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Angiogenesis
Published in: Angiogenesis 3/2016

01-07-2016 | Original Paper

Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness

Authors: Mohamed Abo El-Asrar, Nancy Samir Elbarbary, Eman Abdel Rahman Ismail, AlShaimaa Abo Bakr

Published in: Angiogenesis | Issue 3/2016

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Abstract

Background

Angiopoietin-2 is a growth factor involved in the pathophysiology of vascular and inflammatory diseases such as arteriosclerosis. Carotid or aortic scans provide noninvasive screening tools for assessment of preclinical atherosclerosis in high-risk children.

Aim

We assessed serum angiopoietin-2 in children and adolescents with type 1 diabetes mellitus as a potential marker for vascular complications in relation to glycemic control, inflammation and vascular structure.

Methods

Sixty patients with type 1 diabetes were divided into 2 groups according to the presence of micro-vascular complications and compared with 30 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), urinary albumin/creatinine ratio, serum angiopoietin-2, carotid and aortic intima-media thickness (CIMT and AIMT) were measured.

Results

CIMT, AIMT and serum angiopoietin-2 levels were significantly increased in patients with and without micro-vascular complications compared with controls, and the highest levels were in patients with complications (p < 0.001). Angiopoietin-2 was higher in patients with microalbuminuria than normoalbuminuric group (p < 0.001). Fasting blood glucose, HbA1c, hs-CRP, CIMT and AIMT were independently related to angiopoietin-2 in multiple regression analysis. Disease duration, hyperglycemia, poor glycemic control, hypercholesterolemia, inflammation and angiopoietin-2 were independent factors contributing to atherosclerosis risk.

Conclusion

The relation between angiopoietin-2 and assessed parameters of vascular structure in type 1 diabetes reflects a state of endothelial injury and highlights the role of disturbed angiogenesis and vascular inflammation in the occurrence of diabetic complications.
Literature
1.
James S, Gallagher R, Dunbabin J, Perry L (2014) Prevalence of vascular complications and factors predictive of their development in young adults with type 1 diabetes: systematic literature review. BMC Res Notes 7:593CrossRefPubMedPubMedCentral
2.
Schalkwijk CG, Stehouwer CD (2005) Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 109:143–159CrossRef
3.
Sena CM, Pereira AM, Seiça R (2013) Endothelial dysfunction - a major mediator of diabetic vascular disease. Biochim Biophys Acta 1832:2216–2231CrossRefPubMed
4.
Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 15(287):2570–2581CrossRef
5.
Isoda K, Kamezawa Y, Ayaori M, Kusuhara M, Tada N, Ohsuzu F (2003) Osteopontin transgenic mice fed a high-cholesterol diet develop early fatty-streak lesions. Circulation 107:679–681CrossRefPubMed
6.
Järvisalo MJ, Jartti L, Näntö-Salonen K, Irjala K, Rönnemaa T, Hartiala JJ, Celermajer DS, Raitakari OT (2001) Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children. Circulation 104:2943–2947CrossRefPubMed
7.
Kota SK, Mahapatra GB, Kota SK, Naveed S, Tripathy PR, Jammula S, Modi KD (2013) Carotid intima media thickness in type 2 diabetes mellitus with ischemic stroke. Indian J Endocrinol Metab 17:716–722CrossRefPubMedPubMedCentral
8.
Gupta A, Yadav S, Gupta VK (2013) Carotid intimo-medial thickness [cIMT] and correlation to cardiac risk factors in adolescent type 1 diabetics. J Diabetes Endocrinol 4:12–18
9.
Adly AA, Elbarbary NS, Ismail EA, Hassan SR (2014) Plasminogen activator inhibitor-1 (PAI-1) in children and adolescents with type 1 diabetes mellitus: relation to diabetic micro-vascular complications and carotid intima media thickness. J Diabetes Complications 28:340–347CrossRefPubMed
10.
Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277(5322):55–60CrossRefPubMed
11.
Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev Cell 3:411–423CrossRefPubMed
12.
Rasul S, Reiter MH, Ilhan A, Lampichler K, Wagner L, Kautzky-Willer A (2011) Circulating angiopoietin-2 and soluble Tie-2 in type 2 diabetes mellitus: a cross-sectional study. Cardiovasc Diabetol 10:55CrossRefPubMedPubMedCentral
13.
Peters KG (1998) Vascular endothelial growth factor and the angiopoietins: working together to build a better blood vessel. Circ Res 83:342–343CrossRefPubMed
14.
Marti HH, Risau W (1999) Angiogenesis in ischemic disease. Thromb Haemost 82(Suppl 1):44–52PubMed
15.
Nadar SK, Blann A, Beevers DG, Lip GY (2005) Abnormal angiopoietins 1&2, angiopoietin receptor Tie-2 and vascular endothelial growth factor levels in hypertension: relationship to target organ damage [a sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)]. J Intern Med 258:336–343CrossRefPubMed
16.
Kümpers P, Nickel N, Lukasz A, Golpon H, Westerkamp V, Olsson KM, Jonigk D, Maegel L, Bockmeyer CL, David S, Hoeper MM (2010) Circulating angiopoietins in idiopathic pulmonary arterial hypertension. Eur Heart J 31:2291–2300CrossRefPubMed
17.
David S, Kümpers P, Lukasz A, Fliser D, Martens-Lobenhoffer J, Bode-Böger SM, Kliem V, Haller H, Kielstein JT (2010) Circulating angiopoietin-2 levels increase with progress of chronic kidney disease. Nephrol Dial Transplant 25:2571–2576CrossRefPubMed
18.
DeBusk LM, Chen Y, Nishishita T, Chen J, Thomas JW, Lin PC (2003) Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alpha induced angiogenesis in rheumatoid arthritis. Arthritis Rheum 48:2461–2471CrossRefPubMed
19.
Anuradha S, Mohan V, Gokulakrishnan K, Dixit M (2010) Angiopoietin-2 levels in glucose intolerance, hypertension, and metabolic syndrome in Asian Indians (Chennai Urban Rural Epidemiology Study-74). Metabolism 59:774–779CrossRefPubMed
20.
Chen S, Li H, Zhang C, Li Z, Wang Q, Guo J, Luo C, Wang Y (2015) Urinary angiopoietin-2 is associated with albuminuria in patients with type 2 diabetes mellitus. Int J Endocrinol 2015:163120PubMedPubMedCentral
21.
American Diabetes Association (ADA) (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33(Suppl 1):S62–S69CrossRef
22.
National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114(2 Suppl 4th Report):555–576CrossRef
23.
Wilkinson CP, Ferris FL 3rd, Klein RE, Lee PP, Agardh CD, Davis M, Dills D, Kampik A, Pararajasegaram R, Verdaguer JT (2003) Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 110:1677–1682CrossRefPubMed
24.
Weintrob N, Amitay I, Lilos P, Shalitin S, Lazar L, Josefsberg Z (2007) Bedside neuropathy disability score compared to quantitative sensory testing for measurement of diabetic neuropathy in children, adolescents, and young adults with type 1 diabetes. J Diabetes Complicat 21:13–19CrossRefPubMed
25.
England JD, Gronseth GS, Franklin G, Miller RG, Asbury AK, Carter GT, Cohen JA, Fisher MA, Howard JF, Kinsella LJ, Latov N, Lewis RA, Low PA, Sumner AJ (2005) Distal symmetric polyneuropathy: a definition for clinical research: report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 64:199–207CrossRefPubMed
26.
Third Report of the National Cholesterol Education Program (NCEP) (2002) Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 106:3143–3421
27.
Cook S, Auinger P, Huang TT (2009) Growth curves for cardio-metabolic risk factors in children and adolescents. J Pediatr 155:S6–S26CrossRef
28.
Tabaei BP, Al-Kassab AS, llag LL, Zawacki CM, Herman WH (2001) Does microalbuminuria predict diabetic nephropathy? Diabetes Care 24:1560–1566CrossRefPubMed
29.
Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, Steffes MW (2004) American Diabetes Association. Nephropathy in diabetes. Diabetes Care 27:S79–S83CrossRefPubMed
30.
Miller WG, Bruns DE, Bruns DE, Hortin GL, Sandberg S, Aakre KM, McQueen MJ, Itoh Y, Lieske JC, Seccombe DW, Jones G, Bunk DM, Curhan GC, Narva AS (2009) National Kidney Disease Education Program-IFCC Working Group on Standardization of Albumin in Urine. Current issues in measurement and reporting of urinary albumin excretion. Clin Chem 55:24–38CrossRefPubMed
31.
Dalla Pozza R, Ehringer-Schetitska D, Fritsch P, Jokinen E, Petropoulos A, Oberhoffer R, Association for European Paediatric Cardiology Working Group Cardiovascular Prevention (2015) Intima media thickness measurement in children: a statement from the Association for European Paediatric Cardiology (AEPC) Working Group on Cardiovascular Prevention endorsed by the Association for European Paediatric Cardiology. Atherosclerosis 238:380–387CrossRefPubMed
32.
McGill HC Jr, McMahan CA, Zieske AW, Sloop GD, Walcott JV, Troxclair DA, Malcom GT, Tracy RE, Oalmann MC, Strong JP (2000) Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb Vasc Biol 20:1998–2004CrossRefPubMed
33.
Tremolada G, Lattanzio R, Mazzolari G, Zerbini G (2007) The therapeutic potential of VEGF inhibition in diabetic microvascular complications. Cardiovasc Drugs 6:393–398CrossRef
34.
Young Lee Ji, Miller Edmund J (2014) Angiopoietin-2: a key to understanding sepsis and its pulmonary sequelae? J Pulm Respire Med 4:172–179
35.
He FF, Li HQ, Huang QX, Wang QY, Jiang HJ, Chen S, Su H, Zhang C, Wang YM (2015) Tumor Necrosis Factor-Alpha and 8-Hydroxy-2’-Deoxyguanosine are associated with elevated urinary angiopoietin-2 level in type 2 diabetic patients with albuminuria. Kidney Blood Press Res 40:355–365PubMed
36.
Lim HS, Lip GY, Blann AD (2005) Angiopoietin-1 and angiopoietin-2 in diabetes mellitus: relationship to VEGF, glycaemic control, endothelial damage/dysfunction and atherosclerosis. Atherosclerosis 1:113–118CrossRef
37.
Woolf AS, Gnudi L, Long DA (2009) Roles of angiopoietins in kidney development and disease. Am Soc Nephrol 2:239–244CrossRef
38.
Chang FC, Lai TS, Chiang CK, Chen YM, Wu MS, Chu TS, Wu KD, Lin SL (2013) Angiopoietin-2 is associated with albuminuria and microinflammation in chronic kidney disease. PLoS ONE 8:e54668CrossRefPubMedPubMedCentral
39.
Luo C, Li T, Zhang C, Chen Q, Li Z, Liu J, Wang Y (2014) Therapeutic effect of alprostadil in diabetic nephropathy: possible roles of angiopoietin-2 and IL-18. Cell Physiol Biochem 3:916–928CrossRef
40.
Tuuminen R, Sahanne S, Loukovaara S (2014) Low intravitreal angiopoietin-2 and VEGF levels in vitrectomized diabetic patients with simvastatin treatment. Acta Ophthalmol 92:675–681CrossRefPubMed
41.
David S, Kümpers P, Lukasz A, Kielstein JT, Haller H, Fliser D (2009) Circulating angiopoietin-2 in essential hypertension: relation to atherosclerosis, vascular inflammation, and treatment with olmesartan/pravastatin. Hypertens 8:1641–1647CrossRef
42.
Rabago Rodriguez R, Gomez-Diaz RA, Tanus Haj J, Avelar Garnica FJ, Ramirez Soriano E, Nishimura Meguro E, Aguilar-Salinas CA, Wacher NH (2007) Carotid intima-media thickness in pediatric type 1 diabetic patients. Diabetes Care 30:2599–2602CrossRefPubMed
43.
Schwab KO, Doerfer J, Krebs A, Krebs K, Schorb E, Hallermann K, Superti-Furga A, Zieger B, März W, Schmidt-Trucksäss A, Winkler K (2007) Early atherosclerosis in childhood type 1 diabetes: role of raised systolic blood pressure in the absence of dyslipidaemia. Eur J Pediatr 166:541–548CrossRefPubMed
44.
El-Asrar MA, Andrawes NG, Ismail EA, Salem SM (2015) Kallistatin as a marker of microvascular complications in children and adolescents with type 1 diabetes mellitus: relation to carotid intima media thickness. Vasc Med 20:509–517CrossRefPubMed
45.
El-Beblawy NM, Andrawes NG, Ismail EA, Enany BE, Abou El-Seoud HS, Erfan MA (2016) Serum and urinary orosomucoid in young patients with type 1 diabetes: A link between inflammation, microvascular complications, and subclinical atherosclerosis. Clin Appl Thromb Hemost. doi:10.​1177/​1076029616637185​
46.
Abdelghaffar S, El Amir M, El Hadidi A, El Mougi F (2006) Carotid intima media thickness: an index for subclinical atherosclerosis in type 1 diabetes. J Trop Pediatr 52:39–45CrossRefPubMed
47.
Harrington J, Peña AS, Gent R, Hirte C, Couper J (2010) Aortic intima media thickness is an early marker of atherosclerosis in children with type 1 diabetes mellitus. J Pediatr 156:237–241CrossRefPubMed
48.
Gul K, Ustun I, Aydin Y, Berker D, Erol K, Unal M, Barazi AO, Delibaşi T, Güler S (2010) Carotid intima-media thickness and its relations with the complications in patients with type 1 diabetes mellitus. Anadolu Kardiyol Derg 10:52–58CrossRefPubMed
49.
Distiller LA, Joffe BI, Melville V, Welman T, Distiller GB (2006) Carotid artery intima-media complex thickening in patients with relatively long-surviving type 1 diabetes mellitus. J Diabetes Complications 20:280–284CrossRefPubMed
50.
Glowinska-Olszewska B, Urban M, Urban B, Tolwinska J, Szadkowska A (2007) The association of early atherosclerosis and retinopathy in adolescents with type 1 diabetes: preliminary report. Acta Diabetol 44:131–137CrossRefPubMed
51.
Brown WV (2008) Microvascular complications of diabetes mellitus: renal protection accompanies cardiovascular protection. Am J Cardiol 102(12A):10L–13LCrossRefPubMed
52.
Ahmed A, Fujisawa T (2011) Multiple roles of angiopoietins in atherogenesis. Curr Opin Lipidol 22:380–385CrossRefPubMed
53.
Post S, Peeters W, Busser E, Lamers D, Sluijter JP, Goumans MJ, de Weger RA, Moll FL, Doevendans PA, Pasterkamp G, Vink A (2008) Balance between angiopoietin-1 and angiopoietin-2 is in favor of angiopoietin-2 in atherosclerotic plaques with high microvessel density. Vasc Res 3:244–250CrossRef
54.
Theelen TL, Lappalainen JP, Sluimer JC, Gurzeler E, Cleutjens JP, Gijbels MJ, Biessen EA, Daemen MJ, Alitalo K, Ylä-Herttuala S (2015) Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice. Am J Cardiol 2:297–304
Metadata
Title
Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness
Authors
Mohamed Abo El-Asrar
Nancy Samir Elbarbary
Eman Abdel Rahman Ismail
AlShaimaa Abo Bakr
Publication date
01-07-2016
Publisher
Springer Netherlands
Published in
Angiogenesis / Issue 3/2016
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-016-9517-6

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