Angiotensin II and transforming growth factor β affect cardiovascular and renal disease in patients with type 2 diabetes mellitus: benefits of dpp-4 inhibitors treatment

BACKGROUND: Diabetes mellitus type 2 (T2DM) is associated with impaired glucose metabolism and peripheral insulin resistance, which is accompanied by an high risk of cardiovascular disease (CVD) and nephropathy. Metabolic syndrome and T2DM are accompanied by renin-angiotensin system (RAS) activation, which is also associated with increased risk of CVD and kidney damage. Obesity lead to a wide range of pathophysiological changes, that stimulate cardiac fibrosis, and various fibrosis processes initiation, including activation of transforming growth factor β (TGF-β).

AIMS: To determine activity of angiotensin II (Ang II) and TGF-β in patients with obesity and T2DM and their association with heart and kidney damage.

MATERIALS AND METHODS: Ang II and TGF-β were identified in the peripheral blood of 66 obese patients aged 48-65 years. The first group included 21 patients with coronary heart disease (CHD) and T2DM; The second group included 22 patients with T2DM and excluded CHD; The third group – 20 patients with normal glucose metabolism and excluded CHD.

RESULTS: The values of TGF-β in the 1st group (patients with CHD) were statistically lower than in the group of metabolically healthy obesity (p=0.021). Patients who received DPP-4 inhibitors had a lower Ang II level compared to patients with other hypoglycemic therapy (p=0.005). TGF-β positively correlated with glomerular filtration rate (eGFR) in all patients (r=-0.414, p=0.006). TGF-β negatively correlated with the degree of internal carotid artery stenosis in patients of the 2nd group (r=-0.42, p=0.09) and LDL-cholesterol in all patients (r=-0.426, p=0.038).

CONCLUSIONS: TGF-β negatively correlated with the factors that contribute to CVD progression. TGF-β correlated with pathological angiogenesis and changes in normal cardiac geometry in obesity, T2DM and CHD. DPP-4 inhibitors can improve the cardiovascular prognosis in this group of patients by affecting Ang II level. Low levels of TGF-β were associated with higher cardiovascular risk and were commonly found in patients with more severe nephropathy.

оbesity, diabetes mellitus, cardiovascular disease, transforming growth factor β, fibroblast growth factor

1. Kannel WB, McGee DL. Diabetes and Cardiovascular Disease: The Framingham Study. JAMA. 1979;241(19):2035–2038. DOI:10.1001/jama.1979.03290450033020

2. Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol. 2002;89(2):3-9. DOI:10.1016/S0002-9149(01)02321-9

3. Vejakama P, Thakkinstian A, Lertrattananon D, et al. Reno-protective effects of renin–angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis. Diabetologia. 2012;55(3):566-578. DOI:10.1007/s00125-011-2398-8

4. Швангирадзе Т.А., Бондаренко И.З., Трошина Е.А., Шестакова М.В. МикроРНК в диагностике сердечно-сосудистых заболеваний, ассоциированных с сахарным диабетом 2-го типа и ожирением // Терапевтический архив. — 2016. — Т.88. — №10. — С.87-92. [Shvangiradze TA, Bondarenko IZ, Troshina EA, Shestakova M V. MiRNAs in the diagnosis of cardiovascular diseases associated with type 2 diabetes mellitus and obesity. Terapevticheskiĭ arkhiv. 2016;88(10):87-92. (In Russ).] DOI:10.17116/terarkh201688687-92

5. Kalupahana NS, Moustaid-Moussa N. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev. 2012;13(2):136-149. DOI:10.1111/j.1467-789X.2011.00942.x

6. Giacchetti G, Faloia E, Mariniello B, et al. Overexpression of the Renin-Angiotensin System in Human Visceral Adipose Tissue in Normal and Overweight Subjects. Am J Hypertens. 2002;15(5):381-388. DOI:10.1016/S0895-7061(02)02257-4

7. Bastien M, Poirier P, Lemieux I, Després J-P. Overview of Epidemiology and Contribution of Obesity to Cardiovascular Disease. Prog Cardiovasc Dis. 2014;56(4):369-381. DOI:10.1016/j.pcad.2013.10.016

8. Skov J, Dejgaard A, Frøkiær J, et al. Glucagon-Like Peptide-1 (GLP-1): Effect on Kidney Hemodynamics and Renin-Angiotensin-Aldosterone System in Healthy Men. J Clin Endocrinol Metab. 2013;98(4):E664-E671. DOI:10.1210/jc.2012-3855

9. Cheng Q, Law PK, de Gasparo M, Leung PS. Combination of the Dipeptidyl Peptidase IV Inhibitor LAF237 [( S )-1-[(3-Hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the Angiotensin II Type 1 Receptor Antagonist Valsartan [ N -(1-Oxopentyl)- N -[[2´-(1 H -tetrazol-5-yl)-[1,1´-biphenyl]-4-yl. J Pharmacol Exp Ther. 2008;327(3):683-691. DOI:10.1124/jpet.108.142703

10. Mima A, Hiraoka-Yamomoto J, Li Q, et al. Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKC Activation in Diabetes. Diabetes. 2012;61(11):2967-2979. DOI:10.2337/db11-1824

11. Skov J, Persson F, Frøkiær J, Christiansen JS. Tissue Renin–Angiotensin Systems: A Unifying Hypothesis of Metabolic Disease. Front Endocrinol (Lausanne). 2014;5(11):2967-2979. DOI:10.3389/fendo.2014.00023

12. Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsbøll T. Impaired Regulation of the Incretin Effect in Patients with Type 2 Diabetes. J Clin Endocrinol Metab. 2011;96(3):737-745. DOI:10.1210/jc.2010-2435

13. Швангирадзе Т.А., Бондаренко И.З., Трошина Е.А., и др. Профиль микроРНК, ассоциированных с ИБС, у пациентов с сахарным диабетом 2 типа // Ожирение и метаболизм. - 2016. - Т.13. - №4. - C.34-38. [Shvangiradze TA, Bondarenko IZ, Troshina EA, et al. Profile of microRNAs associated with coronary heart disease in patients with type 2 diabetes. Obesity and Metabolism. 2016;13(4):34-38. (In Russ).] DOI:10.14341/omet2016434-38

14. Cavalera M, Wang J, Frangogiannis NG. Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. Transl Res. 2014;164(4):323-335. DOI:10.1016/j.trsl.2014.05.001

15. Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet. 2006;368(9536):666-678. DOI:10.1016/S0140-6736(06)69251-9

16. Oreopoulos A, McAlister FA, Kalantar-Zadeh K, et al. The relationship between body mass index, treatment, and mortality in patients with established coronary artery disease: a report from APPROACH. Eur Heart J. 2009;30(21):2584-2592. DOI:10.1093/eurheartj/ehp288

17. Grainger DJ, Kemp PR, Metcalfe JC, et al. The serum concentration of active transforming growth factor-β is severely depressed in advanced atherosclerosis. Nat Med. 1995;1(1):74-79. DOI:10.1038/nm0195-74

18. Erren M, Reinecke H, Junker R, et al. Systemic Inflammatory Parameters in Patients With Atherosclerosis of the Coronary and Peripheral Arteries. Arterioscler Thromb Vasc Biol. 1999;19(10):2355-2363. DOI:10.1161/01.ATV.19.10.2355

19. Wang X. Circulating transforming growth factor β1 and coronary artery disease. Cardiovasc Res. 1997;34(2):404-410. DOI:10.1016/S0008-6363(97)00033-3

20. Grainger D. TGF-β and atherosclerosis in man. Cardiovasc Res. 2007;74(2):213-222. DOI:10.1016/j.cardiores.2007.02.022