Elevated Serum Levels of Pregnancy-Associated Plasma Protein-A in Type 2 Diabetics Compared to Healthy Controls: Associations with Subclinical Atherosclerosis Parameters

  • Behnam Heidari Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. AND Endocrinology and Metabolism Research center, Vali-asr Hospital, School of Medicine,Tehran University of Medical Sciences, Tehran, Iran
  • Akbar Fotouhi Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  • Frshad Sharifi Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  • Kazem Mohammad Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  • Mohammad Pajouhi Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  • Koosha Paydary Iranian Research Center for HIV/AIDS (IRCHA), Iranian Institute for Reduction of High-Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran
  • Hossein Fakhrzadeh Mail Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
Pregnancy associated plasma protein-A, Diabetes mellitus, Subclinical atherosclerosis, Augmentation index, Coronary calcium score


Type 2 diabetes mellitus is associated with increased inflammation and accelerated atherosclerosis. The association of the pro-inflammatory and potentially pro-atherosclerotic molecule, pregnancy associated plasma protein-A (PAPP-A) with diabetes and vascular diseases remains to be further established. A total of 107 patients with type 2 diabetes and 101 healthy controls participated in this study. Serum levels of PAPP-A was measured by Enzyme-linked Immunosorbent Assay (ELISA). We also evaluated the lipid profile, aortic augmentation index, coronary calcium score, ankle brachial index, flow mediated dilation, and carotid intima media thickness. Serum level of PAPP-A was significantly higher in patients with diabetes compared to controls (PPP=0.021) and was negatively associated with coronary calcification (P=0.050). In conclusion, serum levels of PAPP-A were significantly higher in diabetics compared to healthy controls and correlated with aortic augmentation index and coronary calcification. Our study results suggest that PAPP-A can be a marker of subclinical atherosclerosis in patients with diabetes.


Lin TM, Galbert SP, Kiefer D, et al. Characterization of four human pregnancy-associated plasma proteins. Am J Obstet Gynecol 1974;118(2):223-36.

Folkersen J, Grudzinskas JG, Hindersson P, et al. Pregnancy-associated plasma protein A: circulating levels during normal pregnancy. Am J Obstet Gynecol 1981;139(8):910-4.

Lawrence JB, Oxvig C, Overgaard MT, et al. The insulinlike growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancyassociated plasma protein-A. Proc Natl Acad Sci U S A 1999;96(6):3149-53.

Bayes-Genis A, Conover CA, Schwartz RS. The insulinlike growth factor axis: A review of atherosclerosis and restenosis. Circ Res 2000;86(2):125-30.

Bayes-Genis A, Conover CA, Overgaard MT, et al. Pregnancy-associated plasma protein an as a marker of acute coronary syndromes. N Engl J Med 2001;345(14):1022-9.

Erbel R, Budoff M. Improvement of cardiovascular risk prediction using coronary imaging: subclinical atherosclerosis: the memory of lifetime risk factor exposure. Eur Heart J 2012;33(10):1201-13.

Naghavi M, Falk E, Hecht HS, et al. From vulnerable plaque to the vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report. Am J Cardiol 2006;98(2A):2H-15H.

Elesber AA, Conover CA, Denktas AE, et al. Prognostic value of circulating pregnancy-associated plasma protein levels in patients with chronic stable angina. Eur Heart J 2006;27(14):1678-84.

Iversen KK, Dalsgaard M, Teisner AS, et al. Pregnancyassociated plasma protein-A, a marker for outcome in patients suspected for acute coronary syndrome. Clin Biochem 2010;43(10-11):851-7.

Sanon S, Patel R, Eshelbrenner C, et al. Acute coronary syndrome in patients with diabetes mellitus: perspectives of an interventional cardiologist. Am J Cardiol 2012;110(9 Suppl):13B-23B.

Astrup AS, Tarnow L, Christiansen M, et al. Pregnancyassociated plasma protein A in a large cohort of Type 1 diabetic patients with and without diabetic nephropathy-a prospective follow-up study. Diabet Med 2007;24(12):1381-5.

Aso Y, Okumura K, Wakabayashi S, et al. Elevatedpregnancy-associated plasma protein-A in sera from type 2 diabetic patients with hypercholesterolemia: Associations with carotid atherosclerosis and toe-brachial index. J Clin Endocrinol Metab 2004;89(11):5713-7.

Pellitero S, Reverter JL, Pizarro E, et al. Pregnancyassociated plasma protein-A levels are related to glycemic control but not to lipid profile or hemostatic parameters in type 2 diabetes. Diabet Care 2007;30(12):3083-5.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2009;32(Suppl 1):S62-7.

Molitch ME, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes. Diabetes Care 2004;27(Suppl 1):S79-83.

Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28(4):956-62.

Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412-9.

Fakhrzadeh H, Yamini-Sharif A, Sharifi F, et al. Cardiac autonomic neuropathy measured by heart rate variability and markers of subclinical atherosclerosis in early type 2 diabetes. ISRN endocrinology 2012;2012:168264.

Stanford W, Thompson BH, Burns TL, et al. Coronary artery calcium quantification at multi-detector row helical CT versus electron-beam CT. Radiology 2004;230(2):397-402.

Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39(2):257-65.

Roos CJ, Auger D, Djaberi R, et al. Relationship between left ventricular diastolic function and arterial stiffness in asymptomatic patients with diabetes mellitus. Int J Cardiovasc Imaging 2013;29(3):609-16.

Grenon SM, Gagnon J, Hsiang Y. Video in clinical medicine. Ankle-brachial index for assessment of peripheral arterial disease. N Engl J Med 2009;361(19):e40.

Calle MC, Fernandez ML. Inflammation and type 2 diabetes. Diabetes Metab 2012;38(3):183-91.

van Greevenbroek MM, Schalkwijk CG, Stehouwer CD. Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences. Neth J Med 2013;71(4):174-87.

Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013;93(1):137-88.

Castro MM, Tanus-Santos JE, Gerlach RF. Matrix metalloproteinases: targets for doxycycline to prevent the vascular alterations of hypertension. Pharmacol Res 2011;64(6):567-72.

Park S, Lakatta EG. Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med J 2012;53(2):258-61.

Yasmin, McEniery CM, Wallace S, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25(2):372.

Medley TL, Cole TJ, Dart AM, et al. Matrix metalloproteinase-9 genotype influences large artery stiffness through effects on aortic gene and protein expression. Arterioscler Thromb Vasc Biol 2004;24(8):1479-84.

Vlachopoulos C, Aznaouridis K, Dima I, et al. Negative association between serum levels of matrix metalloproteinases-2 and -9 and aortic stiffness in healthy adults. Int J Cardiol 2007;122(3):232-8.

Papazafiropoulou A, Perrea D, Moyssakis I, et al. Plasma levels of MMP-2, MMP-9 and TIMP-1 are not associated with arterial stiffness in subjects with type 2 diabetes mellitus. J Diabetes Complications 2010;24(1):20-7.

Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol 2004;15(12):2959-64

Lund J, Qin QP, Ilva T, et al. Circulating pregnancyassociated plasma protein A predicts outcome in patients with acute coronary syndrome but no troponin I elevation. Circulation 2003;108(16):1924-6.

Sanchez-Escuredo A, Pastor MC, Bayes B, et al. Inflammation, Metalloproteinases, and Growth Factors in the Development of Carotid Atherosclerosis in Renal Transplant Patients. Transplantation Proc 2010;42(8):2905-7.

Pellitero S, Reverter JL, Luisa Granada M, et al. Association of the IGF1/pregnancy-associated plasma protein-A system and adipocytokine levels with the presence and the morphology of carotid plaques in type 2 diabetes mellitus patients with stable glycaemic control. Eur J Endocrinol 2009;160(6):925-32.

Beaudeux JL, Burc L, Imbert-Bismut F, et al. Serum plasma pregnancy-associated protein A - A potential marker of echogenic carotid atherosclerotic plaques in asymptomatic hyperlipidemic subjects at high cardiovascular risk. Arterioscler Thromb Vasc Biol 2003;23(1):e7-10.

Woelfle J, Roth CL, Wunsch R, et al. Pregnancyassociated plasma protein A in obese children: relationship to markers and risk factors of atherosclerosis and members of the IGF system. Eur J Endocrinol 2011;165(4):613-22.

Ceska R, Stulc T, Zima T, et al. PAPP-A, a novel marker of unstable plaque, is not influenced by hypolipidemic treatment in contrast to CRP. Atherosclerosis 2003;166:195-6.

Miedema MD, Conover CA, MacDonald H, et al. Pregnancy-associated plasma protein-A elevation in patients with acute coronary syndrome and subsequent Atorvastatin therapy. Am J Cardiol 2008;101(1):35-9.

Stulc T, Malbohan I, Malik J, et al. Increased levels of pregnancy-associated plasma protein-A in patients with hypercholesterolemia: the effect of atorvastatin treatment. Am Heart J 2003;146(6):E21.

How to Cite
Heidari B, Fotouhi A, Sharifi F, Mohammad K, Pajouhi M, Paydary K, Fakhrzadeh H. Elevated Serum Levels of Pregnancy-Associated Plasma Protein-A in Type 2 Diabetics Compared to Healthy Controls: Associations with Subclinical Atherosclerosis Parameters. Acta Med Iran. 53(7):395-402.
Original Article(s)