Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2016; 62(5): 37-44

Role of matrix metalloproteinase 9 and its tissue inhibitor 1 in development and prognosis of diabetic retinopathy

S.V. Ziablitsev1, A.V. Korobova2, O.V. Petrenko3, V.N. Serduk4, S.U. Mogilevsky3

  1. Ukranian science-practical center of endocrine surgery, transplantation of endocrine organs and tis- sue Health Ministry of Ukraine, Kyiv;
  2. M. Gorky Donetsk National Medical University, Krasny Liman;
  3. L.M. Shupik National medical academy of postgradual education, Kyiv;
  4. SE «Dnepropetrovsk Medical Academy Health Ministry of Ukraine», Dnipro


The article presents the results of investigation of violations in the proteolysis system in patients with type 2 diabetes and diabetic retinopathy (DR). We studied the levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the blood and in the intraocular fluid of patients with type 2 diabetes depending upon the stage of DR. We have established that the level of MMP-9 and TIMP-1 in the blood and in the intraocular fluid increased in patients with type 2 diabetes without signs of DR and with any stage of DR compared to the levels of these parameters in patients without diabetes. Increasing the levels of MMP-9 and TIMP-1 took place with increasing of DR severity and reached its maximum levels at the proliferative stage of DR. It was found that the levels of MMP-9 in the intraocular fluid and type 2 diabetes duration affected the probability of developing diabetic macular edema. At the level of MMP-9 ≥ 105 ng/ml and 2 diabetes duration ≥ 10 years, the probability of developing macular edema was 100%. As a result of the construction of predictive models it was found that the level of MMP-9 in the intraocular fluid, stage of DR at the beginning of observation and type 2 diabetes duration had influence on the probability of the development of proliferative DR over 4 years of follow-up. If the level of MMP-9 ≥ 100 ng/ml, type 2 diabetes duration ≥ 10 years and absence of DR at the beginning of observation were observed the probability of developing proliferative DR would compose 85.9%.

Keywords: proteolysis system; metalloproteinase-9; tissue inhibitor of matrix metalloproteinase-1; intraocular fluid; diabetic retinopathy.


  1. Evrosimovska B, Velickovski B, Dimova C, VeleskaStefkovska D. Matrix metalloproteinases (with accent to collagenases). J Cell Anim Biol. 2011; 5(7). 113-20.
  3. Raffetto JD, Khalil RA. Matrix Metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol. 2008; 75(2): 346-59..
  5. Nagase H, Woessner JF. Matrix metalloproteinases. J Biol Chem. 1999; 274: 21491-4..
  7. Giebel SJ, Menicucci G, McGuire PG. Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood-retinal barrier. Lab Invest. 2005; 85(5): 597-607. CrossRef PubMed
  9. Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosc. 2006; 11. 1696-701.
  11. Rogowicz A, Zozulińska D, Wierusz-Wysocka B. Role of matrix metalloproteinases in the development of vascular complications of diabetes mellitus – clinical implications. Pol Arch Med Wewn. 2007; 117 (3): 1-7.
  13. Bhatt LK, Addepalli V. Attenuation of diabetic retinopathy by enhanced inhibition of MMP-2 and MMP-9 using aspirin and minocycline in streptozotocin-diabetic rats. Amer J Translat Res. 2010; 2(2): 181-9.
  15. Kowluru RA, Mohammad G, dos Santos JM, Zhong Q. Abrogation of MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage. Diabetes. 2011; 60(11): 3023-33. CrossRef PubMed PubMedCentral
  17. Derosa G, D'Angelo A, Tinelli C, Devangelio E, Consoli A, Miccoli R, Penno G, Del Prato S, Paniga S, Cicero AFG. Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in diabetic and healthy subjects. Diabet Metabol. 2007; 33(2): 129-34. CrossRef PubMed
  19. Rangasamy S, McGuire PG, Das A. Diabetic retinopathy and inflammation: novel therapeutic targets. Middle East Afr J Ophthalmol. 2012; 19 (1): 52-9. CrossRef PubMed PubMedCentral
  21. Kowluru RA. Role of Matrix Metalloproteinase-9 in the development of diabetic retinopathy and its regulation by H-Ras. Invest Ophthalmol Visual Sci. 2010; 51(8): 4320-26. CrossRef PubMed PubMedCentral
  23. Zheng Y, He M, Congdon N. The worldwide epidemic of diabetic retinopathy. Ind J Ophthalmol. 2012; 60(5): 428–31. CrossRef PubMed PubMedCentral
  25. El-Azab MF, Mysona BA, El-Remessy AB. Statins for prevention of diabetic-related blindness: a new treatment option? Exp Rev Ophthalmol. 2011; 6(3): 269-72. CrossRef PubMed PubMedCentral
  27. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010; 87(1): 4-14. CrossRef PubMed
  29. International Diabetes Federation. IDF Diabetes Atlas, 7 ed. Brussels, Belgium: International Diabetes Federation, 2015.
  31. Wilkinson-Berka JL. Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol. 2006; 38: 752-65. CrossRef PubMed
  33. Cheung N, Mitchell P, Wong TY. Diabetic retinopath. Lancet. 2010; 376(9735): 124-36. CrossRef  
  34. Tronko MD, Sokolova LK, Vlasenko NV, Kostukevich AA., 2015. Achieving the goals in treatment of patients with diabetes mellitus in Ukraine. Results Diabetes Management Practices Study (IDMPS). Endokrynologia. 20(4): 658-68. [Ukrainian].
  36. Kowluru RA, Zhong Q, Santos JM. Matrix metalloproteinases in diabetic retinopathy: potential role of MMP- 9. Exp Opin Invest Drugs. 2012; 21(6): 797-805. CrossRef PubMed PubMedCentral
  38. Demirel S, Argo C, Agarwal A, Parriott J, Sepah YJ, Do DV, Nguyen QD. Updates on the clinical trials in diabetic macular edema. Middle East Afr J Ophthalmol. 2016; 23(1): 3-12. CrossRef PubMed PubMedCentral
  40. Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003; 110(9): 1677-82. CrossRef  
  41. Tayebjee MH, Lim HS, Macfadyen RJ. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 and -2 in type 2 diabetes. Diabetes Care. 2004; 27(8): 2049-51. CrossRef PubMed
  43. Heo SH, Cho CH, Kim HO, Jo YH, Yoon KS, Lee JH, Park JC, Park KC, Ahn TB, Chung KC, Yoon SS, Chang DI. Plaque rupture is a determinant of vascular events in carotid artery atherosclerotic disease: involvement of Matrix Metalloproteinases 2 and 9. J Clin Neurol. 2011; 7(2): 69-76. CrossRef PubMed PubMedCentral
  45. Beránek M, Kolar P, Tschoplova S, Kankova K, Vasku A. Genetic variations and plasma levels of gelatinase A (matrix metalloproteinase-2) and gelatinase B (matrix metalloproteinase-9) in proliferative diabetic retinopathy. Mol Vis. 2008; 14: 1114-21.
  47. Abu El-Asrar AM, Mohammad G, Nawaz MI et al. Relationship between vitreous levels of Matrix Metalloproteinases and Vascular Endothelial Growth Factor in proliferative diabetic retinopathy. PLoS One. 2013; 8(12): e85857.

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.