Microcirculatory dopplerography as a method to evaluate drugs endothelial protective properties in type 2 diabetic patients

Objective - to identify the most accurate way of drugs endothelial protective properties evaluation. Material and methods. Blood endothelin-1 (E) and acetylcholine-induced endothelial dependent vasodilation (EDV) were measured for 9 months in type 2 diabetic patients receiving either metformin (MET) (group 1) or MET and liraglutide (LIR) (group 2). Results. E was normal in group 1 at baseline and decreased only with glycaemia decline, in group 2 it was primarily increased and declined independently on glycaemia dynamics. In both groups E normalized in 6 months. EDV was impaired primarily in groups 1 and 2 and normalized only in group 2 in 9 months. Conclusions. LIR improves endothelial function, independently on glycaemia. Dopplerography in more accurate in drugs endothelial protective effects evaluation than circulating markers.

сахарный диабет 2-го типа, эндотелиальная дисфункция, допплерография, эндотелийзависимая вазодилатация, лираглутид, type 2 diabetes mellitus, endothelial dysfunction, dopplerography, endothelial dependent vasodilation, liraglutide

1. Алгоритмы специализированной медицинской помощи больным сахарным диабетом / под ред. И. И. Дедова, М. В. Шестаковой, А. Ю. Майорова. 8-й вып. // Сахар. диаб. - 2017. - № 20 (1S). - С. 1-112. doi: 10.14341/DM20171S8. [Algoritmy spetsial’zirovannoi pomoshchi bol’nym sakharnym diabetom. Diabetes mellitus. 2017;20(1S):1-112 (In Russ.)].

2. Малахова З. Л., Васина Е. Ю., Власов Т. Д. Эндотелий-зависимая вазодилатация сосудов кожи здорового человека: оксид азота или гиперполяризующий фактор? // Росс. физиолог. журн. им. И. М. Сеченова. - 2017. - Т. 103. - № 8. - С. 930-939. [Malakhova ZL, Vasina EYu, Vlasov TD. Endothelium-dependent vasodilation of the skin of a healthy man: nitrogen oxide or hyperpolarizing factor? Neuroscience and behavioral physiology. 2017;103(8):930-939 (In Russ.)].

3. Малахова З. Л., Васина Е. Ю., Воробьев Е. А. и др. Неинвазивный метод исследования эндотелиального гиперполяризующего фактора в клинике // Регионарное кровообращение и микроциркуляция. - 2013. - Т. 12. - № 4 (48). - С. 70-74. [Malakhova ZL, Vasina EYu, Vorobiev EA, et al. Non-invasive method of assessment of endothelium-derived hyperpolarizing factor in human. Regional hemodynamics and microcirculation. 2013;12:4(48):70-74 (In Russ.)].

4. Симаненкова А. В., Макарова М. Н., Бутомо М. И. и др. Эндотелиопротективный эффект лираглутида у больных сахарным диабетом 2-го типа // Артериальная гипертензия. - 2018. - Т. 24. - № 1. - С. 81-92. doi: 10.18705/1607-419X-2018-24-1-81-92. [Simanenkova AV, Makarova MN, Butomo MI, et al. Endothelial protective effect of liraglutide in type 2 diabetes mellitus. Arterial Hypertension. 2018;24(1):81-92 (In Russ.)].

5. Симаненкова А. В., Макарова М. Н., Васина Л. В. и др. Агонист рецептора глюкагоноподобного пептида-1 уменьшает дисфункцию эндотелия у больных сахарным диабетом 2-го типа // Регионарное кровообращение и микроциркуляция. - 2018. - Т. 17. - № 2. - С. 59-65. [Simanenkova AV, Makarova MN, Vasina LV, et al. Glucagon-like peptide-1 receptor agonist diminishes endothelial dysfunction in type 2 diabetic patients. Regional hemodynamics and microcirculation. 2018;17(2):59-65 (In Russ.)].

6. Chadderdon SM, Belcik JT, Bader L, et al. Temporal changes in skeletal muscle capillary responses and endothelial-derived vasodilators in obesity-related insulin resistance. Diabetes 2016;65:2249-2257. doi: 10.2337/db15-1574.

7. Godo S, Sawada A, Saito H, et al. Disruption of physiological balance between nitric oxide and endothelium-dependent hyperpolarization impairs cardiovascular homeostasis in mice. Arterioscler Thromb Vasc Biol 2016;36:97-107. doi: 10.1161/ATVBAHA.115.306499.

8. IDF Diabetes Atlas. 8th ed. 2017. URL: http://www.diabetesatlas.org/across-the-globe.html.

9. Jia G, Sowers JR. Endothelial dysfunction potentially interacts with impaired glucose metabolism to increase cardiovascular risk. Hypertension 2014;64:1192-11931. doi: U61/HYPERTENSIONAHA.U4.04348.

10. Kagota S, Yamaguchi Y, Nakamura K, et al. Altered endothelium-dependent responsiveness in the aortas and renal arteries of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus. Gen Pharmacol. 2000;34:201-209. doi: 10.1016/S0306-3623(00)000616

11. Katakam PV, Ujhelyi MR, Miller AW. EDHF-mediated relaxation is impaired in fructose-fed rats. J Cardiovasc Pharmacol. 1999;34:461-467.

12. Kobuchi S, Miura K, Iwao H, et al. Nitric oxide modulation of endothelium-derived hyperpolarizing factor in agonist-induced depressor responses in anesthetized rats. Eur J Pharmacol 2015;762:26-34. doi: 10.1016/j.ejphar.2015.04.053.

13. Li N, Zhao Y, Yue Y, et al. Liraglutide ameliorates palmitate-induced endothelial dysfunction through activating AMPK and reversing leptin resistance. Biochem Biophys Res Commun. 2016 Sep 9;478(1):46-52. doi: 10.1016/j.bbrc.2016.07.095.

14. Liu H, Dear AE, Knudsen LB, et al. A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol. 2009 Apr;201(1):59-66. doi: 10.1677/JOE-08-0468.

15. Mattace Raso G, Pirozzi C, d’Emmanuele di Villa Bianca R, et al. Palmitoylethanolamide treatment reduces blood pressure in spontaneously hypertensive rats: involvement of cytochrome p450-derived eicosanoids and renin angiotensin system. PLoS One 2015;10:e0123602. doi: 10.1371/journal.pone.0123602.

16. Miller AW, Katakam PV, Ujhelyi MR. Impaired endothelium-mediated relaxation in coronary arteries from insulin-resistant rats. J Vasc Res. 1999;36:385-392.

17. Minami A, Ishimura N, Harada N, et al. Exercise training improves acetylcholine-induced endothelium-dependent hyperpolarization in type 2 diabetic rats, Otsuka Long-Evans Tokushima fatty rats. Atherosclerosis. 2002;162:85-92.

18. Sowers JR. Diabetes mellitus and vascular disease. Hypertension 2013;61:943-947. doi: 10.1161/HYPERTENSIONAHA.111.00612.

19. Vincent MA, Clerk LH, Lindner JR, et al. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes. 2004;53:1418-1423. doi: 10.2337/diabetes.53.6.1418.

20. Wu X, Makynen H, Kahonen M, et al. Mesenteric arterial function in vitro in three models of experimental hypertension. J Hypertens. 1996;14:365-372.