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Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Review Article

Diabetes, Incretin Therapy and Thoracic Aortic Aneurysm – What Does the Evidence Show?

Author(s): Camilla Krizhanovskii * and Anders Franco-Cereceda

Volume 17, Issue 5, 2019

Page: [432 - 439] Pages: 8

DOI: 10.2174/1570161116666180828155622

Price: $65

Abstract

Epidemiological evidence supports a reduced prevalence of Thoracic Aortic Aneurysm (TAA) and Abdominal Aortic Aneurysm (AAA) in patients with Diabetes (DM). The mechanisms underlying this negative association are unknown. Some studies support that hyperglycemia has effects on the Extracellular Matrix (ECM), resulting in collagen cross-links and altered proteolytic activity, which ultimately counteracts aneurysm formation. However, recent experimental research indicates that incretin- based anti-diabetic therapy and Glucagon-Like Peptide-1 (GLP-1) may reduce the formation of TAA. GLP-1 is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signaling exerts numerous pleiotropic effects on various tissues, including protective effects on the myocardium and vascular endothelium. Recent studies also report protective effects of GLP-1 based therapy on the formation of aneurysms in animal models and direct effects of GLP-1 signaling on the molecular mechanisms suggested to influence TAA formation, including inflammation, proteolytic activity and collagen composition. In this narrative review, we present the available evidence for effects of GLP-1 on experimental aneurysm development and discuss the potential role of GLP-1 in aneurysm formation based on available data from pre-clinical and clinical studies.

Keywords: Thoracic aortic aneurysm, aorta, proteolytic activity, incretin therapy, type 2 diabetes, glucagon-like peptide-1.

Graphical Abstract
[1]
Goes AMOJ, Mascarenhas BI, Rodrigues SC, de Andrade MC, Franco RSM. Thoracic and abdominal aneurysms as incidental findings. J Vasc Bras 2016; 15: 106-12.
[2]
Elefteriades JA. Thoracic aortic aneurysm: Reading the enemy’s playbook. Yale J Biol Med 2008; 81: 175-86.
[3]
Bruemmer D, Daugherty A, Lu H, Rateri DL. Relevance of angiotensin II-induced aortic pathologies in mice to human aortic aneurysms. Ann N Y Acad Sci 2011; 1245: 7-10.
[4]
Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 2011; 473: 308-16.
[5]
El-Hamamsy I, Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol 2009; 6: 771-86.
[6]
Buxton DB. Molecular imaging of aortic aneurysms. Circ Cardiovasc Imaging 2012; 5: 392-9.
[7]
Cornuz J, Sidoti Pinto C, Tevaearai H, Egger M. Risk factors for asymptomatic abdominal aortic aneurysm: Systematic review and meta-analysis of population-based screening studies. Eur J Public Health 2004; 14: 343-9.
[8]
Kaschina E, Scholz H, Steckelings UM, et al. Transition from atherosclerosis to aortic aneurysm in humans coincides with an increased expression of RAS components. Atherosclerosis 2009; 205: 396-403.
[9]
Agmon Y, Khandheria BK, Meissner I, et al. Is aortic dilatation an atherosclerosis-related process? Clinical, laboratory, and transesophageal echocardiographic correlates of thoracic aortic dimensions in the population with implications for thoracic aortic aneurysm formation. J Am Coll Cardiol 2003; 42: 1076-83.
[10]
Nakashima Y, Kurozumi T, Sueishi K, Tanaka K. Dissecting aneurysm: A clinicopathologic and histopathologic study of 111 autopsied cases. Hum Pathol 1990; 21: 291-6.
[11]
Achneck H, Modi B, Shaw C, et al. Ascending thoracic aneurysms are associated with decreased systemic atherosclerosis. Chest 2005; 128: 1580-6.
[12]
Hung A, Zafar M, Mukherjee S, Tranquilli M, Scoutt LM, Elefteriades JA. Carotid intima-media thickness provides evidence that ascending aortic aneurysm protects against systemic atherosclerosis. Cardiology 2012; 123: 71-7.
[13]
Chau K, Elefteriades JA. Ascending thoracic aortic aneurysms protect against myocardial infarctions. Int J Angiol 2014; 23: 177-82.
[14]
Mordi I, Tzemos N. Bicuspid aortic valve disease: A comprehensive review. Cardiol Res Pract 2012; 2012196037
[15]
Kang SS, Littooy FN, Gupta SR, et al. Higher prevalence of abdominal aortic aneurysms in patients with carotid stenosis but without diabetes. Surgery 1999; 126: 687-91.
[16]
Maleki S, Bjorck HM, Folkersen L, et al. Identification of a novel flow-mediated gene expression signature in patients with bicuspid aortic valve. J Mol Med (Berl) 2013; 91: 129-39.
[17]
Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol 2010; 55: 2789-800.
[18]
Paloschi V, Gadin JR, Khan S, et al. Aneurysm development in patients with a bicuspid aortic valve is not associated with transforming growth factor-beta activation. Arterioscler Thromb Vasc Biol 2015; 35: 973-80.
[19]
Folkersen L, Wagsater D, Paloschi V, et al. Unraveling divergent gene expression profiles in bicuspid and tricuspid aortic valve patients with thoracic aortic dilatation: The ASAP study. Mol Med 2011; 17: 1365-73.
[20]
McNally A, Madan A, Sucosky P. Morphotype-dependent flow characteristics in bicuspid aortic valve ascending aortas: A benchtop particle image velocimetry study. Front Physiol 2017; 8: 44.
[21]
Golledge J, Karan M, Moran CS, et al. Reduced expansion rate of abdominal aortic aneurysms in patients with diabetes may be related to aberrant monocyte-matrix interactions. Eur Heart J 2008; 29: 665-72.
[22]
Miyama N, Dua MM, Yeung JJ, et al. Hyperglycemia limits experimental aortic aneurysm progression. J Vasc Surg 2010; 52: 975-83.
[23]
Tsai CL, Lin CL, Wu YY, Shieh DC, Sung FC, Kao CH. Advanced complicated diabetes mellitus is associated with a reduced risk of thoracic and abdominal aortic aneurysm rupture: A population-based cohort study. Diabetes Metab Res Rev 2015; 31: 190-7.
[24]
Radak D, Tanaskovic S, Katsiki N, Isenovic ER. Protective role of diabetes mellitus on abdominal aortic aneurysm pathogenesis: Myth or reality? Curr Vasc Pharmacol 2016; 14: 196-200.
[25]
Climent E, Benaiges D, Chillaron JJ, Flores-Le Roux JA, Pedro-Botet J. Diabetes mellitus as a protective factor of abdominal aortic aneurysm: Possible mechanisms. Clin Investig Arterioscler 2018; 30: 181-7.
[26]
Pafili K, Gouni-Berthold I, Papanas N, Mikhailidis DP. Abdominal aortic aneurysms and diabetes mellitus. J Diabetes Complications 2015; 29: 1330-6.
[27]
Larsson SC, Wallin A, Hakansson N, Stackelberg O, Back M, Wolk A. Type 1 and type 2 diabetes mellitus and incidence of seven cardiovascular diseases. Int J Cardiol 2018; 262: 66-70.
[28]
Prakash SK, Pedroza C, Khalil YA, Milewicz DM. Diabetes and reduced risk for thoracic aortic aneurysms and dissections: A nationwide case-control study. J Am Heart Assoc 2012; 1(2): pii: jah3-e000323.
[29]
Guo DC, Papke CL, He R, Milewicz DM. Pathogenesis of thoracic and abdominal aortic aneurysms. Ann N Y Acad Sci 2006; 1085: 339-52.
[30]
Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: Sparking the development of diabetic vascular injury. Circulation 2006; 114: 597-605.
[31]
Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens 2003; 21: 3-12.
[32]
Susic D, Varagic J, Ahn J, Frohlich ED. Crosslink breakers: A new approach to cardiovascular therapy. Curr Opin Cardiol 2004; 19: 336-40.
[33]
Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014; 18: 1-14.
[34]
Tsamis A, Krawiec JT, Vorp DA. Elastin and collagen fibre microstructure of the human aorta in ageing and disease: A review. J R Soc Interface 2013; 1020121004
[35]
Wagsater D, Paloschi V, Hanemaaijer R, et al. Impaired collagen biosynthesis and cross-linking in aorta of patients with bicuspid aortic valve. J Am Heart Assoc 2013; 2e000034
[36]
Norman PE, Davis TM, Le MT, Golledge J. Matrix biology of abdominal aortic aneurysms in diabetes: Mechanisms underlying the negative association. Connect Tissue Res 2007; 48: 125-31.
[37]
Koole D, van Herwaarden JA, Schalkwijk CG, et al. A potential role for glycated cross-links in abdominal aortic aneurysm disease. J Vasc Surg 2017; 65: 1493-503.
[38]
Lee VS, Halabi CM, Hoffman EP, et al. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci USA 2016; 113: 8759-64.
[39]
LeMaire SA, Wang X, Wilks JA, et al. Matrix metalloproteinases in ascending aortic aneurysms: Bicuspid versus trileaflet aortic valves. J Surg Res 2005; 123: 40-8.
[40]
Fujimura N, Xiong J, Kettler EB, et al. Metformin treatment status and abdominal aortic aneurysm disease progression. J Vasc Surg 2016; 64: 46-54.
[41]
Torsney E, Pirianov G, Cockerill GW. Diabetes as a negative risk factor for abdominal aortic aneurysm - does the disease aetiology or the treatment provide the mechanism of protection? Curr Vasc Pharmacol 2013; 11: 293-8.
[42]
Yu J, Morimoto K, Bao W, Yu Z, Okita Y, Okada K. Glucagon-like peptide-1 prevented abdominal aortic aneurysm development in rats. Surg Today 2016; 46: 1099-107.
[43]
Lu HY, Huang CY, Shih CM, et al. Dipeptidyl peptidase-4 inhibitor decreases abdominal aortic aneurysm formation through GLP-1-dependent monocytic activity in mice. PLoS One 2015; 10e0121077
[44]
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-57.
[45]
Kuhre RE, Holst JJ, Kappe C. The regulation of function, growth and survival of GLP-1-producing L-cells. Clin Sci (Lond) 2016; 130: 79-91.
[46]
Vilsboll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004; 47: 357-66.
[47]
Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87: 1409-39.
[48]
Elrick H, Stimmler L, Hlad CJ, Arai Y. plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964; 24: 1076-82.
[49]
Meier JJ, Nauck MA. Glucagon-Like Peptide 1 (GLP-1) in biology and pathology. Diabetes Metab Res Rev 2005; 21: 91-117.
[50]
Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7-36) amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 1999; 140: 5356-63.
[51]
Sandoval D, Sisley SR. Brain GLP-1 and insulin sensitivity. Mol Cell Endocrinol 2015; 418: 27-32.
[52]
Kang YM, Jung CH. Cardiovascular effects of glucagon-like peptide-1 receptor agonists. Endocrinol Metab (Seoul) 2016; 31: 258-74.
[53]
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-22.
[54]
Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017; 377: 1228-39.
[55]
Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015; 373: 2247-57.
[56]
Bao W, Morimoto K, Hasegawa T, et al. Orally administered dipeptidyl peptidase-4 inhibitor (alogliptin) prevents abdominal aortic aneurysm formation through an antioxidant effect in rats. J Vasc Surg 2014; 59: 1098-108.
[57]
Takahara Y, Tokunou T, Ichiki T. Suppression of abdominal aortic aneurysm formation in mice by teneligliptin, a dipeptidyl peptidase-4 inhibitor. J Atheroscler Thromb 2018; 25: 698-708.
[58]
Nystrom T, Gonon AT, Sjoholm A, Pernow J. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept 2005; 125: 173-7.
[59]
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: 1209-15.
[60]
Richter G, Feddersen O, Wagner U, Barth P, Goke R, Goke B. GLP-1 stimulates secretion of macromolecules from airways and relaxes pulmonary artery. Am J Physiol 1993; 265: 374-81.
[61]
Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens 2010; 23: 334-9.
[62]
Cardus A, Uryga AK, Walters G, Erusalimsky JD. SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence. Cardiovasc Res 2013; 97: 571-9.
[63]
Balestrieri ML, Rizzo MR, Barbieri M, et al. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of incretin treatment. Diabetes 2015; 64: 1395-406.
[64]
Lee YS, Jun HS. Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. mediators inflamm. 2016; 2016: 3094642.
[65]
Lee WY. New potential targets of glucagon-like peptide 1 receptor agonists in pancreatic beta-cells and hepatocytes. Endocrinol Metab 2017; 32: 1-5.
[66]
Ceriello A, La Sala L, De Nigris V, Pujadas G, Rondinelli M, Genovese S. GLP-1 reduces metalloproteinase-9 induced by both hyperglycemia and hypoglycemia in type 1 diabetes. The possible role of oxidative stress. Ther Clin Risk Manag 2015; 11: 901-3.
[67]
Arakawa M, Mita T, Azuma K, et al. 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: 1030-7.
[68]
Fadini GP, Boscaro E, Albiero M, et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: Ppossible role of stromal-derived factor-1alpha. Diabetes Care 2010; 33: 1607-9.
[69]
Tashiro Y, Sato K, Watanabe T, et al. A glucagon-like peptide-1 analog liraglutide suppresses macrophage foam cell formation and atherosclerosis. Peptides 2014; 54: 19-26.
[70]
Ma GF, Chen S, Yin L, Gao XD, Yao WB. Exendin-4 ameliorates oxidized-LDL-induced inhibition of macrophage migration in vitro via the NF-kappaB pathway. Acta Pharmacol Sin 2014; 35: 195-202.
[71]
Burgmaier M, Liberman A, Mollmann J, et al. Glucagon-Like Peptide-1 (GLP-1) and its split products GLP-1(9-37) and GLP-1(28-37) stabilize atherosclerotic lesions in apoe(-)/(-) mice. Atherosclerosis 2013; 231: 427-35.
[72]
Bloomgarden ZT. Incretin concepts. Diabetes Care 2010; 33: e20-5.
[73]
Kappe C, Zhang Q, Holst JJ, Nystrom T, Sjoholm A. Evidence for paracrine/autocrine regulation of GLP-1-producing cells. Am J Physiol Cell Physiol 2013; 305: C1041-9.
[74]
Phillippi JA, Eskay MA, Kubala AA, Pitt BR, Gleason TG. Altered oxidative stress responses and increased type I collagen expression in bicuspid aortic valve patients. Ann Thorac Surg 2010; 90: 1893-8.
[75]
Li DY, Brooke B, Davis EC, et al. Elastin is an essential determinant of arterial morphogenesis. Nature 1998; 393: 276-80.
[76]
Qa’aty N, Wang Y, Wang A, et al. The antidiabetic hormone glucagon-like peptide-1 induces formation of new elastic fibers in human cardiac fibroblasts after cross-activation of IGF-IR. Endocrinology 2015; 156: 90-102.
[77]
Wright EJ, Hodson NW, Sherratt MJ, et al. Combined MSC and GLP-1 therapy modulates collagen remodeling and apoptosis following myocardial infarction. Stem Cells Int 2016; 20167357096
[78]
Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab 2018; 27: 740-56.
[79]
Mannucci E, Ognibene A, Cremasco F, et al. Glucagon-Like Peptide (GLP)-1 and leptin concentrations in obese patients with Type 2 diabetes mellitus. Diabet Med 2000; 17: 713-9.
[80]
Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001; 50: 609-13.
[81]
Lugari R, Dei Cas A, Ugolotti D, et al. Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes. Horm Metab Res 2002; 34: 150-4.
[82]
Ahren B, Carr RD, Deacon CF. Incretin hormone secretion over the day. Vitam Horm 2010; 84: 203-20.
[83]
Vollmer K, Holst JJ, Baller B, et al. Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance. Diabetes 2008; 57: 678-87.
[84]
Krizhanovskii C, Ntika S, Olsson C, Eriksson P, Franco-Cereceda A. Elevated circulating fasting glucagon-like peptide-1 in surgical patients with aortic valve disease and diabetes. Diabetol Metab Syndr 2017; 9: 79.
[85]
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 USA 1987; 84: 3434-8.
[86]
Fehmann HC, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev 1995; 16: 390-410.
[87]
Holz GG. EPAC: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell. Diabetes 2004; 53: 5-13.
[88]
Kahles F, Meyer C, Mollmann J, et al. GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes 2014; 63: 3221-9.
[89]
Kappe C, Patrone C, Holst JJ, Zhang Q, Sjoholm A. Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells. J Gastroenterol 2013; 48: 322-32.
[90]
Kappe C, Zhang Q, Nystrom T, Sjoholm A. Effects of high-fat diet and the anti-diabetic drug metformin on circulating GLP-1 and the relative number of intestinal L-cells. Diabetol Metab Syndr 2014; 6: 70.
[91]
Wu T, Thazhath SS, Bound MJ, Jones KL, Horowitz M, Rayner CK. Mechanism of increase in plasma intact GLP-1 by metformin in type 2 diabetes: Stimulation of GLP-1 secretion or reduction in plasma DPP-4 activity? Diabetes Res Clin Pract 2014; 106: e3-6.
[92]
Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology 2011; 152: 4610-9.
[93]
Hinchliffe RJ. Metformin and abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 2017; 54: 679-80.
[94]
Lysgaard Poulsen J, Stubbe J, Lindholt JS. Animal models used to explore abdominal aortic aneurysms: A systematic review. Eur J Vasc Endovasc Surg 2016; 52: 487-99.
[95]
Gertz SD, Mintz Y, Beeri R, et al. Lessons from animal models of arterial aneurysm. Aorta (Stamford) 2013; 1: 244-54.

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