Перспективы применения метформина у пациентов с нарушением уратного обмена

1. Zhang Y, Yamamoto T, Hisatome I, et al. Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells. Mol Cell Endocrinol. 2013;375(1-2):89-96. DOI:10.1016/j.mce.2013.04.027
2. Lanaspa MA, Cicerchi C, Garcia G, et al. Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver. PLoS One. 2012;7(11):e48801. DOI:10.1371/journal.pone.0048801
3. Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67(5):1739-42. DOI:10.1111/j.1523-1755.2005.00273.x
4. Johnson RJ, Perez-Pozo SE, Sautin YY, et al. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev. 2009;30(1):96-116. DOI:10.1210/er.2008-0033
5. Matsuoka T, Kajimoto Y, Watada H, et al. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest. 1997;99(1):144-50. DOI:10.1172/JCI119126
6. Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA. 1991;266(21):3008-11. DOI:10.1001/jama.1991.03470210076036
7. Muscelli E, Natali A, Bianchi S, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens. 1996;9(8):746-52. DOI:10.1016/0895-7061(96)00098-2
8. Dehghan A, van Hoek M, Sijbrands EJ, et al. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care. 2008;31(2):361-2. DOI:10.2337/dc07-1276
9. Kodama S, Saito K, Yachi Y, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care. 2009;32(9):1737-42. DOI:10.2337/dc09-0288
10. Lai HM, Chen CJ, Su BY, et al. Gout and type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences. Rheumatology (Oxford). 2012;51(4):715-20. DOI:10.1093/rheumatology/ker373
11. Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006;290(3):F625-31. DOI:10.1152/ajprenal.00140.2005
12. Sánchez-Lozada LG, Tapia E, Bautista-García P, et al. Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2008;294(4):F710-8. DOI:10.1152/ajprenal.00454.2007
13. Паневин Т.С., Желябина О.В., Елисеев М.С., Шестакова М.В. Уратснижающие эффекты ингибиторов дипептидилпептидазы-4. Сахарный диабет. 2020;23(4):349-56 [Panevin TS, Zhelyabina OV, Eliseev MS, Shestakova MV. Urate-lowering effects of dipeptidyl peptidase-4 inhibitors. Diabetes Mellitus. 2020;23(4):349-56 
(in Russian)]. DOI:10.14341/DM12412
14. Паневин Т.С., Елисеев М.С., Шестакова М.В., Насонов Е.Л. Преимущества терапии ингибиторами натрий-глюкозного котранспортера 2-го типа у пациентов с сахарным диабетом 2-го типа в сочетании с гиперурикемией и подагрой. Терапевтический архив. 2020;92(5):110-8 [Panevin TS, Eliseev MS, Shestakova MV, Nasonov EL. Advantages of therapy with sodium glucose cotransporter type 2 inhibitors in patients with type 2 diabetes mellitus in combination with hyperuricemia and gout. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(5):110-8 (in Russian)]. DOI:10.26442/00403660.2020.05.000633
15. Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566-76. DOI:10.1007/s00125-017-4318-z
16. Дедов И.И., Шестакова М.В., Майоров А.Ю., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. 9-й вып. Сахарный диабет. 2019;22(1S1):1-144 [Dedov II, Shestakova MV, Mayorov AY, et al. Standards of specialized diabetes care. 9th ed. Diabetes mellitus. 2019;22(1S1):1-144 (in Russian)]. DOI:10.14341/dm221s1
17. Aroda VR, Knowler WC, Crandall JP, et al. Metformin for diabetes prevention: insights gained fr om the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study. Diabetologia. 2017;60(9):1601-11. DOI:10.1007/s00125-017-4361-9
18. Дедов И.И., Шестакова М.В., Викулова О.К., и др. Атлас регистра сахарного диабета Российской Федерации. Статус 2018 г. Сахарный диабет. 2019;22(2S):4-61 [Dedov II, Shestakova MV, Vikulova OK, et al. Atlas of Diabetes Register in Russian Federation, status 2018. Diabetes mellitus. 2019;22(2S):4-61 (in Russian)].
DOI:10.14341/dm12208
19. Sharma M, Nazareth I, Petersen I. Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study. BMJ Open. 2016;6(1):e010210. DOI:10.1136/bmjopen-2015-010210
20. DeFronzo RA, Stonehouse AH, Han J, Wintle ME. Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: a meta-analysis of randomized clinical trials. Diabet Med. 2010;27(3):309-17. DOI:10.1111/j.1464-5491.2010.02941
21. Zhou K, Yee SW, Seiser EL, et al. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet. 2016;48(9):1055-9. DOI:10.1038/ng.3632
22. Domecq JP, Prutsky G, Leppin A, et al. Drugs Commonly Associated With Weight Change: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2015;100(2):363-70. DOI:10.1210/jc.2014-3421
23. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-65. DOI:10.1016/s0140-6736(98)07037-8
24. Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017;60(9):1620-9. DOI:10.1007/s00125-017-4337-9
25. U.K. Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249-58. DOI:10.2337/diabetes.44.11.1249
26. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin. Diabetes Care. 2006;29(2):254-8. DOI:10.2337/diacare.29.02.06.dc05-1558
27. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2003. DOI:10.1002/14651858.cd002967
28. Connelly PJ, Lonergan M, Soto-Pedre E, et al. Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: A GoDarts study. Diabetes Obes Metab. 2017;19(11):1579-86. DOI:10.1111/dom.12978
29. Coperchini F, Leporati P, Rotondi M, Chiovato L. Expanding the therapeutic spectrum of metformin: from diabetes to cancer. J Endocrinol Invest. 2015;38(10):1047-55. DOI:10.1007/s40618-015-0370-z
30. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-85. DOI:10.1007/s00125-017-4342-z
31. Anabtawi A, Miles JM. Metformin: nonglycemic effects and potential novel indications. Endocr Pract. 2016;22(8):999-1007.DOI:10.4158/ep151145.ra
32. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 2016;23(6):1060-5.DOI:10.1016/j.cmet.2016.05.011
33. 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(3):607-14.DOI:10.1042/bj3480607
34. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2010;12(1):21-35. DOI:10.1038/nrm3025
35. Lin HH, Chang KT, Hung CC, et al. Effects of the mTOR inhibitor Rapamycin on Monocyte-Secreted Chemokines. BMC Immunol. 2014;15(1). DOI:10.1186/s12865-014-0037-0
36. Vazirpanah N, Ottria A, van der Linden M, et al. mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy? Ann Rheum Dis. 2019;78(5):663-71. DOI:10.1136/annrheumdis-2018-214656
37. Saleiro D, Platanias LC. Intersection of mTOR and STAT signaling in immunity. Trends Immunol. 2015;36(1):21-9. DOI:10.1016/j.it.2014.10.006
38. Ursini F, Russo E, Pellino G, et al. Metformin and Autoimmunity: 
A “New Deal” of an Old Drug. Front Immunol. 2018;9. DOI:10.3389/fimmu.2018.01236
39. O’Neill LAJ, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493(7432):346-55. DOI:10.1038/nature11862
40. Kelly B, Tannahill GM, Murphy MP, O’Neill LAJ. Metformin Inhibits the Production of Reactive Oxygen Species from NADH: Ubiquinone Oxidoreductase to Lim it Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages. J Biol Chem. 2015;290(33):20348-59. 
DOI:10.1074/jbc.m115.662114
41. Bułdak Ł, Machnik G, Bułdak RJ, et al. Exenatide and metformin express their anti-inflammatory effects on human monocytes/macrophages by the attenuation of MAPKs and NFκB signaling. Naunyn Schmiedeberg Arch Pharmacol. 2016;389(10):1103-15. DOI:10.1007/s00210-016-1277-8
42. Krysiak R, Gdula-Dymek A, Okopień B. Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance. Pharmacol Rep. 2013;65(5):1311-6. DOI:10.1016/s1734-1140(13)71489-0
43. Krysiak R, Okopien B. The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose. Metabolism. 2013;62(1):39-43. DOI:10.1016/j.metabol.2012.06.009
44. Cameron AR, Morrison VL, Levin D, et al. Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ Res. 2016;119(5):652-65. DOI:10.1161/circresaha.116.308445
45. Yang H, Biermann MH, Brauner JM, et al. New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation. Front Immunol. 2016;7. DOI:10.3389/fimmu.2016.00302
46. Wang H, Li T, Chen S, et al. Neutrophil Extracellular Trap Mitochondrial DNA and Its Autoantibody in Systemic Lupus Erythematosus and a Proof-of-Concept Trial of Metformin. Arthritis Rheumatol. 2015;67(12):3190-200. DOI:10.1002/art.39296
47. Чикина М.Н. Профилактика приступов артрита при назначении уратснижающей терапии у больных подагрой. Научно-практическая ревматология. 2018;56(6):760-6 [Chikina MN. Prevention of arthritis attacks in the use of urate-lowering therapy in patients with gout. Rheumatology Science and Practice. 2018;56(6):760-6 (in Russian)]. DOI:10.14412/1995-4484-2018-760-766
48. Menegazzo L, Ciciliot S, Poncina N, et al. NETosis is induced by high glucose and associated with type 2 diabetes. Acta Diabetol. 2014;52(3):497-503. DOI:10.1007/s00592-014-0676-x
49. Menegazzo L, Scattolini V, Cappellari R, et al. The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo. Acta Diabetol. 2018;55(6):593-601. DOI:10.1007/s00592-018-1129-8
50. Bruderer SG, Bodmer M, Jick SS, Meier CR. Poorly controlled type 2 diabetes mellitus is associated with a decreased risk of incident gout: 
a population-based case-control study. Ann Rheum Dis. 2014;74(9):1651-8. DOI:10.1136/annrheumdis-2014-205337
51. Шестаков А.В., Саприна Т.В., Ануфрак И.А., и др. Метформин: новые перспективы в химиопрофилактике и терапии рака. Российский биотерапевтический журнал. 2018;17(3):12-9 [Shestakov AV, Saprina TV, Anufrak IA, et al. Metformin: new perspectives in chemoprevention and therapy of cancer. Russian Journal of Biotherapy. 2018;17(3):12-9 (in Russian)]. DOI:10.17650/1726-9784-2018-17-3-12-19
52. Барскова В.Г., Елисеев М.С., Кудаева Ф.М., и др. Влияние метформина на течение подагры и инсулинорезистентность. Клиническая медицина. 2009;87(7):41-6 [Barskova VG, Eliseev MS, Kudaeva FM, et al. Effect of metformine on the clinical course of gout and insulin resistance. Clinical medicine. 2009;87(7):41-6 (in Russian)].
53. Matsuura F, Yamashita S, Nakamura T, et al. Effect of visceral fat accumulation on uric acid metabolism in male obese subjects: Visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity. Metabolism. 1998;47(8):929-33.DOI:10.1016/s0026-0495(98)90346-8
54. Morales DR, Morris AD. Metformin in Cancer Treatment and Prevention. Ann Rev Med. 2015;66(1):17-29.DOI:10.1146/annurev-med-062613-093128
55. Lawrence T. The Nuclear Factor NF-κB Pathway in Inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651.DOI:10.1101/cshperspect.a001651
56. Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin Inhibits Cytokine-Induced Nuclear Factor κB Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells. Hypertension. 2006;47(6):1183-8. DOI:10.1161/01.hyp.0000221429.94591.72
57. Bijland S, Mancini SJ, Salt IP. Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin Sci. 2013;124(8):491-507. DOI:10.1042/cs20120536
58. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Nat Acad Sci U S A. 2012;110(3):972-7.DOI:10.1073/pnas.1221055110
59. The Diabetes Prevention Program Research Group. Intensive Lifestyle Intervention or Metformin on Inflammation and Coagulation in Participants With Impaired Glucose Tolerance. Diabetes. 2005;54(5):1566-72. DOI:10.2337/diabetes.54.5.1566
60. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-41. DOI:10.1038/nature04516
61. Jacques C, Gosset M, Berenbaum F, Gabay C. The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation. Vitam Horm. 2006;74:371-403. DOI:10.1016/S0083-6729(06)74016-X
62. Joosten LA, Netea MG, Mylona E, et al. Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1β production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis. Arthritis Rheum. 2010;62(11):3237-48.DOI:10.1002/art.27667
63. Nishimura A, Akahoshi T, Takahashi M, et al. Attenuation of monosodium urate crystal-induced arthritis in rabbits by a neutralizing antibody against interleukin-8. J Leukoc Biol. 1997;62(4):444-9. DOI:10.1002/jlb.62.4.444
64. Huang Z, Kraus VB. Does lipopolysaccharide-mediated inflammation have a role in OA? Nat Rev Rheumatol. 2016;12(2):123-9.DOI:10.1038/nrrheum.2015.158
65. Collins KH, Paul HA, Reimer RA, et al. Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model. Osteoarthritis Cartilage. 2015;23(11):1989-98. DOI:10.1016/j.joca.2015.03.014
66. Bramante C, Ingraham N, Murray T, et al. Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19. MedRxiv. 2020;2020.06.19.20135095. DOI:10.1101/2020.06.19.20135095
67. Matsiukevich D, Piraino G, Lahni P, et al. Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock. Biochim Biophys Acta Mol Basis Dis. 2017;1863(10 Pt. B):2680-91. DOI:10.1016/j.bbadis.2017.05.027
68. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38. DOI:10.1038/nri.2016.90
69. Son HJ, Lee J, Lee SY, et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators Inflamm. 2014;2014:973986. DOI:10.1155/2014/973986
70. Dai XJ, Tao JH, Fang X, et al. Changes of Treg/Th17 Ratio in Spleen of Acute Gouty Arthritis Rat Induced by MSU Crystals. Inflammation. 2018;41(5):1955-64. DOI:10.1007/s10753-018-0839-y
71. Shin N-R, Lee J-C, Lee H-Y, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2013;63(5):727-35. DOI:10.1136/gutjnl-2012-303839
72. Lee H, Ko G. Effect of Metformin on Metabolic Improvement and Gut Microbiota. Appl Environ Microbiol. 2014;80(19):5935-43. DOI:10.1128/aem.01357-14
73. Lee H, Lee Y, Kim J, et al. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes. 2018;9(2):155-65. DOI:10.1080/19490976.2017.1405209
74. Bauer PV, Duca FA, Waise TMZ, et al. Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. Cell Metab. 2018;27(1):101-17.e5. DOI:10.1016/j.cmet.2017.09.019
75. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262-6. DOI:10.1038/nature15766
76. De la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, et al. Metformin Is Associated With Higher Relative Abundance of Mucin-DegradingAkkermansia muciniphilaand Several Short-Chain Fatty Acid-Producing Microbiota in the Gut. Diabetes Care. 2016;40(1):54-62. DOI:10.2337/dc16-1324

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1. Zhang Y, Yamamoto T, Hisatome I, et al. Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells. Mol Cell Endocrinol. 2013;375(1-2):89-96. DOI:10.1016/j.mce.2013.04.027
2. Lanaspa MA, Cicerchi C, Garcia G, et al. Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver. PLoS One. 2012;7(11):e48801. DOI:10.1371/journal.pone.0048801
3. Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67(5):1739-42. DOI:10.1111/j.1523-1755.2005.00273.x
4. Johnson RJ, Perez-Pozo SE, Sautin YY, et al. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev. 2009;30(1):96-116. DOI:10.1210/er.2008-0033
5. Matsuoka T, Kajimoto Y, Watada H, et al. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest. 1997;99(1):144-50. DOI:10.1172/JCI119126
6. Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA. 1991;266(21):3008-11. DOI:10.1001/jama.1991.03470210076036
7. Muscelli E, Natali A, Bianchi S, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens. 1996;9(8):746-52. DOI:10.1016/0895-7061(96)00098-2
8. Dehghan A, van Hoek M, Sijbrands EJ, et al. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care. 2008;31(2):361-2. DOI:10.2337/dc07-1276
9. Kodama S, Saito K, Yachi Y, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care. 2009;32(9):1737-42. DOI:10.2337/dc09-0288
10. Lai HM, Chen CJ, Su BY, et al. Gout and type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences. Rheumatology (Oxford). 2012;51(4):715-20. DOI:10.1093/rheumatology/ker373
11. Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006;290(3):F625-31. DOI:10.1152/ajprenal.00140.2005
12. Sánchez-Lozada LG, Tapia E, Bautista-García P, et al. Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2008;294(4):F710-8. DOI:10.1152/ajprenal.00454.2007
13. Panevin TS, Zhelyabina OV, Eliseev MS, Shestakova MV. Urate-lowering effects of dipeptidyl peptidase-4 inhibitors. Diabetes Mellitus. 2020;23(4):349-56 
(in Russian) DOI:10.14341/DM12412
14. Panevin TS, Eliseev MS, Shestakova MV, Nasonov EL. Advantages of therapy with sodium glucose cotransporter type 2 inhibitors in patients with type 2 diabetes mellitus in combination with hyperuricemia and gout. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(5):110-8 (in Russian) DOI:10.26442/00403660.2020.05.000633
15. Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566-76. DOI:10.1007/s00125-017-4318-z
16. Dedov II, Shestakova MV, Mayorov AY, et al. Standards of specialized diabetes care. 9th ed. Diabetes mellitus. 2019;22(1S1):1-144 (in Russian) DOI:10.14341/dm221s1
17. Aroda VR, Knowler WC, Crandall JP, et al. Metformin for diabetes prevention: insights gained fr om the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study. Diabetologia. 2017;60(9):1601-11. DOI:10.1007/s00125-017-4361-9
18. Dedov II, Shestakova MV, Vikulova OK, et al. Atlas of Diabetes Register in Russian Federation, status 2018. Diabetes mellitus. 2019;22(2S):4-61 (in Russian)
DOI:10.14341/dm12208
19. Sharma M, Nazareth I, Petersen I. Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study. BMJ Open. 2016;6(1):e010210. DOI:10.1136/bmjopen-2015-010210
20. DeFronzo RA, Stonehouse AH, Han J, Wintle ME. Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: a meta-analysis of randomized clinical trials. Diabet Med. 2010;27(3):309-17. DOI:10.1111/j.1464-5491.2010.02941
21. Zhou K, Yee SW, Seiser EL, et al. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet. 2016;48(9):1055-9. DOI:10.1038/ng.3632
22. Domecq JP, Prutsky G, Leppin A, et al. Drugs Commonly Associated With Weight Change: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2015;100(2):363-70. DOI:10.1210/jc.2014-3421
23. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-65. DOI:10.1016/s0140-6736(98)07037-8
24. Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017;60(9):1620-9. DOI:10.1007/s00125-017-4337-9
25. U.K. Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249-58. DOI:10.2337/diabetes.44.11.1249
26. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin. Diabetes Care. 2006;29(2):254-8. DOI:10.2337/diacare.29.02.06.dc05-1558
27. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2003. DOI:10.1002/14651858.cd002967
28. Connelly PJ, Lonergan M, Soto-Pedre E, et al. Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: A GoDarts study. Diabetes Obes Metab. 2017;19(11):1579-86. DOI:10.1111/dom.12978
29. Coperchini F, Leporati P, Rotondi M, Chiovato L. Expanding the therapeutic spectrum of metformin: from diabetes to cancer. J Endocrinol Invest. 2015;38(10):1047-55. DOI:10.1007/s40618-015-0370-z
30. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-85. DOI:10.1007/s00125-017-4342-z
31. Anabtawi A, Miles JM. Metformin: nonglycemic effects and potential novel indications. Endocr Pract. 2016;22(8):999-1007.DOI:10.4158/ep151145.ra
32. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 2016;23(6):1060-5.DOI:10.1016/j.cmet.2016.05.011
33. 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(3):607-14.DOI:10.1042/bj3480607
34. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2010;12(1):21-35. DOI:10.1038/nrm3025
35. Lin HH, Chang KT, Hung CC, et al. Effects of the mTOR inhibitor Rapamycin on Monocyte-Secreted Chemokines. BMC Immunol. 2014;15(1). DOI:10.1186/s12865-014-0037-0
36. Vazirpanah N, Ottria A, van der Linden M, et al. mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy? Ann Rheum Dis. 2019;78(5):663-71. DOI:10.1136/annrheumdis-2018-214656
37. Saleiro D, Platanias LC. Intersection of mTOR and STAT signaling in immunity. Trends Immunol. 2015;36(1):21-9. DOI:10.1016/j.it.2014.10.006
38. Ursini F, Russo E, Pellino G, et al. Metformin and Autoimmunity: 
A “New Deal” of an Old Drug. Front Immunol. 2018;9. DOI:10.3389/fimmu.2018.01236
39. O’Neill LAJ, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493(7432):346-55. DOI:10.1038/nature11862
40. Kelly B, Tannahill GM, Murphy MP, O’Neill LAJ. Metformin Inhibits the Production of Reactive Oxygen Species from NADH: Ubiquinone Oxidoreductase to Lim it Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages. J Biol Chem. 2015;290(33):20348-59. 
DOI:10.1074/jbc.m115.662114
41. Bułdak Ł, Machnik G, Bułdak RJ, et al. Exenatide and metformin express their anti-inflammatory effects on human monocytes/macrophages by the attenuation of MAPKs and NFκB signaling. Naunyn Schmiedeberg Arch Pharmacol. 2016;389(10):1103-15. DOI:10.1007/s00210-016-1277-8
42. Krysiak R, Gdula-Dymek A, Okopień B. Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance. Pharmacol Rep. 2013;65(5):1311-6. DOI:10.1016/s1734-1140(13)71489-0
43. Krysiak R, Okopien B. The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose. Metabolism. 2013;62(1):39-43. DOI:10.1016/j.metabol.2012.06.009
44. Cameron AR, Morrison VL, Levin D, et al. Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ Res. 2016;119(5):652-65. DOI:10.1161/circresaha.116.308445
45. Yang H, Biermann MH, Brauner JM, et al. New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation. Front Immunol. 2016;7. DOI:10.3389/fimmu.2016.00302
46. Wang H, Li T, Chen S, et al. Neutrophil Extracellular Trap Mitochondrial DNA and Its Autoantibody in Systemic Lupus Erythematosus and a Proof-of-Concept Trial of Metformin. Arthritis Rheumatol. 2015;67(12):3190-200. DOI:10.1002/art.39296
47. Chikina MN. Prevention of arthritis attacks in the use of urate-lowering therapy in patients with gout. Rheumatology Science and Practice. 2018;56(6):760-6 (in Russian). DOI:10.14412/1995-4484-2018-760-766
48. Menegazzo L, Ciciliot S, Poncina N, et al. NETosis is induced by high glucose and associated with type 2 diabetes. Acta Diabetol. 2014;52(3):497-503. DOI:10.1007/s00592-014-0676-x
49. Menegazzo L, Scattolini V, Cappellari R, et al. The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo. Acta Diabetol. 2018;55(6):593-601. DOI:10.1007/s00592-018-1129-8
50. Bruderer SG, Bodmer M, Jick SS, Meier CR. Poorly controlled type 2 diabetes mellitus is associated with a decreased risk of incident gout: 
a population-based case-control study. Ann Rheum Dis. 2014;74(9):1651-8. DOI:10.1136/annrheumdis-2014-205337
51. Shestakov AV, Saprina TV, Anufrak IA, et al. Metformin: new perspectives in chemoprevention and therapy of cancer. Russian Journal of Biotherapy. 2018;17(3):12-9 (in Russian) DOI:10.17650/1726-9784-2018-17-3-12-19
52. Barskova VG, Eliseev MS, Kudaeva FM, et al. Effect of metformine on the clinical course of gout and insulin resistance. Clinical medicine. 2009;87(7):41-6 (in Russian)
53. Matsuura F, Yamashita S, Nakamura T, et al. Effect of visceral fat accumulation on uric acid metabolism in male obese subjects: Visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity. Metabolism. 1998;47(8):929-33.DOI:10.1016/s0026-0495(98)90346-8
54. Morales DR, Morris AD. Metformin in Cancer Treatment and Prevention. Ann Rev Med. 2015;66(1):17-29.DOI:10.1146/annurev-med-062613-093128
55. Lawrence T. The Nuclear Factor NF-κB Pathway in Inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651.DOI:10.1101/cshperspect.a001651
56. Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin Inhibits Cytokine-Induced Nuclear Factor κB Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells. Hypertension. 2006;47(6):1183-8. DOI:10.1161/01.hyp.0000221429.94591.72
57. Bijland S, Mancini SJ, Salt IP. Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin Sci. 2013;124(8):491-507. DOI:10.1042/cs20120536
58. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Nat Acad Sci U S A. 2012;110(3):972-7.DOI:10.1073/pnas.1221055110
59. The Diabetes Prevention Program Research Group. Intensive Lifestyle Intervention or Metformin on Inflammation and Coagulation in Participants With Impaired Glucose Tolerance. Diabetes. 2005;54(5):1566-72. DOI:10.2337/diabetes.54.5.1566
60. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-41. DOI:10.1038/nature04516
61. Jacques C, Gosset M, Berenbaum F, Gabay C. The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation. Vitam Horm. 2006;74:371-403. DOI:10.1016/S0083-6729(06)74016-X
62. Joosten LA, Netea MG, Mylona E, et al. Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1β production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis. Arthritis Rheum. 2010;62(11):3237-48.DOI:10.1002/art.27667
63. Nishimura A, Akahoshi T, Takahashi M, et al. Attenuation of monosodium urate crystal-induced arthritis in rabbits by a neutralizing antibody against interleukin-8. J Leukoc Biol. 1997;62(4):444-9. DOI:10.1002/jlb.62.4.444
64. Huang Z, Kraus VB. Does lipopolysaccharide-mediated inflammation have a role in OA? Nat Rev Rheumatol. 2016;12(2):123-9.DOI:10.1038/nrrheum.2015.158
65. Collins KH, Paul HA, Reimer RA, et al. Relationship between inflammation, the gut microbiota, and metabolic osteoarthritis development: studies in a rat model. Osteoarthritis Cartilage. 2015;23(11):1989-98. DOI:10.1016/j.joca.2015.03.014
66. Bramante C, Ingraham N, Murray T, et al. Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19. MedRxiv. 2020;2020.06.19.20135095. DOI:10.1101/2020.06.19.20135095
67. Matsiukevich D, Piraino G, Lahni P, et al. Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock. Biochim Biophys Acta Mol Basis Dis. 2017;1863(10 Pt. B):2680-91. DOI:10.1016/j.bbadis.2017.05.027
68. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38. DOI:10.1038/nri.2016.90
69. Son HJ, Lee J, Lee SY, et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators Inflamm. 2014;2014:973986. DOI:10.1155/2014/973986
70. Dai XJ, Tao JH, Fang X, et al. Changes of Treg/Th17 Ratio in Spleen of Acute Gouty Arthritis Rat Induced by MSU Crystals. Inflammation. 2018;41(5):1955-64. DOI:10.1007/s10753-018-0839-y
71. Shin N-R, Lee J-C, Lee H-Y, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2013;63(5):727-35. DOI:10.1136/gutjnl-2012-303839
72. Lee H, Ko G. Effect of Metformin on Metabolic Improvement and Gut Microbiota. Appl Environ Microbiol. 2014;80(19):5935-43. DOI:10.1128/aem.01357-14
73. Lee H, Lee Y, Kim J, et al. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes. 2018;9(2):155-65. DOI:10.1080/19490976.2017.1405209
74. Bauer PV, Duca FA, Waise TMZ, et al. Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. Cell Metab. 2018;27(1):101-17.e5. DOI:10.1016/j.cmet.2017.09.019
75. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262-6. DOI:10.1038/nature15766
76. De la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, et al. Metformin Is Associated With Higher Relative Abundance of Mucin-DegradingAkkermansia muciniphilaand Several Short-Chain Fatty Acid-Producing Microbiota in the Gut. Diabetes Care. 2016;40(1):54-62. DOI:10.2337/dc16-1324

М.С. Елисеев1, Т.С. Паневин*1, О.В. Желябина1, Е.Л. Насонов1,2

1 ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой», Москва, Россия;
2 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
*tarasel@list.ru

________________________________________________

Maksim S. Eliseev1, Taras S. Panevin*1, Olga V. Zhelyabina1, Evgeny L. Nasonov1,2

1 Nasonova Research Institute of Rheumatology, Moscow, Russia;
2 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
*tarasel@list.ru