Metformin in patients with ischemic heart disease and type 2 diabetes mellitus: mechanism of action and clinical efficiency
https://doi.org/10.14341/2072-0351-3590
Abstract
Diabetes mellitus is one of the leading causes of death in modern society, primarily due to its cardiovascular complications. This factor drives search for novel pharmacologic agents to affect not only glycemic levels, but also the cardiovascular prognosis in diabetic patients with ischemic heart disease. Recent studies demonstrate that aside from basic blood glucose lowering action, metformin shows beneficial influence on blood rheology and vascular tone, hemostasis, oxidative stress, lipid spectrum and delivers and an ant-ischemic effect. Here we review clinical and experimental evidence on cardio- and vasoprotective effects of metformin, highlighting their molecular mechanisms.
About the Authors
Ekaterina Nikodimovna Kravchuk
V.A. Almazov Federal Heart, Blood and Endocrinology Centre, St-Petersburg, Russian Federation
M M Galagudza
V.A. Almazov Federal Heart, Blood and Endocrinology Centre, St-Petersburg, Russian Federation; I.P. Pavlov State Medical University, St-Petersburg, Russian Federation
References
1. Кисляк ОА, Мышляева ТО, Малышева НВ. Сахарный диабет 2 типа, артериальная гипертензия и риск сер- дечно-сосудистых осложнений. Сахарный диабет. 2008;(1):45–49.
2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004 May;27(5):1047–1053.
3. Ярек-Мартынова ИР, Шестакова МВ. Сердечно-сосудистые заболевания у больных сахарным диабетом. CardioСоматика. 2010;(1):46–50.
4. Сахарный диабет – глобальная медико-социальная проблема современности. Интервью с МВ. Шестаковой. Участковый терапевт. 2009;(5):1–2.
5. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary artery disease in subject with type 2 diabetes and nondiabetic subjects with and without myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229–234.
6. Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care. 1979 Mar–Apr;2(2):120–126.
7. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M,Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010 Jun 26;375(9733):2215– 2222. doi: 10.1016/S0140-6736(10)60484-9.
8. Демидова ТЮ. Сосудистые осложнения сахарного диабета типа за гранью гликемического контроля. Сахарный диабет. 2010;(3):111–116.
9. Балаболкин МИ. Эндокринология. М: Универсум паблишинг; 1994.
10. Superko HR, Krauss RM, DiRicco C. Effect of fluvastatin on low-density lipoprotein peak particle diameter. Am J Cardiol. 1997 Jul 1;80(1):78–81.
11. Северина АС, Галицина НА, Парфенова ЕВ, Пахомова ЕА, Цоколева ЗИ, Велиткевич ЕА, Ратнер ЕИ, Шестакова МВ. Роль дисфункции эндотелия в развитии диабетических макроангиопатий. М; 2007.
12. Hsueh WA, Law RE. Cardiovascular risk continuum: implica- tions of insulin resistance and diabetes. Am J Med. 1998 Jul 6;105(1A):4S–14S.
13. Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet. 2008 May 24;371(9626):1800–1809. doi: 10.1016/ S0140-6736(08)60768-0.
14. Jialal I, Amess W, Kaur M. Management of hypertriglyceridemia in the diabetic patient. Curr Diab Rep. 2010 Aug;10(4):316–320. doi: 10.1007/s11892-010-0124-4.
15. Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med. 2007 Aug;262(2):157–172.
16. Lemkes BA, Hermanides J, Devries JH, Holleman F, Meijers JC, Hoekstra JB. Hyperglycemia: a prothrombotic factor? J Thromb Haemost. 2010 Aug;8(8):1663–1669. doi: 10.1111/j.1538-7836.2010.03910.x.
17. Hadden DR. Goat's rue – French lilac – Italian fitch – Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection. J R Coll Physicians Edinb. 2005 Oct;35(3):258–260.
18. Keeler RF, Baker DC, Evans JO. Individual animal susceptibility and its relationship to induced adaptation or tolerance in sheep to Galega officinalis L. Vet Hum Toxicol. 1988 Oct;30(5):420–423.
19. Bailey CJ, Day C. Traditional plant medicines as treatments for diabetes. Diabetes Care. 1989 Sep;12(8):553–564.
20. Joslin EP. The outlook for the diabetic. Cal. Cal West Med. 1927 Mar;26(3):328–331.
21. Sterne J. Du Nouveau dans les antidiabétiques. La NN diméthylamino guanyl guanidine (N.N.D.G.). Maroc. Med. 1957;36:1295–1296. French.
22. Балаболкин МИ, Креминская ВМ, Клебанова ЕМ. Бигуаниды: антигипергликемическое и вазопротективное действия. Consilium medicum. 2003;5(9): 487–491.
23. Кондратьева ЛВ. Метформин – испытание временем. РМЖ. 2007; (27):2098–2102.
24. Hadden DR. Goat's rue – French lilac – Italian fitch – Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection. J R Coll Physicians Edinb. 2005 Oct;35(3):258–260.
25. Lucis OJ. The status of metformin in Canada. Can Med Assoc J. 1983 Jan 1;128(1):24–26.
26. Campbell IW. Metformin — life begins at 50. Br. J. Diabetes Vasc. Dis. 2007;7(5):247–252.
27. Effect of intensive blood–glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854–865.
28. Singh M, Gersh BJ, McClelland RL, Ho KK, Willerson JT, Penny WF, Holmes DR Jr. Clinical and angiographic predictors of restenosis after percutaneous coronary intervention: insights from the Prevention of Restenosis With Tranilast and Its Outcomes (PRESTO) trial. Circulation. 2004 Jun 8;109(22):2727–2731.
29. Kao J, Tobis J, McClelland RL, Heaton MR, Davis BR, Holmes DR Jr, Currier JW; Investigators in the Prevention of Restenosis With Tranilast and Its Outcomes Trial. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004 Jun 1;93(11):1347–1350, A5.
30. Mathew V, Gersh BJ, Williams BA, Laskey WK, Willerson JT, Tilbury RT, Davis BR, Holmes DR Jr. Outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention in the current era: a report from the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation. 2004 Feb 3;109(4):476–480.
31. Charles MA, Morange P, Eschwège E, André P, Vague P, Juhan-Vague I. Effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese nondiabetic subjects: the BIGPRO1 Study. Biguanides and the Prevention of the Risk of Obesity. Diabetes Care. 1998 Nov;21(11):1967–1972.
32. Дедов ИИ, Мельниченко ГА. Эндокринология. Национальное руководство. М: Геотар-Медиа; 2011.
33. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996 Feb 29;334(9):574–579.
34. Аметов АС, Козедубова ИВ. Роль и место метформина в лечении сахарного диабета типа 2. Consilium Medicum. 2006;8(9):23–26.
35. Argaud D, Roth H, Weimsperger N, Leverve XM. Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur J Biochem. 1993 May 1;213(3):1341–1348.
36. Perriello G, Misericordia P, Volpi E, Santucci A, Santucci C, Ferrannini E, Ventura MM, Santeusanio F, Brunetti P, Bolli GB. Acute antihyperglycemic mechanisms of metformine in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes. 1994 Jul;43(7):920–928.
37. Sum CF, Webster JM, Johnson AB, Catalano C, Cooper BG, Taylor R. The effect of intravenous metformine on glucose metabolism during hyperglycaemia in type 2 diabetes. Diabet Med. 1992 Jan–Feb;9(1):61–65.
38. Borst SE, Snellen HG. Metformin, but not exercise training, increases insulin responsiveness in skeletal muscle of Sprague- Dawley rats. Life Sci. 2001 Aug 17;69(13):1497-1507.
39. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994 Jan;24(1):49–57.
40. Bailey CJ, Mynett KJ, Page T. Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol. 1994 Jun;112(2):671–675.
41. Mithieux G, Rajas F, Zitoun C. Glucose utilization is suppressed in the gut of insulin-resistant high fat-fed rats and is restored by metformin. Biochem Pharmacol. 2006;72(12):1757–1762.
42. Bailey CJ. Metformin-an update. Gen Pharmacol. 1993 Nov;24(6):1299–1309.
43. Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology. 2011 Dec;152(12):4610–4619. doi: 10.1210/en.2011-1485.
44. Lv WS, Wen JP, Li L, Sun RX, Wang J, Xian YX, Cao CX, Wang YL, Gao YY. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res. 2012 Mar 20;1444:11–19. doi: 10.1016/j. brainres.2012.01.028.
45. Granger CB, Califf RM, Young S, Candela R, Samaha J, Worley S, Kereiakes DJ, Topol EJ. Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. J Am Coll Cardiol. 1993 Mar 15;21(4):920–925.
46. Wulffelé MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004 Jul;256(1):1–14.
47. Wu MS, Johnston P, Sheu WH, Hollenbeck CB, Jeng CY, Goldfine ID, Chen YD, Reaven GM. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care. 1990 Jan;13(1):1–8.
48. Mamputu JC, Wiernsperger N, Renier G. Metformin inhibits monocyte adhesion to endothelial cells and foam cell formation. Br. J. Diabetes Vasc. Dis. 2003;3(4):302 –310.
49. Caballero AE, Delgado A, Aguilar-Salinas CA, Herrera AN, Castillo JL, Cabrera T, Gomez-Perez FJ, Rull JA. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab. 2004 Aug;89(8):3943–3948.
50. Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med. 2007 Aug;262(2):157–172.
51. Gregorio F, Ambrosi F, Manfrini S, Velussi M, Carle F, Testa R, Merante D, Filipponi P. Poorly controlled elderly Type 2 diabetic patients: the effects of increasing sulphonylurea dosages or adding metformin. Diabet Med. 1999 Dec;16(12):1016–1024.
52. Formoso G, De Filippis EA, Michetti N, Di Fulvio P, Pandolfi A, Bucciarelli T, Ciabattoni G, Nicolucci A, Davì G, Consoli A. Decreased in vivo oxidative stress and decreased platelet activation following metformin treatment in newly diagnosed type 2 diabetic subjects. Diabetes Metab Res Rev. 2008 Mar– Apr;24(3):231–237.
53. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care. 1993 Apr;16(4):621–629.
54. Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome: the links, causes and consequences. Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2200–2207.
55. Gin H, Roudaut MF, Vergnot V, Baillet L, Rigalleau V. Effect of metformin on fibrinolytic parameters in insulintreated, type 2 diabetic patients. Diabetes Metab. 2003 Nov;29(5):505–508.
56. Fanghänel G, Silva U, Sanchez-Reyes L, Sisson D, Sotres D, Torres EM. Effects of metformin on fibrinogen levels in obese patients with type 2 diabetes. Rev Invest Clin. 1998 Sep– Oct;50(5):389–394.
57. Grant PJ. Metformin reduces circulating factor VII concentrations in patients with type 2 diabetes mellitus. Thromb Haemost. 1998 Jul;80(1):209–210.
58. Sobel BE, Hardison RM, Genuth S, Brooks MM, McBane RD 3rd, Schneider DJ, Pratley RE, Huber K, Wolk R, Krishnaswami A, Frye RL. Profibrinolytic, antithrombotic, and antiinflammatory effects of an insulin-sensitizing strategy in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation. 2011 Aug 9;124(6):695–703. doi: 10.1161/CIRCULA- TIONAHA.110.014860.
59. Standeven KF, Ariëns RA, Whitaker P, Ashcroft AE, Weisel JW, Grant PJ. The effect of dimethylbiguanide on thrombin activity, FXIII activation, fibrin polymerization, and fibrin clot formation. Diabetes. 2002 Jan;51(1):189–197.
60. Grant PJ. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab. 2003 Sep;29(4 Pt 2):6S44–52.
61. Le Devehat C, Khodabandehlou T, Vimeux M. Impaired hemorheological properties in diabetic patients with lower limb arterial ischaemia. Clin Hemorheol Microcirc. 2001;25(2):43–48.
62. Wiernsperger NF, Bouskela E. Microcirculation in insulin resistance and diabetes: more than just a complication. Diabetes Metab. 2003 Sep;29(4 Pt 2):6S77–87.
63. Muller S, Denet S, Candiloros H, Barrois R, Wiernsperger N, Donner M, Drouin P. Action of metformin on erythrocyte membrane fluidity in vitro and in vivo. Eur J Pharmacol. 1997 Oct 15;337(1):103–110.
64. Bestermann WH Jr. The ADMA-Metformin Hypothesis: Linking the Cardiovascular Consequences of the Metabolic Syndrome and Type 2 Diabetes. Cardiorenal Med. 2011;1(4):211–219.
65. Asagami T, Abbasi F, Stuelinger M, Lamendola C, McLaughlin T, Cooke JP, Reaven GM, Tsao PS. Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. Metabolism. 2002 Jul;51(7):843–846.
66. Marfella R, Acampora R, Verrazzo G, Ziccardi P, De Rosa N, Giunta R, Giugliano D. Metformin improves hemodynamic and rheological responses to L-arginine in NIDDM patients. Diabetes Care. 1996 Sep;19(9):934–939.
67. Jansson PA, Gudbjörnsdóttir HS, Andersson OK, Lönnroth PN. The effect of metformin on adipose tissue metabolism and peripheral blood flow in subjects with NIDDM. Diabetes Care. 1996 Feb;19(2):160–164.
68. Schäfers RF. Do effects on blood pressure contribute to improved clinical outcomes with metformin? Diabetes Metab. 2003 Sep;29(4 Pt 2):6S62–70.
69. Katakam PV, Ujhelyi MR, Hoenig M, Miller AW. Metformin improves vascular function in insulin-resistant rats. Hypertension. 2000 Jan;35(1 Pt 1):108–112.
70. Lobato NS, Filgueira FP, Hagihara GN, Akamine EH, Pariz JR, Tostes RC, Carvalho MH, Fortes ZB. Improvement of metabolic parameters and vascular function by metformin in obese nondiabetic rats. Life Sci. 2012 Jan 30;90(5–6):228–235. doi: 10.1016/j.lfs.2011.11.005.
71. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001 Apr;37(5):1344–1350.
72. Kim YW, Park SY, Kim JY, Huh JY, Jeon WS, Yoon CJ, Yun SS, Moon KH. Metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. J Androl. 2007 Jul– Aug;28(4):555–560.
73. Hou X, Song J, Li XN, Zhang L, Wang X, Chen L, Shen YH. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun. 2010 May 28;396(2):199–205. doi: 10.1016/j. bbrc.2010.04.017.
74. Olukman M, Sezer ED, Ulker S, Sözmen EY, Cınar GM. Fenofibrate treatment enhances antioxidant status and attenuates endothelial dysfunction in streptozotocin-induced diabetic rats. Exp Diabetes Res. 2010;2010:828531. doi: 10.1155/2010/828531.
75. Li L, Mamputu JC, Wiernsperger N, Renier G. Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin. Diabetes. 2005 Jul;54(7):2227–2234.
76. Pavlović D, Kocić R, Kocić G, Jevtović T, Radenković S, Mikić D, Stojanović M, Djordjević PB. Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type diabetes. Diabetes Obes Metab. 2000 Aug;2(4):251–256.
77. Esteghamati A, Eskandari D, Mirmiranpour H, Noshad S, Mousavizadeh M, Hedayati M, Nakhjavani M. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: A randomized clinical trial. Clin Nutr. 2012 Aug 21.
78. Chakraborty A, Chowdhury S, Bhattacharyya M. Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res Clin Pract. 2011 Jul;93(1):56–62. doi: 10.1016/j.diabres.2010.11.030.
79. Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes. 2008 Mar;57(3):696–705.
80. Charlon V, Boucher F, Mouhieddine S, de Leiris J. Reduction of myocardial infarct size by metformin in rats submitted to permanent left coronary artery ligation. Diabetes Metab. 1988; 14:591–595.
81. Solskov L, Lofgren B, Kristiansen SB, Jessen N, Pold R, Nielsen TT, Bøtker HE, Schmitz O, Lund S. Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 h after administration. Basic Clin Pharmacol Toxicol. 2008 Jul;103(1):82–87. doi: 10.1111/j.1742- 7843.2008.00234.x.
82. Legtenberg RJ, Houston RJ, Oeseburg B, Smits P. Metformin improves cardiac functional recovery after ischemia in rats. Horm Metab Res. 2002 Apr;34(4):182–185.
83. Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, Mocanu MM, Yellon DM. Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol. 2008 May;103(3):274–284.
84. Paiva MA, Goncalves LM, Providencia LA, Davidson SM, Yellon DM, Mocanu MM. Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction. Cardiovasc Drugs Ther. 2010 Feb;24(1):25–32. doi: 10.1007/s10557-010-6222-3.
85. Kravchuk E, Grineva E, Bairamov A, Galagudza M, Vlasov T. The effect of metformin on the myocardial tolerance to ischemia-reperfusion injury in the rat model of diabetes mellitus type II. Exp Diabetes Res. 2011;2011:907496. doi: 10.1155/2011/907496.
86. Кравчук ЕН, Гринева ЕН, Галагудза ММ, Костарева АA, Байрамов АА. Роль АМФ-активируемой протеинкиназы в изменении устойчивости миокарда к ишемическому и реперфузионному повреждению под действием метформина при сахарном диабете тип 2. Артериальная гипертензия. 2012; 18(3):206–212.
87. Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA, Kemp BE. Mammalian AMP-activated protein kinase subfamily. J Biol Chem. 1996 Jan 12;271(2):611–614.
88. Shirwany NA, Zou MH. AMPK in cardiovascular health and disease. Acta Pharmacol Sin. 2010 Sep;31(9):1075–1084. doi: 10.1038/aps.2010.139.
89. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007 Oct;8(10):774–785.
90. Ruderman NB, Keller C, Richard AM, Saha AK, Luo Z, Xiang X, Giralt M, Ritov VB, Menshikova EV, Kelley DE, Hidalgo J, Pedersen BK, Kelly M. Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes. 2006 Dec;55 Suppl 2:S48–54.
91. Lim CT, Kola B, Korbonits M. AMPK as a mediator of hormonal signaling. J Mol Endocrinol. 2010 Feb;44(2):87–97. doi: 10.1677/JME-09-0063.
92. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001 Oct;108(8):1167–1174.
93. Fryer LG, Parbu-Patel A, Carling D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem. 2002 Jul 12;277(28):25226–25232.
94. Ewart MA, Kennedy S. AMPK and vasculoprotection. Pharmacol Ther. 2011 Aug;131(2):242–253. doi: 10.1016/j. pharmthera.2010.11.002.
95. Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT, Hohnen-Behrens C, Gosby A, Kraegen EW, James DE, Kim JB. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulinresistant states. Diabetes. 2006 Aug;55(8):2256–2264.
96. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337–342.
97. Misra P. AMP activated protein kinase: a next generation target for total metabolic control. Expert Opin Ther Targets. 2008 Jan;12(1):91–100.
98. Hallows KR, Kobinger GP, Wilson JM, Witters LA, Foskett JK. Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells. Am J Physiol Cell Physiol. 2003 May;284(5):C1297–1308.
99. Hong YH, Varanasi US, Yang W, Leff T. AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J Biol Chem. 2003 Jul 25;278(30):27495–27501.
100. Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, Takemori H, Montminy M. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005 Oct 20;437(7062):1109–1111.
101. Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez- Crespo I, Witters LA, Power DA, Ortiz de Montellano PR, Kemp BE. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 1999 Jan 29;443(3):285–289.
102. Camici M, Ahmad Z, DePaoli-Roach AA, Roach PJ. Phosphorylation of rabbit liver glycogen synthase by multiple protein kinases. J Biol Chem. 1984 Feb 25;259(4):2466–2473.
103. Jakobsen SN, Hardie DG, Morrice N, Tornqvist HE. 5'-AMPactivated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. J Biol Chem. 2001 Dec 14;276(50):46912–46916.
104. Yang W, Hong YH, Shen XQ, Frankowski C, Camp HS, Leff T. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J Biol Chem. 2001 Oct 19;276(42):38341–38344.
105. Nagata D, Hirata Y. The role of AMP-activated protein kinase in the cardiovascular system. Hypertens Res. 2010 Jan;33(1):22–28. doi: 10.1038/hr.2009.187
106. Ye Y, Perez-Polo JR, Aguilar D, Birnbaum Y. The potential effects of anti-diabetic medications on myocardial ischemiareperfusion injury. Basic Res Cardiol. 2011 Nov;106(6):925–952. doi: 10.1007/s00395-011-0216-6.
Review
For citations:
Kravchuk E.N., Galagudza M.M. Metformin in patients with ischemic heart disease and type 2 diabetes mellitus: mechanism of action and clinical efficiency. Diabetes mellitus. 2013;16(1):5-14. (In Russ.) https://doi.org/10.14341/2072-0351-3590
Views:
11265
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).
Email this article 
