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Open Access 01-12-2014 | Review

Do incretins improve endothelial function?

Authors: Jun-ichi Oyama, Yukihito Higashi, Koichi Node

Published in: Cardiovascular Diabetology | Issue 1/2014

Abstract

An impaired endothelial function has been recognized in the early stage of atherosclerosis, and is a major factor affecting the future development of cardiovascular events. Type 2 diabetes mellitus (T2DM) is widely prevalent, and is one of the most important risk factors for cardiovascular disease. T2DM is associated with increases in both morbidity and mortality, particularly from cardiovascular disease.

New therapies based on the incretin hormone and its actions are now becoming widely used, and appear to offer advantages over conventional therapies by keeping the body weight steady and limiting hypoglycemia, while also achieving attractive glycemic control. However, there is little data available about the effects of incretins on the cardiovascular system.

This review will focus on the effects of incretin therapies, including glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase (DPP)-4 inhibitors, on the endothelial function, and will discuss the potential mechanisms underlying these effects.

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Lerman A, Burnett JC: Intact and altered endothelium in regulation of vasomotion. Circulation. 1992, 86: III-12-II-19. 10.1161/01.CIR.86.1.12.CrossRef

Uehata A, Lieberman EH, Gerhard MD, Anderson TJ, Ganz P, Polak JF, Creager MA, Yeung AC: Noninvasive assessment of endothelium-dependent flow-mediated dilation of the brachial artery. Vasc Med. 1997, 2: 87-92.PubMed

Anderson TJ, Uehata A, Gerhard MD: Close relationship of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995, 26: 1235-1241. 10.1016/0735-1097(95)00327-4.CrossRefPubMed

Celermajer D: Endothelial dysfunction: does it matter? Is it reversible?. J Am Coll Cardiol. 1997, 30: 325-333. 10.1016/S0735-1097(97)00189-7.CrossRefPubMed

Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF: Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A. 1987, 84: 3434-3438. 10.1073/pnas.84.10.3434.PubMedCentralCrossRefPubMed

Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M: Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008, 117: 2340-2350. 10.1161/CIRCULATIONAHA.107.739938.CrossRefPubMed

Gallwitz B: Review of sitagliptin phosphate: a novel treatment for type 2 diabetes. Vasc Health Risk Manag. 2007, 3: 203-210. 10.2147/vhrm.2007.3.2.203.PubMedCentralCrossRefPubMed

Liu H, Hu Y, Simpson RW, Dear AE: Glucagon-like peptide-1 attenuates tumour necrosis factor-alpha-mediated induction of plasminogen activator inhibitor-1 expression. J Endocrinol. 2008, 196: 57-65. 10.1677/JOE-07-0387.CrossRefPubMed

Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S: Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun. 2010, 391: 1405-1408. 10.1016/j.bbrc.2009.12.075.CrossRefPubMed

10.

Ding L, Zhang J: Glucagon-like peptide-1 activates endothelial nitric oxide synthase in human umbilical vein endothelial cells. Acta Pharmacol Sin. 2012, 33: 75-81. 10.1038/aps.2011.149.PubMedCentralCrossRefPubMed

11.

Oeseburg H, de Boer RA, Buikema H, van der Harst P, van Gilst WH, Silljé HH: Glucagon-like peptide 1 prevents reactive oxygen species-induced endothelial cell senescence through the activation of protein kinase A. Arterioscler Thromb Vasc Biol. 2010, 30: 1407-1414. 10.1161/ATVBAHA.110.206425.CrossRefPubMed

12.

Wang D, Luo P, Wang Y, Li W, Wang C, Sun D, Zhang R, Su T, Ma X, Zeng C, Wang H, Ren J, Cao F: Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes. 2013, 62: 1697-1708. 10.2337/db12-1025.PubMedCentralCrossRefPubMed

13.

Aronis KN, Chamberland JP, Mantzoros CS: GLP-1 promotes angiogenesis in human endothelial cells in a dose-dependent manner, through the Akt, Src and PKC pathways. Metabolism. 2013, 62: 1279-1286. 10.1016/j.metabol.2013.04.010.PubMedCentralCrossRefPubMed

14.

Liu FQ, Zhang XL, Gong L, Wang XP, Wang J, Hou XG, Sun Y, Qin WD, Wei SJ, Zhang Y, Chen L, Zhang MX: Glucagon-like peptide 1 protects microvascular endothelial cells by inactivating the PARP-1/iNOS/NO pathway. Mol Cell Endocrinol. 2011, 339: 25-33. 10.1016/j.mce.2011.03.007.CrossRefPubMed

15.

Xiao-Yun X, Zhao-Hui M, Ke C, Hong-Hui H, Yan-Hong X: Glucagon-like peptide-1 improves proliferation and differentiation of endothelial progenitor cells via upregulating VEGF generation. Med Sci Monit. 2011, 17: BR35-BR41.CrossRefPubMed

16.

Erdogdu O, Nathanson D, Sjöholm A, Nyström T, Zhang Q: Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol. 2010, 325: 26-35. 10.1016/j.mce.2010.04.022.CrossRefPubMed

17.

Erdogdu O, Eriksson L, Xu H, Sjöholm A, Zhang Q, Nyström T: Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. J Mol Endocrinol. 2013, 50: 229-241. 10.1530/JME-12-0166.CrossRefPubMed

18.

Schisano B, Harte AL, Lois K, Saravanan P, Al-Daghri N, Al-Attas O, Knudsen LB, McTernan PG, Ceriello A, Tripathi G: GLP-1 analogue, Liraglutide protects human umbilical vein endothelial cells against high glucose induced endoplasmic reticulum stress. Regul Pept. 2012, 174: 46-52. 10.1016/j.regpep.2011.11.008.CrossRefPubMed

19.

Gaspari T, Liu H, Welungoda I, Hu Y, Widdop RE, Knudsen LB, Simpson RW, Dear AE: A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE−/− mouse model. Diab Vasc Dis Res. 2011, 8: 117-124. 10.1177/1479164111404257.CrossRefPubMed

20.

Shiraki A, Oyama J, Komoda H, Asaka M, Komatsu A, Sakuma M, Kodama K, Sakamoto Y, Kotooka N, Hirase T, Node K: The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis. 2012, 221: 375-382. 10.1016/j.atherosclerosis.2011.12.039.CrossRefPubMed

21.

Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S: Sitagliptin augments protective effects of GLP-1 against advanced glycation end product receptor axis in endothelial cells. Horm Metab Res. 2011, 43: 731-734.CrossRefPubMed

22.

Shah Z, Pineda C, Kampfrath T, Maiseyeu A, Ying Z, Racoma I, Deiuliis J, Xu X, Sun Q, Moffatt-Bruce S, Villamena F, Rajagopalan S: Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vascul Pharmacol. 2011, 55: 2-9. 10.1016/j.vph.2011.03.001.CrossRefPubMed

23.

Han L, Yu Y, Sun X, Wang B: Exendin-4 directly improves endothelial dysfunction in isolated aortas from obese rats through the cAMP or AMPK-eNOS pathways. Diabetes Res Clin Pract. 2012, 97: 453-460. 10.1016/j.diabres.2012.04.001.CrossRefPubMed

24.

Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, Fujitani Y, Hirose T, Kawamori R, Watada H: Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010, 59: 1030-1037. 10.2337/db09-1694.PubMedCentralCrossRefPubMed

25.

Gaspari T, Welungoda I, Widdop RE, Simpson RW, Dear AE: The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE−/− mouse model. Diab Vasc Dis Res. 2013, 10: 353-360. 10.1177/1479164113481817.CrossRefPubMed

26.

Liu L, Liu J, Wong WT, Tian XY, Lau CW, Wang YX, Xu G, Pu Y, Zhu Z, Xu A, Lam KS, Chen ZY, Ng CF, Yao X, Huang Y: Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension. 2012, 60: 833-841. 10.1161/HYPERTENSIONAHA.112.195115.CrossRefPubMed

27.

Nathanson D, Erdogdu O, Pernow J, Zhang Q, Nyström T: Endothelial dysfunction induced by triglycerides is not restored by exenatide in rat conduit arteries ex vivo. Regul Pept. 2009, 157: 8-13. 10.1016/j.regpep.2009.07.003.CrossRefPubMed

28.

Sakamoto Y, Oyama J, Ikeda H, Kuroki S, Gondo S, Iwamoto T, Uchida Y, Kodama K, Hiwatashi A, Shimomura M, Taguchi I, Inoue T, Node K, S-DOG investigators: Effects of sitagliptin beyond glycemic control: focus on quality of life. Cardiol Diabetol. 2013, 12: 35-10.1186/1475-2840-12-35.CrossRef

29.

Scheen AJ: Cardiovascular effects of gliptins. Nat Rev Cardiol. 2013, 10: 73-84. 10.1038/nrcardio.2012.183.CrossRefPubMed

30.

Gutzwiller JP, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, Gutmann H, Drewe J, Henzen C, Goeke B, Beglinger C: Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004, 89: 3055-3061. 10.1210/jc.2003-031403.CrossRefPubMed

31.

Huang PL, Huang Z, Mashimo H, Block KD, Moskowitz MA, Bevan JA, Fishman MC: Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995, 377: 239-242. 10.1038/377239a0.CrossRefPubMed

32.

Rees DD, Palmer RM, Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A. 1989, 86: 3375-3378. 10.1073/pnas.86.9.3375.PubMedCentralCrossRefPubMed

33.

Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, Simpson JA, Drucker DJ: GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013, 19: 567-575. 10.1038/nm.3128.CrossRefPubMed

34.

Vanderheyden M, Bartunek J, Goethals M, Verstreken S, Lambeir AM, De Meester I, Scharpé S: Dipeptidyl-peptidase IV and B-type natriuretic peptide. From bench to bedside. Clin Chem Lab Med. 2009, 47: 248-252.CrossRefPubMed

35.

Flock G, Baggio LL, Longuet C, Drucker DJ: Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes. 2007, 56: 3006-3013. 10.2337/db07-0697.CrossRefPubMed

36.

Qin X, Shen H, Liu M, Yang Q, Zheng S, Sabo M, D'Alessio DA, Tso P: GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastrointest Liver Physiol. 2005, 288: G943-G949. 10.1152/ajpgi.00303.2004.CrossRefPubMed

37.

Tesauro M, Schinzari F, Adamo A, Rovella V, Martini F, Mores N, Barini A, Pitocco D, Ghirlanda G, Lauro D, Campia U, Cardillo C: Effects of GLP-1 on forearm vasodilator function and glucose disposal during hyperinsulinemia in the metabolic syndrome. Diabetes Care. 2013, 36: 683-689. 10.2337/dc12-0763.PubMedCentralCrossRefPubMed

38.

Kelly AS, Bergenstal RM, Gonzalez-Campoy JM, Bank AJ, Katz H: Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial. Cardiovasc Diabetol. 2012, 11: 64-10.1186/1475-2840-11-64.PubMedCentralCrossRefPubMed

39.

Hopkins ND, Cuthbertson DJ, Kemp GJ, Pugh C, Green DJ, Cable NT, Jones H: Effects of 6 months glucagon-like peptide-1 receptor agonist treatment on endothelial function in type 2 diabetes mellitus patients. Diabetes Obes Metab. 2013, 15: 770-773. 10.1111/dom.12089.CrossRefPubMed

40.

Ayaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T, Iizuka M, Takiguchi S, Yakushiji E, Nakaya K, Yogo M, Ogura M, Takase B, Murakami T, Ikewaki K: Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc. 2013, 2: e003277.PubMedCentralCrossRefPubMed

41.

Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ: Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab. 2007, 293: E1289-E1295. 10.1152/ajpendo.00373.2007.CrossRefPubMed

42.

Kubota Y, Miyamoto M, Takagi G, Ikeda T, Kirinoki-Ichikawa S, Tanaka K, Mizuno K: The dipeptidyl peptidase-4 inhibitor sitagliptin improves vascular endothelial function in type 2 diabetes. J Korean Med Sci. 2012, 27: 1364-1370. 10.3346/jkms.2012.27.11.1364.PubMedCentralCrossRefPubMed

43.

Nyström T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahrén B, Sjöholm A: 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: E1209-E1215. 10.1152/ajpendo.00237.2004.CrossRefPubMed

44.

Koska J, Schwartz EA, Mullin MP, Schwenke DC, Reaven PD: Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabetes Care. 2010, 33: 1028-1030. 10.2337/dc09-1961.PubMedCentralCrossRefPubMed

45.

Noda Y, Miyoshi T, Oe H, Ohno Y, Nakamura K, Toh N, Kohno K, Morita H, Kusano K, Ito H: Alogliptin ameliorates postprandial lipemia and postprandial endothelial dysfunction in non- diabetic subjects: a preliminary report. Cardiovasc Diabetol. 2013, 12: 8-10.1186/1475-2840-12-8.PubMedCentralCrossRefPubMed

46.

van Poppel PC, Netea MG, Smits P, Tack CJ: Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care. 2011, 34: 2072-2077. 10.2337/dc10-2421.PubMedCentralCrossRefPubMed

47.

Ceriello A, Esposito K, Testa R, Bonfigli AR, Marra M, Giugliano D: The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an “endothelial resistance” to glucagon-like peptide 1 in diabetes. Diabetes Care. 2011, 34: 697-702. 10.2337/dc10-1949.PubMedCentralCrossRefPubMed

48.

Irace C, De Luca S, Shehaj E, Carallo C, Loprete A, Scavelli F, Gnasso A: Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an observational research. Diab Vasc Dis Res. 2013, 10: 72-77. 10.1177/1479164112449562.CrossRefPubMed

49.

White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F, EXAMINE Investigators: Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013, 369: 1327-1335. 10.1056/NEJMoa1305889.CrossRefPubMed

50.

Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I, SAVOR-TIMI 53 Steering Committee and Investigators: Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013, 369: 1317-1326. 10.1056/NEJMoa1307684.CrossRefPubMed

51.

Gokce N, Keaney JF, Hunter LM, Watkins MT, Menzoian JO, Vita JA: Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002, 105: 1567-1572. 10.1161/01.CIR.0000012543.55874.47.CrossRefPubMed

52.

Gokce N, Keaney JF, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA: Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol. 2003, 41: 1769-1775. 10.1016/S0735-1097(03)00333-4.CrossRefPubMed

53.

Widlansky ME, Gokce N, Keaney JF, Vita JA: The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003, 42: 1149-1160. 10.1016/S0735-1097(03)00994-X.CrossRefPubMed

54.

Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R, International brachial artery reactivity task force: Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force. J Am Coll Cardiol. 2002, 39: 257-265.CrossRefPubMed

55.

Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ: Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011, 300: H2-H12. 10.1152/ajpheart.00471.2010.PubMedCentralCrossRefPubMed

56.

Hausenloy DJ, Whittington HJ, Wynne AM, Begum SS, Theodorou L, Riksen N, Mocanu MM, Yellon DM: Dipeptidyl peptidase-4 inhibitors and GLP-1 reduce myocardial infarct size in a glucose-dependent manner. Cardiovasc Diabetol. 2013, 12: 154-10.1186/1475-2840-12-154.PubMedCentralCrossRefPubMed

57.

Hu G, Zhang Y, Jiang H, Hu X: Exendin-4 attenuates myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein expression. Cardiol J. 2013, 20: 600-604. 10.5603/CJ.2013.0159.CrossRefPubMed

58.

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009, 339: b2700-10.1136/bmj.b2700.PubMedCentralCrossRefPubMed

Title: Do incretins improve endothelial function?
Authors: Jun-ichi Oyama
Yukihito Higashi
Koichi Node
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Cardiovascular Diabetology / Issue 1/2014
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/1475-2840-13-21

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