Metformin and vildagliptin combination: A new approach of endothelial nitric oxide synthase activity regulation and metabolism in diabetes mellitus type 2

Cover Page

Abstract


This review analyzes the research results of additional effects and mechanisms of action of sugar-reducing drugs. Hence it has been suggested that asymmetric dimethylarginine may be a target molecule for metformin, vildagliptin, and combinations thereof.


Aleksandr L. Urakov

Izhevsk State Medical Academy

Author for correspondence.
Email: urakoval@live.ru

Russian Federation, Izhevsk

Dr. Med. Sci., Professor, Head, Dept. of General and Clinical Pharmacology

Konstantin G. Gurevich

A.I. Yevdokimov Moscow State University of Medicine and Dentistry of the Ministry of Healthcare of the Russian Federation

Email: kgurevich@mail.ru

Russian Federation, Moscow

PhD, Assistant Professor, Head, Department of UNESCO

Iuliia A. Sorokina

Privolzhskii Research Medical University

Email: zwx@inbox.ru

Russian Federation, Nizhnii Novgorod

PhD, Assistant Professor, Department of General and Clinical Pharmacology

Liubov V. Lovtsova

Privolzhskii Research Medical University

Email: lovcovalubov@mail.ru

Russian Federation, Nizhnii Novgorod

Dr. Med. Sci., Assistant Professor, Head, Department of General and Clinical Pharmacology

Olga V. Zanozina

Privolzhskii Research Medical University

Email: zwx@inbox.ru

Russian Federation, Nizhnii Novgorod

Dr. Med. Sci., Professor, Department of Hospital Therapy

Andrei A. Monakhov

Privolzhskii Research Medical University

Email: and.monahov2017@yandex.ru

Russian Federation, Nizhnii Novgorod

PhD, Assistant Professor, Department of General and Clinical Pharmacology

  1. Арутюнян А.В., Пустыгина А.В., Милютина Ю.П., Залозняя И.В. Молекулярные маркеры окислительного стресса у потомства при экспериментальной гипергомоцистеинемии // Молекулярная медицина. - 2015. - № 5. - С. 41-46. [Arutyunyan AV, Pustygina AV, Milyutina YP, Zaloznyaya IV. Prenatal hyperhomocysteinemia and oxidative stress profile in the rat offspring. Molekukiarnaia meditsina. 2015;(5):41-46. (In Russ.)]
  2. Барсук А.Л., Возова А.М., Малинок Е.В., и др. Динамика и взаимосвязь показателей состояния эндотелия и иммунного статуса у пациентов, находящихся на программном гемодиализе, на фоне лечения препаратом аторвастатин // Современные технологии в медицине. - 2013. - Т. 5. - № 2. - С. 78-83. [Barsuk AL, Vozova AM, Malinok EV, et al. The Dynamics and Interaction of Endothelium State and Immune Status Variations in Program Hemodialysis Patients against the Background of Atorvastatin Therapy. Modern technologies in medicine. 2013;5(2):78-83. (In Russ.)]
  3. Громова О.А., Стаховская Л.В., Торшин И.Ю., Томилова И.К. Прием метформина провоцирует нарушения гомеостаза витамина В12 // Consilium Medicum. - 2017. - Т. 19. - № 4. - С. 58-64. [Gromova OA, Stakhovskaya LV, Torshin IY, Tomilova IK. The application of metformin provokes disturbance in vitamin B12 homeostasis. Consilium Medicum. 2017;19(4):58-64. (In Russ.)]
  4. Далантаева Н.С. Роль метформина в нейропротекции // Ожирение и метаболизм. - 2013. - Т. 10. - № 1. - С. 47-48. [Dalantaeva NS. The role of metformin in neuroprotection. Obesity and metabolism. 2013;10(1):47-48. (In Russ.)]. doi: 10.14341/2071-8713-5072.
  5. Дедов И.И., Шестакова М.В., Майоров А.Ю., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. - Вып. 8 / Под ред. И.И. Дедова, М.В. Шестаковой // Сахарный диабет. - 2017. - Т. 20. - № 1S. - C. 1-121. [Dedov II, Shestakova MV, Mayorov AY, et al. Ed by I.I. Dedov, M.V. Shestakova. Standards of specialized diabetes care. 8th ed. Diabetes mellitus. 2017;20(1S): 1-121. (In Russ.)]. doi: 10.14341/DM20171S8.
  6. Жлоба А.А. Роль АДМА в качестве эндогенного ингибитора eNOS и одного из медиаторов развития вазомоторной эндотелиальной дисфункции // Регионарное кровообращение и микроциркуляция. - 2007. - Т. 6. - № 3. - С. 4-14. [Zhloba AA. Rol’ ADMA v kachestve endogennogo ingibitora eNOS i odnogo iz mediatorov razvitiya vazomotornoy endotelial’noy disfunktsii. Regionarnoe krovoobrashchenie i mikrotsirkuliatsiia. 2007;6(3):4-14. (In Russ.)]
  7. Кравчук Е.Н., Галагудза М.М. Применение метформина при сочетании ишемической болезни сердца и сахарного диабета 2-го типа: механизмы действия и клиническая эффективность // Сахарный диабет. - 2013. - Т. 16. - № 1. - С. 5-14. [Kravchuk EN, Galagudza MM. 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.)]. doi: 10.14341/2072-0351-3590.
  8. Кузнецов И.С., Сереженков В.А., Романцова Т.И., Ванин А.Ф. Роль метформина как донора оксида азота в регуляции углеводного обмена у пациентов с сахарным диабетом 2-го типа // Сахарный диабет. - 2013. - Т. 16. - № 3. - С. 41-45. [Kuznetsov IS, Serezhenkov VA, Romantsova TI, Vanin AF. Metformin regulates glycemic homeostasis in patients with type 2 diabetes mellitus as an NO donor. Diabetes mellitus. 2013;16(3):41-45. (In Russ.)]. doi: 10.14341/2072-0351-816.
  9. Малинок Е.В., Барсук А.Л., Возова А.М., и др. Взаимосвязь маркеров воспаления и показателей состояния эндотелия сосудов у пациентов, находящихся на программном гемодиализе, при лечении дезоксирибонуклеатом натрия // Современные технологии в медицине. - 2014. - Т. 6. - № 4. - С. 127-133. [Malinok EV, Barsuk AL, Vozova AM, et al. The Relationship of Inflammation Markers and Vascular Endothelial Indicators in Program Hemodialysis Patients in Sodium Deoxyribonucleate Treatment. Modern technologies in medicine. 2014;6(4):127-133. (In Russ.)]
  10. Недосугова Л.В. Место метформина в лечении сахарного диабета 2-го типа на современном этапе // Терапия. - 2015. - № 4. - C. 24-31. [Nedosugova LV. Current place of metformin in the treatment of type 2 diabetes. Terapiya. 2015;(4):24-31. (In Russ.)]
  11. Родионов Р.Н., Блохин И.О., Галагудза М.М., и др. Асимметричный диметиларгинин и его роль в этиологии и патогенезе сердечно-сосудистых заболеваний // Артериальная гипертензия. - 2008. - Т. 14. - № 4. - С. 306-314. [Rodionov RN, Blokhin IO, Galagudza MM. The emerging role of asymmetric dimethylarginine in cardiovascular disease. Arterialʹnaia gipertenziia. 2008;14(4):306-314. (In Russ.)]
  12. Руяткина Л.А., Руяткин Д.С. Многоплановые эффекты метформина у пациентов с сахарным диабетом 2-го типа // Сахарный диабет. - 2017. - Т. 20. - № 3. - С. 210-219. [Ruyatkina LA, Ruyatkin DS. Multidimensional effects of metformin in patients with type 2 diabetes. Diabetes mellitus. 2017;20(3):210-219. (In Russ.)]. doi: 10.14341/DM2003458-64.
  13. Сорокина Ю.А., Ловцова Л.В., Богдарина А.В., и др. Синергизм при комбинированном использовании пероральных сахароснижающих препаратов // Современные технологии в медицине. - 2014. - Т. 6. - № 3. - С. 85-90. [Sorokina YA, Lovtsova LV, Bogdarina AV, et al. Synergism in Combined Use of Oral Antihyperglycemic Drugs. Modern technologies in medicine. 2014;6(3):85-90. (In Russ.)]
  14. Шестакова Е.А. Выбор второй линии терапии у пациентов с сахарным диабетом 2-го типа: активация метаболической памяти // Сахарный диабет. - 2017. - Т. 20. - № 5. - С. 356-362. [Shestakova EA. Second line therapy in type 2 diabetes: legacy effect activation. Diabetes mellitus. 2017;20(5):356-362. (In Russ.)]. doi: 10.14341/DM8793.
  15. Шпаков А.О., Деркач К.В. Молекулярные механизмы влияния метформина на функциональную активность нейронов мозга // Российский физиологический журнал им. И.М. Сеченова. - 2017. - Т. 103. - № 5. - С. 504-517. [Shpakov AO, Derkach KV. The Melanocortin Signal System of the Hypothalamus and Its Functional State in Type 2 Diabetes Mellitus and Metabolic Syndrome. Russian journal of physiology. 2017;103(5):504-517. (In Russ.)]
  16. Ali MA, El-Abhar HS, Kamel MA, Attia AS. Antidiabetic Effect of Galantamine: Novel Effect for a Known Centrally Acting Drug. PloS one. 2015;10(8):e0134648. doi: 10.1371/journal.pone.0134648.z.
  17. Ando R, Ueda S, Yamagishi S, et al. Involvement of advanced glycation end product-induced asymmetric dimethylarginine generation in endothelial dysfunction. Diab Vasc Dis Res. 2013;10(5):436-441. doi: 10.1177/1479164113486662.
  18. Bahne E, Hansen M, Bronden A, et al. Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin. Diabetes Obes Metab. 2016;18(10):955-961. doi: 10.1111/dom.12697.
  19. 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. doi: 10.1159/000332382.
  20. Beulens JW, Hart HE, Kuijs R, et al. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetol. 2015;52(1):47-53. doi: 10.1007/s00592-014-0597-8.
  21. Davis BJ, Xie Z, Viollet B, Zou MH. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes. 2006;55(2):496-505. doi: 10.2337/diabetes.55.02.06.db05-1064.
  22. Bronden A, Alber A, Rohde U, et al. Single-Dose Metformin Enhances Bile Acid-Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes. J Clin Endocrinol Metab. 2017;102(11):4153-4162. doi: 10.1210/jc.2017-01091.
  23. Cakirca M, Karatoprak C, Zorlu M, et al. Effect of vildagliptin add-on treatment to metformin on plasma asymmetric dimethylarginine in type 2 diabetes mellitus patients. Drug Des Devel Ther. 2014;8:239-243. doi: 10.2147/DDDT.S52545.
  24. Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2016;42(5):316-327. doi: 10.1016/j.diabet.2016.03.008.
  25. Devangelio E, Santilli F, Formoso G, et al. Soluble RAGE in type 2 diabetes: association with oxidative stress. Free Radic Biol Med. 2007;43(4):511-518. doi: 10.1016/j.freeradbiomed.2007.03.015.
  26. El-Mesallamy HO, Hamdy NM, Ezzat OA, Reda AM. Levels of soluble advanced glycation end product-receptors and other soluble serum markers as indicators of diabetic neuropathy in the foot. J Investig Med. 2011;59(8):1233-8. doi: 10.2130/JIM.0b013e318231db64.
  27. Green BD, Irwin N, Duffy NA, et al. Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1. Eur J Pharmacol. 2006;547(1-3):192-199. doi: 10.1016/j.ejphar.2006.07.043.
  28. Hsu CP, Hsu PF, Chung MY, et al. Asymmetric dimethylarginine and long-term adverse cardiovascular events in patients with type 2 diabetes: relation with the glycemic control. Cardiovasc Diabetol. 2014;13:156. doi: 10.1186/s12933-014-0156-1.
  29. Hussain M, Majeed Babar MZ, Hussain MS, Akhtar L. Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with non alcoholic fatty liver disease. Pak J Med Sci. 2016;32(6):1396-1401. doi: 10.12669/pjms.326.11133.
  30. Johanns M, Lai YC, Hsu MF, 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.
  31. Lin CH, Cheng YC, Nicol CJ, et al. Activation of AMPK is neuroprotective in the oxidative stress by advanced glycosylation end products in human neural stem cells. Exp Cell Res. 2017;359(2):367-373. doi: 10.1016/j.yexcr.2017.08.019.
  32. Lindsay RS, Loeken MR. Metformin use in pregnancy: promises and uncertainties. Diabetologia. 2017;60(9):1612-1619. doi: 10.1007/s00125-017-4351-y.
  33. Maas R. Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA). Vasc Med. 2005;10 Suppl 1:S49-57. doi: 10.1191/1358863x05vm605oa.
  34. Macauley M, Hollingsworth KG, Smith FE, et al. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab. 2015;100(4):1578-1585. doi: 10.1210/jc.2014-3794.
  35. Marshall SM. 60 years of metformin use: a glance at the past and a look to the future. Diabetologia. 2017;60(9):1561-1565. doi: 10.1007/s00125-017-4343-y.
  36. Mason RP, Jacob RF, Kubant R, et al. Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats. J Atheroscler Thromb. 2011;18(9):774-783. doi: 10.5551/jat.7666.
  37. Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287(6):E1209-1215. doi: 10.1152/ajpendo.00237.2004.
  38. Obeid R, Jung J, Falk J, et al. Serum vitamin B12 not reflecting vitamin B12 status in patients with type 2 diabetes. Biochimie. 2013;95(5):1056-1061. doi: 10.1016/j.biochi.2012.10.028.
  39. Ojima A, Ishibashi Y, Matsui T, et al. Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. Am J Pathol. 2013;182(1):132-141. doi: 10.1016/j.ajpath.2012.09.016.
  40. Park MJ, Han HJ, Kim DI. Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress. Int J Mol Sci. 2017;18(7). doi: 10.3390/ijms18071421.
  41. Phung OJ, Sobieraj DM, Engel SS, Rajpathak SN. Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(5):410-417. doi: 10.1111/dom.12233.
  42. Scheen AJ. Pharmacological management of type 2 diabetes: what’s new in 2017? Expert Rev Clin Pharmacol. 2017;10(12):1383-1394. doi: 10.1080/17512433.2017.1376652.
  43. Thondam SK, Cross A, Cuthbertson DJ, et al. Effects of chronic treatment with metformin on dipeptidyl peptidase-4 activity, glucagon-like peptide 1 and ghrelin in obese patients with Type 2 diabetes mellitus. Diabet Med. 2012;29(8):e205-210. doi: 10.1111/j.1464-5491.2012.03675.x.
  44. Tsai CM, Kuo HC, Hsu CN, et al. Metformin reduces asymmetric dimethylarginine and prevents hypertension in spontaneously hypertensive rats. Transl Res. 2014;164(6):452-459. doi: 10.1016/j.trsl.2014.07.005.
  45. Wojcicka G, Jamroz-Wisniewska A, Czechowska G, et al. The paraoxonase 1 (PON1), platelet-activating factor acetylohydrolase (PAF-AH) and dimethylarginine dimethylaminohydrolase (DDAH) activity in the metformin treated normal and diabetic rats. Eur J Pharmacol. 2016;789:187-94. doi: 10.1016/j.ejphar.2016.07.034.
  46. Wu D, Li L, Liu C. Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Obes Metab. 2014;16(1):30-37. doi: 10.1111/dom.12174.
  47. Xia XS, Li X, Wang L, et al. Supplementation of folic acid and vitamin B(1)(2) reduces plasma levels of asymmetric dimethylarginine in patients with acute ischemic stroke. J Clin Neurosci. 2014;21(9):1586-1590. doi: 10.1016/j.jocn.2013.11.043.
  48. Zhang Q, Xiao X, Li M, et al. Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats. PloS one. 2017;12(10):e0184735. doi: 10.1371/journal.pone.0184735.
  49. Zhou Z, Tang Y, Jin X, et al. Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFkappaB Pathway Suppression. J Diabetes Res. 2016;2016:4847812. doi: 10.1155/2016/4847812.
  50. Zhu XC, Jiang T, Zhang QQ, et al. Chronic Metformin Preconditioning Provides Neuroprotection via Suppression of NF-kappaB-Mediated Inflammatory Pathway in Rats with Permanent Cerebral Ischemia. Mol Neurobiol. 2015;52(1):375-385. doi: 10.1007/s12035-014-8866-7.
  51. Zobel EH, von Scholten BJ, Reinhard H, et al. Symmetric and asymmetric dimethylarginine as risk markers of cardiovascular disease, all-cause mortality and deterioration in kidney function in persons with type 2 diabetes and microalbuminuria. Cardiovasc Diabetol. 2017;16(1):88. doi: 10.1186/s12933-017-0569-8.

Views

Abstract - 153

PDF (Russian) - 157

PlumX

Comments on this article

View all comments

Copyright (c) 2018 Urakov A.L., Gurevich K.G., Sorokina I.A., Lovtsova L.V., Zanozina O.V., Monakhov A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.