Keywords
How to Cite
Abstract
The aim of the study was to investigate the effect of the Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor dapagliflozin on the activity of angiotensin-converting enzyme (ACE) in the centers regulating the hypothalamic-pituitary-adrenocortical system (HPAS), as well as the level of corticosteroids and ACE activity in the serum of rats with type 2 diabetes (T2D). Material and methods. T2D was modeled using a high-calorie diet and injections of low doses of streptozotocin (15 and 25 mg/kg) in intact male rats. A suspension of dapagliflozin (DGF) was administered to rats with T2D per os at a dose of 1 mg/kg once a day for 8 days. ACE activity in the hypothalamus, adenohypophysis, adrenal glands, and serum of rats was determined by a fluorimetric method using
Benzoyl-Gly-His-Leu as a substrate («Sigma», USA). The content of 11-hydroxycorticosteroids (11-OHCS) in the serum of rats was measured using a fluorimetric micromethod. Results. It was shown that in rats at the early stage of T2D (2 weeks after finding impaired glucose tolerance and increased basal glycemia level) ACE activity in the structures of HPAS — the hypothalamus, adenohypophysis, adrenal glands and serum does not differ from the enzyme activity in control. A significant increase in the level of protein and peptide substances was revealed in the neurohypophysis of rats with twoweek T2D in contrast to the structures of HPAS. Elevated level of 11- OHCS was detected in the serum of rats with T2D. According to the obtained data, multiple administration of DGF to diabetic rats for 8 days leads to a decrease in ACE activity and the level of 11-OHCS in the serum of animals with T2D. In the adrenal glands of these animals, ACE activity tends to decrease. Studies of the effect of the administration of DGF in the central links of HPAS revealed a significant increase in ACE activity in the adenohypophysis of rats with T2D. Conclusions. At an early stage of T2D development, ACE is not involved in HPAS dysfunction, — changes in enzyme activity in the hypothalamus, adenohypophysis, adrenal glands were not detected. Increased level of protein and peptide substances in the neurohypophysis of rats with T2D at the early stages indicates increased biosynthesis of nаnоpeptide hormones, in particular oxytocin and vasopressin. The consequence of the direct action of which is obviously an increase in the secretory activity of the adrenal segment in HPAS, namely the level of corticosteroids, found in our experiments.
Decreased activity of circulating form of serum ACE and corticosteroid level in rats with diabetes after 8 days of administration of the SGLT2 inhibitor, dapagliflozin, may be the important factors which provide a decrease in insulin resistance, the formation of which is enhanced by the angiotensin system, and also provide a decrease in arterial blood pressure, that positively affect the function of the kidneys and the circulatory system.
References
Washburn WN. Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents. Expert Opin Ther Pat. 2009 Nov;19(11):1485-99. doi: 10.1517/13543770903337828.
Merovci A, Mari A, Solis-Herrera C, Xiong J, Daniele G, Chavez-Velazquez A, et al. Dapagliflozin lowers plasma glucose concentration and improves β-cell function. J Clin Endocrinol Metab. 2015 May;100(5):1927-32. doi: 10.1210/jc.2017-02166.
Plosker GL. Dapagliflozin: a review of its use in patients with type 2 diabetes. Drugs. 2014 Dec;74(18):2191-209. doi: 10.1007/s40265-014-0324-3.
Scheen AJ. Pharmacodynamics, efficacy and safety of sodiumglucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015 Jan;75(1):33-59. doi: 10.1007/s40265-014-0337-y.
Sjöström CD, Johansson P, Ptaszynska A, List J, Johnsson E. Dapagliflozin lowers blood pressure in hypertensive and nonhypertensive patients with type 2 diabetes. Diab Vasc Dis Res. 2015 Sep;12(5):352-8. doi: 10.1177/1479164115585298.
Hooper NM. Angiotensin converting enzyme: implications from molecular biology for its physiological functions. Int J Biochem. 1991;23(7-8):641-7. doi: 10.1016/0020-711x(91)90032-i.
Anderson S. Role of local and systemic angiotensin in diabetic renal disease. Kidney Int Suppl. 1997 Dec;63: S107-10.
Eлисеева ЮЕ. Ангиотензин-превращающий фермент, его физиологическая роль. Вопросы медицинской химии. 2001;47(1):43-54 (Elisseeva YuE. Angiotensin-converting enzyme, its physiological role. Vopr Med Khim. 2001 Jan-Feb;47(1):43-54. Russian).
Kалинська ЛМ. Роль ангіотензинів у нейроендокринній регуляції гіпоталамо-гіпофізарно-надниркової системи у нормі та патології. Едокринологія. 2000; 5(2):228-40 (Kalynska LM. The role of angiotensins in neuroendocrine regulation of the hypothalamic-pituitary-adrenal system in normal and pathology. Endokrynologia. 2000;5(2):228-40. Ukrainian).
Mазурина НК. Нарушения гипоталамо-гипофизарно-над-почечниковой системы при сахарном диабете. Проблемы эндокринологии. 2007;53(2):29-34 (Mazurina NK. Hypothalamopituitary-adrenal axis disorders in diabetes. Probl Endokrinol (Mosk). 2007 Apr 15;53(2):29-34. Russian). doi: 10.14341/probl200753229-34.
Kалинська ЛМ, Єфімов АС. Динаміка компонентів ангіотензинової і калікреїн-кінінової систем та їх взаємодія в структурах гіпоталамо-гіпофізарно-адренокортикальної системи за умов розвитку стрептозотоцинового діабету. Ендокринологія. 2011;16(1):67-75 (Kalynska LM, Yefimov AS. Dynamics of components of angiotensin and kallikrein-kinine systems and their interaction in the structures of hypothalamus-pituitaryadrenocortical axis under development of streptozotocin-induced diabetes. Endokrynologia. 2011;16(1):67-75. Ukrainian).
Gaboury CL, Simonson DC, Seely EW, Hollenberg NK, Williams GH. Relation of pressor responsiveness to angiotensin II and insulin resistance in hypertension. J Clin Invest. 1994 Dec;94(6):2295-300. doi: 10.1172/JCI117593.
Nicola W, Sidhom G, El Khyat Z, Ibrahim S, Salah A, El Sayed A. Plasma angiotensin II, renin activity and serum angiotensin-converting enzyme activity in non-insulin dependent diabetes mellitus patients with diabetic nephropathy. Endocr J. 2001 Feb;48(1):25-31. doi: 10.1507/endocrj.48.25.
Lin S, Yang J, Wu G, Liu M, Luan X, Lv Q at al. Preventive effect of taurine on experimental type II diabetic nephropathy. J Biomed Sci. 2010 Aug 24;17 Suppl 1(Suppl 1): S46. doi: 10.1186/1423-0127-17-S1-S46.
Mansor LS, Gonzalez ER, Cole MA, Tyler DJ, Beeson JH, Clarke K, et al. Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin. Cardiovasc Diabetol. 2013 Sep 24;12:136. doi: 10.1186/1475-2840-12-136.
Yang HY, Neff NH. Distribution and properties of angiotensin converting enzyme of rat brain. J Neurochem. 1972 Oct;19(10):2443-50. doi:10.1111/j.1471-4159.1972.tb01298.x.
Павлихина ЛВ, Елисеева ЮЕ, Позднев ВФ, Орехович ВН. Определение активности карбоксикатепсина в сыворотке крови человека. Вопр. мед. химии. 1975;21(1):54-9 (Pavlikhina LV, Eliseeva IuE, Pozdnev VF, Orekhovich VN. Determination of carboxycathepsin (peptidyl dipeptidase) activity in human blood serum. Vopr Med Khim. 1975 Jan-Feb;21(1):54-60. Russian).
Балашов ЮГ. Флюориметрический микрометод определения кортикостероидов: сравнение с другими методами. Физиол. журн. СССР. 1990;76(2):280-3 (Balashov YuG. Fluorometric micromethod of corticosteroids determination; comparison with other methods. Fiziologicheskij zhurnal SSSR. 1990;76(2):280-3. Russian).
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265-75.
Guillon G, Grazzini E, Andrez M, Breton C, Trueba M, Serradeil-LeGal C. Vasopressin: a potent autocrine/paracrine regulator of mammal adrenal functions. Endocr Res. 1998 Aug-Nov;24(3-4):703-10. doi:10.3109/07435809809032672.
Tanoue A, Ito S, Honda K, Oshikawa S, Kitagawa Y, Koshimizu TA, et al. The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions. J Clin Invest. 2004 Jan;113(2):302-9. doi:10.1172/JCI19656.
Шестакова СА, Степанов РП, Григоренко ГА, Федорова НВ, Тишковская ЮН. Антиоксидантная защита и структурные изменения в головном мозге у крыс при экспериментальном сахарном диабете. Пробл. эндокринологии. 2006;52(5):37-43 (Shestakova SA, Stepanov RP, Grigorenko GA, Fedorova NV, Tishkovskaya YuN. Antioxidative defense and structural changes in the brain of rats with experimental diabetes mellitus. Problems of Endocrinology. 2006;52(5):37-43. Russian).
Корпачева-Зінич ОВ, Калинська ЛМ. Активність сироваткового ангіотензин-перетворювального ферменту у хворих на цукровий діабет 2 типу залежно від статі та андрогенного забезпечення. Укр. терапевт. журнал. 2009;(1):68-75 (Korpacheva-Zinich OV, Kalynska LM. The activity of serum angiotensinconverting enzyme in patients with type 2 diabetes mellitus depending on gender and androgen supply. Ukr Therap Zhurn. 2009;(1):68-75).
Galletti F, Strazzullo P, Capaldo B, Carretta R, Fabris F, Ferrara LA, et al. Controlled study of the effect of angiotensin converting enzyme inhibition versus calcium-entry blockade on insulin sensitivity in overweight hypertensive patients: Trandolapril Italian Study (TRIS). J Hypertens. 1999 Mar;17(3):439-45. doi:10.1097/00004872-199917030-00018.
Oksa A, Gajdos M, Fedelesová V, Spustová V, Dzürik R. Effects of angiotensin-converting enzyme inhibitors on glucose and lipid metabolism in essential hypertension. J Cardiovasc Pharmacol. 1994 Jan;23(1):79-86. doi: 10.1097/00005344-199401000-00010.
Kudoh A, Matsuki A. Effects of angiotensin-converting enzyme inhibitors on glucose uptake. Hypertension. 2000 Aug;36(2):239-44. doi: 10.1161/01.hyp.36.2.239.
Колесник ЮМ, Орестенко ЮН, Абрамов АВ. Состояние вазопрессин-, окситоцин- и кортиколиберинсинтезирующих структур гипоталамуса при экспериментальном сахарном диабете у крыс различного пола. Проблемы эндокринологии. 1993;39(1):45-48 (Kolesnik YuM, Orestenko YuN, Abramov AV. Vasopressin, oxitocin, and corticoliberin-synthesizing hypothalamic structures in rats of both sexes with induced diabetes mellitus. Problems of Endocrinology.1993;39(1):45-48. Russian).
Тржецинський СД. Вплив екзогенних нейропептидів на ендокринну функцію підшлункової залози та асоційовані метаболічні процеси в нормі і при цукровому діабеті (експериментальне дослідження) [дисертація]. Запоріжжя: Запоріжський медичний університет; 2011. 376 с. (Trzhecynsky SD. Influence of exogenous neuropeptides on endocrine function of the pancreas and associated metabolic processes in normal and in diabetes mellitus (experimental study) [dissertation]. Zaporizhzhia: Zaporizhzhia Medical University; 2011. 376 p. Ukrainian).
Chan O, Chan S, Inouye K, Vranic M, Matthews SG. Molecular regulation of the hypothalamo-pituitary-adrenal axis in streptozotocin-induced diabetes: effects of insulin treatment. Endocrinology. 2001 Nov;142(11):4872-9. doi: 10.1210/endo.142.11.8474.
Chan O, Inouye K, Akirav E, Park E, Riddell MC, Vranic M, Matthews SG. Insulin alone increases hypothalamo-pituitaryadrenal activity, and diabetes lowers peak stress responses. Endocrinology. 2005 Mar;146(3):1382-90. doi: 10.1210/en.2004-0607. Epub 2004 Nov 24.
Kоваленко ВН, Талаева ТВ, Братусь ВВ. Сердечно-сосудистые заболевания и ренин-ангиотензиновая системa. К.: Морион. 2013. 232 с. (Kovalenko VN, Talayeva TV, Bratus VV. Cardiovascular diseases and renin-angiotensin system. K.: Morion. 2013. 232 p.).