, Volume 19, Issue 3, pp 421–431 | Cite as

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

  • Mohamed Abo El-Asrar
  • Nancy Samir ElbarbaryEmail author
  • Eman Abdel Rahman Ismail
  • AlShaimaa Abo Bakr
Original Paper



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.


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.


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.


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.


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.


Type 1 diabetes Angiopoietin-2 Nephropathy Aortic/carotid intima-media thickness Atherosclerosis 


Compliance with ethical standards

Conflict of interest

Nothing to declare.


  1. 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 7:593CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schalkwijk CG, Stehouwer CD (2005) Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 109:143–159CrossRefGoogle Scholar
  3. 3.
    Sena CM, Pereira AM, Seiça R (2013) Endothelial dysfunction - a major mediator of diabetic vascular disease. Biochim Biophys Acta 1832:2216–2231CrossRefPubMedGoogle Scholar
  4. 4.
    Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 15(287):2570–2581CrossRefGoogle Scholar
  5. 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 107:679–681CrossRefPubMedGoogle Scholar
  6. 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 104:2943–2947CrossRefPubMedGoogle Scholar
  7. 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 17:716–722CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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 4:12–18Google Scholar
  9. 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 28:340–347CrossRefPubMedGoogle Scholar
  10. 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):55–60CrossRefPubMedGoogle Scholar
  11. 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 3:411–423CrossRefPubMedGoogle Scholar
  12. 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 10:55CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Peters KG (1998) Vascular endothelial growth factor and the angiopoietins: working together to build a better blood vessel. Circ Res 83:342–343CrossRefPubMedGoogle Scholar
  14. 14.
    Marti HH, Risau W (1999) Angiogenesis in ischemic disease. Thromb Haemost 82(Suppl 1):44–52PubMedGoogle Scholar
  15. 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 258:336–343CrossRefPubMedGoogle Scholar
  16. 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 31:2291–2300CrossRefPubMedGoogle Scholar
  17. 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 25:2571–2576CrossRefPubMedGoogle Scholar
  18. 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 48:2461–2471CrossRefPubMedGoogle Scholar
  19. 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 59:774–779CrossRefPubMedGoogle Scholar
  20. 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 2015:163120PubMedPubMedCentralGoogle Scholar
  21. 21.
    American Diabetes Association (ADA) (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33(Suppl 1):S62–S69CrossRefGoogle Scholar
  22. 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):555–576CrossRefGoogle Scholar
  23. 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 110:1677–1682CrossRefPubMedGoogle Scholar
  24. 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 21:13–19CrossRefPubMedGoogle Scholar
  25. 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 64:199–207CrossRefPubMedGoogle Scholar
  26. 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 106:3143–3421Google Scholar
  27. 27.
    Cook S, Auinger P, Huang TT (2009) Growth curves for cardio-metabolic risk factors in children and adolescents. J Pediatr 155:S6–S26CrossRefGoogle Scholar
  28. 28.
    Tabaei BP, Al-Kassab AS, llag LL, Zawacki CM, Herman WH (2001) Does microalbuminuria predict diabetic nephropathy? Diabetes Care 24:1560–1566CrossRefPubMedGoogle Scholar
  29. 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–S83CrossRefPubMedGoogle Scholar
  30. 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 55:24–38CrossRefPubMedGoogle Scholar
  31. 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 238:380–387CrossRefPubMedGoogle Scholar
  32. 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 20:1998–2004CrossRefPubMedGoogle Scholar
  33. 33.
    Tremolada G, Lattanzio R, Mazzolari G, Zerbini G (2007) The therapeutic potential of VEGF inhibition in diabetic microvascular complications. Cardiovasc Drugs 6:393–398CrossRefGoogle Scholar
  34. 34.
    Young Lee Ji, Miller Edmund J (2014) Angiopoietin-2: a key to understanding sepsis and its pulmonary sequelae? J Pulm Respire Med 4:172–179Google Scholar
  35. 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 40:355–365PubMedGoogle Scholar
  36. 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 1:113–118CrossRefGoogle Scholar
  37. 37.
    Woolf AS, Gnudi L, Long DA (2009) Roles of angiopoietins in kidney development and disease. Am Soc Nephrol 2:239–244CrossRefGoogle Scholar
  38. 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:e54668CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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 3:916–928CrossRefGoogle Scholar
  40. 40.
    Tuuminen R, Sahanne S, Loukovaara S (2014) Low intravitreal angiopoietin-2 and VEGF levels in vitrectomized diabetic patients with simvastatin treatment. Acta Ophthalmol 92:675–681CrossRefPubMedGoogle Scholar
  41. 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 8:1641–1647CrossRefGoogle Scholar
  42. 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 30:2599–2602CrossRefPubMedGoogle Scholar
  43. 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 166:541–548CrossRefPubMedGoogle Scholar
  44. 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 20:509–517CrossRefPubMedGoogle Scholar
  45. 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. 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 52:39–45CrossRefPubMedGoogle Scholar
  47. 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 156:237–241CrossRefPubMedGoogle Scholar
  48. 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 10:52–58CrossRefPubMedGoogle Scholar
  49. 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 20:280–284CrossRefPubMedGoogle Scholar
  50. 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 44:131–137CrossRefPubMedGoogle Scholar
  51. 51.
    Brown WV (2008) Microvascular complications of diabetes mellitus: renal protection accompanies cardiovascular protection. Am J Cardiol 102(12A):10L–13LCrossRefPubMedGoogle Scholar
  52. 52.
    Ahmed A, Fujisawa T (2011) Multiple roles of angiopoietins in atherogenesis. Curr Opin Lipidol 22:380–385CrossRefPubMedGoogle Scholar
  53. 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 3:244–250CrossRefGoogle Scholar
  54. 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 2:297–304Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Mohamed Abo El-Asrar
    • 1
  • Nancy Samir Elbarbary
    • 1
    Email author
  • Eman Abdel Rahman Ismail
    • 2
  • AlShaimaa Abo Bakr
    • 1
  1. 1.Pediatric Department, Faculty of MedicineAin Shams UniversityCairoEgypt
  2. 2.Clinical Pathology Department, Faculty of MedicineAin Shams UniversityCairoEgypt

Personalised recommendations