-U1049. (doi:10.1126/science.1241214)
60. Saltiel AR & Kahn CR 2001 Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414 799-806. (doi:10.1038/414799a)
61. Scott MJ & Billiar TR 2008 b2-integrin-induced p38 MAPK activation is a key mediator in the CD14/TLR4/MD2-dependent uptake of lipopolysaccharide by hepatocytes. Journal of Biological Chemistry 283 29433-29446. (doi:10.1074/jbc.M803905200)
62. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, DePinho RA, Montminy M & Cantley LC 2005 The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310 1642-1646. (doi:10.1126/science.1120781)
63. Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS & Bae JW 2014 An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63 727-735. (doi:10.1136/gutjnl-2012-303839)
64. Song SM, Andrikopoulos S, Filippis C, Thorburn AW, Khan D & Proietto J 2001 Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin. American Journal of Physiology. Endocrinology and Metabolism 281 E275-E282.
65. Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA et al. 1996 Mammalian AMP-activated protein kinase subfamily. Journal of Biological Chemistry 271 611-614. (doi:10.1074/jbc.271.2.611)
66. Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, Sherwin R, Devaskar S, Lesche R, Magnuson MA et al. 2004 Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. PNAS 101 2082-2087. (doi:10.1073/pnas.0308617100)
67. Stumvoll M, Nurjhan N, Perriello G, Dailey G & Gerich JE 1995 Metabolic effects of metformin in non-insulin-dependent diabetes-mellitus. New England Journal of Medicine 333 550-554. (doi:10.1056/NEJM199508313330903)
68. Takashima M, Ogawa W, Hayashi K, Inoue H, Kinoshita S, Okamoto Y, Sakaue H, Wataoka Y, Emi A, Senga Y et al. 2010 Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action. Diabetes 59 1608-1615. (doi:10.2337/db09-1679)
69. Wajngot A, Chandramouli V, Schumann WC, Ekberg K, Jones PK, Efendic S & Landau BR 2001 Quantitative contributions of gluconeogenesis to glucose production during fasting in type 2 diabetes mellitus. Metabolism: Clinical and Experimental 50 47-52. (doi:10.1053/meta. 2001.19422)
70. Wang PY, Caspi L, Lam CK, Chari M, Li XS, Light PE, Gutierrez-Juarez R, Ang M, Schwartz GJ & Lam TK 2008 Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 452 1012-1016. (doi:10.1038/nature06852)
71. Watanabe CK 1918 Studies in the metabolic changes induced by administration of guanidine bases. I. Influence of injected guanidine hydrochloride upon blood sugar content. Journal of Biological Chemistry 33 253-265.
72. Wilcock C & Bailey CJ 1994 Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24 49-57. (doi:10.3109/00498259409043220)
73. Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF et al. 2011 Structure of mammalian AMPK and its regulation by ADP. Nature 472 230-233. (doi:10.1038/nature09932)
74. Zhou GC, Myers R, Li Y, Chen YL, Shen XL, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N et al. 2001 Role of AMP-activated protein kinase in mechanism of metformin action. Journal of Clinical Investigation 108 1167-1174. (doi:10.1172/JCI13505)