Utility of Tissue Inhibitor Metalloproteinase-1 and Osteopontin as Prospective Biomarkers of Early Cardiovascular Complications in Type 2 Diabetes

  • Doaa Samir Salah El-Din Chemistry, Faculty of Science, Cairo University, Giza 12613
  • Ahmed Ibrahim Amin Chemistry, Faculty of Science, Cairo University, Giza 12613
  • Ahmed Osman Egiza Chemistry, Faculty of Science, Cairo University, Giza 12613
Keywords: Molecular markers, expression level, tissue inhibitor metalloproteinase-1, OPN concentrations, diabetic cardiovascular diseases


AIM: This work investigated associations between tissue inhibitor metalloproteinase-1 and diabetic cardiovascular diseases in type 2 diabetic patients; also it investigated the role of osteopontin in the diagnosis of type 2 cardiovascular diabetes complications.

SUBJECTS AND METHODS: These were examined on eighty subjects, divided into three groups as follows: twenty volunteer healthy control subjects, thirty type 2 diabetes mellitus (DM) patients, and thirty cardiovascular, diabetic patients. Full clinical measurements were carried out, and the expression level of tissue inhibitor metalloproteinase-1 in blood samples was analysed by real-time PCR, using gene-specific primer pairs. Also osteopontin concentrations had been measured by the enzyme-linked immunosorbent assay. Data were tested statistically by parametric tests.

RESULTS: The concentrations of osteopontin and the expression levels of tissue inhibitor metalloproteinase-1 were significantly increased in diabetic and cardiovascular diabetic groups compared to control group also they were significantly increased in the cardiovascular diabetic group compared to the diabetic group.

CONCLUSION: Tissue inhibitor metalloproteinase-1 and osteopontin concentrations were significantly increased in diabetic patients with cardiovascular complications than other groups.


Download data is not yet available.


Metrics Loading ...

Plum Analytics Artifact Widget Block


Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004; 27:1047-53. https://doi.org/10.2337/diacare.27.5.1047

Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Considerations. Circulation. 2016; 133:2459-502. https://doi.org/10.1161/CIRCULATIONAHA.116.022194 PMid:27297342 PMCid:PMC4910510

American Diabetes Association. Standards of medical care in diabetes. Diabet Care. 2015; 38(Suppl. 1):S1-S94. PMCid:PMC4582912

International Expert Committee. International expert committee report on the role of the a1c assay in the diagnosis of diabetes. Diabet Care. 2009; 32:1327-34. https://doi.org/10.2337/dc09-9033 PMid:19502545 PMCid:PMC2699715

Tuomilehto J, Lindström J, Hellmich M et al. Development and validation of a risk-score model for subjects with impaired glucose tolerance for the assessment of the risk of type 2 diabetes mellitus—the stop-niddm risk-score. Diabet Res Clin Pract. 2010; 87:267-74. https://doi.org/10.1016/j.diabres.2009.11.011 PMid:20022651

Tayebjee MH, MacFadyen RJ, Lip GYH. Extracellular matrix biology: A new frontier in linking the pathology and therapy of hypertension? J Hypertens. 2003;21:2211-18. https://doi.org/10.1097/00004872-200312000-00002 PMid:14654734

Tayebjee MH, Lim HS, Nadar S, MacFadyen RJ, Lip GYH. Tissue inhibitor of metalloproteinseâ€1 is a marker of diastolic dysfunction using tissue doppler in patients with type 2 diabetes and hypertension. Eur J Clin Invest. 2005;35:8-12. https://doi.org/10.1111/j.1365-2362.2005.01438.x PMid:15638813

Maxwell P, Timms P, Chandran S, Gordon D. Peripheral blood level alterations of timpâ€1, mmpâ€2 and mmpâ€9 in patients with type 1 diabetes. Diabet Med. 2001;18:777-80. https://doi.org/10.1046/j.1464-5491.2001.00542.x PMid:11678966

Van Bortel LM, Struijker-Boudier HA, Safar ME. Pulse pressure, arterial stiffness, and drug treatment of hypertension. Hypertension. 2001;38:914-21. https://doi.org/10.1161/hy1001.095773 PMid:11641309

Tayebjee MH, Lim HS, MacFadyen RJ, Lip GYH. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 and -2 in type 2 diabetes: Effect of 1 year's cardiovascular risk reduction therapy. Diabet Care. 2004;27:2049-51. https://doi.org/10.2337/diacare.27.8.2049

Zhong X-J, Shen X-D, Wen J-B et al. Osteopontin-induced brown adipogenesis from white preadipocytes through a pi3k-akt dependent signaling. Biochem Biophys Res Commun. 2015;459:553-9. https://doi.org/10.1016/j.bbrc.2015.02.153 PMid:25749339

Minoretti P, Falcone C, Calcagnino M et al. Prognostic significance of plasma osteopontin levels in patients with chronic stable angina. Eur Heart J. 2006;27:802-7. https://doi.org/10.1093/eurheartj/ehi730 PMid:16421174

Nilsson-Berglund LM, Zetterqvist AV, Nilsson-Öhman J et al. Nuclear factor of activated t cells regulates osteopontin expression in arterial smooth muscle in response to diabetes-induced hyperglycemia. Arterioscler Thromb Vasc Bio. 2010;30:218-24. https://doi.org/10.1161/ATVBAHA.109.199299 PMid:19965778 PMCid:PMC2823568

Nathan DM, Singer DE, Hurxthal K, Goodson JD. The clinical information value of the glycosylated hemoglobin assay. N Eng J Med. 1984;310:341-6. https://doi.org/10.1056/NEJM198402093100602 PMid:6690962

Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem. 1982;28:2077-80. PMid:6812986

Sugiuchi H, Uji Y, Okabe H et al. Direct measurement of high-density lipoprotein cholesterol in serum with polyethylene glycol-modified enzymes and sulfated alpha-cyclodextrin. Clin Chem. 1995;41:717-23. PMid:7729051

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502. PMid:4337382

Pasupathi P, Rao YY, Farook J, Bakthavathsalam G. Biochemical cardiac markers in clinical cardiology. Medicine. 2009;10:100-8.

Lyonsa TJ, Basub A. Biomarkers in diabetes: Hemoglobin A1c, vascular and tissue markers. Transl Res. 2012;159: 303-12. https://doi.org/10.1016/j.trsl.2012.01.009 PMid:22424433 PMCid:PMC3339236

Usmanova ZA. Relationship between the levels of mmp-9, timp-1, and zinc in biological samples of patients with carotid atherosclerosis. Int J BioMedicine. 2015;5:60-4. https://doi.org/10.21103/Article5(2)_CR2

Lee SW, Song KE, Shin DS et al. Alterations in peripheral blood levels of timp-1, mmp-2, and mmp-9 in patients with type-2 diabetes. Diabet Res Clin Pract. 2005;69:175-9. https://doi.org/10.1016/j.diabres.2004.12.010 PMid:16005367

Papazafiropoulou A, Tentolouris N. Matrix metalloproteinases and cardiovascular diseases. Hippokratia. 2009;13(2):76-82. PMid:19561775 PMCid:PMC2683462

Lim H, Tayebjee M, MacFadyen R, Lip GY. Tissue inhibitor of matrix metalloproteinase-1 is a marker of left ventricular diastolic dysfunction in diabetic heart disease. Am Coll Cardiol. 2004;43:221A. https://doi.org/10.1016/S0735-1097(04)90938-2

Schram M, Henry R, Van Dijk R et al. Increased central artery stiffness in impaired glucose metabolism and type 2 diabetes: the Hoorn Study. Hypertension. 2004;43:176-81. https://doi.org/10.1161/01.HYP.0000111829.46090.92 PMid:14698999

Bidder M, Shao J-S, Charlton-Kachigian N et al. Osteopontin transcription in aortic vascular smooth muscle cells is controlled by glucose-regulated upstream stimulatory factor and activator protein-1 activities. J Biol Chem. 2002;277:44485-96. https://doi.org/10.1074/jbc.M206235200 PMid:12200434

Takemoto M, Yokote K, Nishimura M et al. Enhanced expression of osteopontin in human diabetic artery and analysis of its functional role in accelerated atherogenesis. Arterioscler Thromb Vasc Bio. 2000;20:624-28. https://doi.org/10.1161/01.ATV.20.3.624

Lorenzen JM, Neunhoffer H, David S et al. Angiotensin II receptor blocker and statins lower elevated levels of osteopontin in essential hypertension-Results from the EUTOPIA trial. Atherosclerosis 2010;209:184-8. https://doi.org/10.1016/j.atherosclerosis.2009.09.009 PMid:19801149

Riedl M, Vila G, Maier C et al. Plasma osteopontin increases after bariatric surgery and correlates with markers of bone turnover but not with insulin resistance. J Clin Endocrinol Metab. 2008;93:2307-12. https://doi.org/10.1210/jc.2007-2383 PMid:18334587

Ikeda T, Shirasawa T, Esaki Y et al. Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta. J Clin Invest. 1993;92:2814-20. https://doi.org/10.1172/JCI116901 PMid:8254036 PMCid:PMC288482

Isoda K, Kamezawa Y, Ayaori M et al. Osteopontin transgenic mice fed a highcholesterol diet develop early fatty-streak lesions. Circulation. 2003;107:679-81. https://doi.org/10.1161/01.CIR.0000055739.13639.D7 PMid:12578867

Ohmori R, Momiyama Y, Taniguchi H et al. Plasma osteopontin levels are associated with the presence and extent of coronary artery disease. Atherosclerosis. 2003;170: 333-7. https://doi.org/10.1016/S0021-9150(03)00298-3

Kato R, Momiyama Y, Ohmori R et al. High plasma levels of osteopontin in patients with restenosis after percutaneous coronary intervention. Arterioscler Thromb Vasc Biol.2006;26:1-2. https://doi.org/10.1161/01.ATV.0000194157.26665.e6 PMid:16373617

Kurata M, Okura T, Watanabe S et al. Osteopontin and carotid atherosclerosis in patients with essential hypertension. Clin Sci (Lond). 2006;111:319-24. https://doi.org/10.1042/CS20060074 PMid:16776647

Scatena M, Liaw L, Giachelli CM. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol. 2007;27:2302-9. https://doi.org/10.1161/ATVBAHA.107.144824 PMid:17717292

Yan X, Sano M, Lu L et al. Plasma concentrations of osteopontin, but not thrombin-cleaved osteopontin, are associated with the presence and severity of nephropathy and coronary artery disease in patients with type 2 diabetes mellitus. Cardiovascular Diabetology. 2010;9:70. https://doi.org/10.1186/1475-2840-9-70 PMid:21034455 PMCid:PMC2988001

How to Cite
Salah El-Din DS, Amin AI, Egiza AO. Utility of Tissue Inhibitor Metalloproteinase-1 and Osteopontin as Prospective Biomarkers of Early Cardiovascular Complications in Type 2 Diabetes. Open Access Maced J Med Sci [Internet]. 2018Feb.10 [cited 2020Nov.29];6(2):314-9. Available from: https://www.id-press.eu/mjms/article/view/oamjms.2018.081
B - Clinical Sciences