© 1999 American Heart Association, Inc.
Original Contributions |
Relative Contribution of Insulin and Its Precursors to Fibrinogen and PAI-1 in a Large Population With Different States of Glucose Tolerance
The Insulin Resistance Atherosclerosis Study (IRAS)
From the Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio (A.F., L.M., S.M.H.); the Department of Public Health Sciences, Bowman Gray School of Medicine, Winston Salem, NC (R.D., D.J.Z.); the Department of Pathology, University of Vermont School of Medicine, Burlington (R.P.T.); and the Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK (C.N.H.).
Correspondence to Andreas Festa, MD, Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284-7873. E-mail festa{at}uthscsa.edu
Abstract—Hyperinsulinemia is associated with the development of coronary heart disease. However, the underlying mechanisms are still poorly understood. Hypercoagulability and impaired fibrinolysis are possible candidates linking hyperinsulinism with atherosclerotic disease, and it has been suggested that proinsulin rather than insulin is the crucial pathophysiological agent. The aim of this study was to investigate the relationship of insulin and its precursors to markers of coagulation and fibrinolysis in a large triethnic population. A strong and independent relationship between plasminogen activator inhibitor-1 (PAI-1) antigen and insulin and its precursors (proinsulin, 32-33 split proinsulin) was found consistently across varying states of glucose tolerance (PAI-1 versus fasting insulin [proinsulin], r=0.38 [r=0.34] in normal glucose tolerance; r=0.42 [r=0.43] in impaired glucose tolerance; and r=0.38 [r=0.26] in type 2 diabetes; all P<0.001). The relationship remained highly significant even after accounting for insulin sensitivity as measured by a frequently sampled intravenous glucose tolerance test. In a stepwise multiple regression model after adjusting for age, sex, ethnicity, and clinic, both insulin and its precursors were significantly associated with PAI-1 levels. The relationship between fibrinogen and insulin and its precursors was significant in the overall population (r=0.20 for insulin and proinsulin; each P<0.001) but showed a more inconsistent pattern in subgroup analysis and after adjustments for demographic and metabolic variables. Stepwise multiple regression analysis showed that proinsulin (split products) but not fasting insulin significantly contributed to fibrinogen levels after adjustment for age, sex, clinic, and ethnicity. Decreased insulin sensitivity was independently associated with higher PAI-1 and fibrinogen levels. In summary, we were able to demonstrate an independent relationship of 2 crucial factors of hemostasis, fibrinogen and PAI-1, to insulin and its precursors. These findings may have important clinical implications in the risk assessment and prevention of macrovascular disease, not only in patients with overt diabetes but also in nondiabetic subjects who are hyperinsulinemic.
Key Words: non–insulin-dependent diabetes mellitus • plasminogen activator inhibitor-1 • fibrinogen • insulin • proinsulin
This article has been cited by other articles:
 |
|
 |
|
  S. R. de Rooij, G. Nijpels, P. M. Nilsson, J. J. Nolan, R. Gabriel, E. Bobbioni-Harsch, G. Mingrone, J. M. Dekker, and for the Relationship Between Insulin Sensitivity a Low-Grade Chronic Inflammation in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) Population: Associations with insulin resistance and cardiometabolic risk profile Diabetes Care, July 1, 2009; 32(7): 1295 - 1301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Dandona, A. Chaudhuri, H. Ghanim, and P. Mohanty Insulin as an anti-inflammatory and antiatherogenic modulator. J. Am. Coll. Cardiol., February 3, 2009; 53(5 Suppl): S14 - S20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Lorenzo, S. D. Nath, A. J.G. Hanley, H. E. Abboud, and S. M. Haffner Relation of Low Glomerular Filtration Rate to Metabolic Disorders in Individuals without Diabetes and with Normoalbuminuria Clin. J. Am. Soc. Nephrol., May 1, 2008; 3(3): 783 - 789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Caballero, K. Bousquet-Santos, L. Robles-Osorio, V. Montagnani, G. Soodini, S. Porramatikul, O. Hamdy, A. C.L. Nobrega, and E. S. Horton Overweight Latino Children and Adolescents Have Marked Endothelial Dysfunction and Subclinical Vascular Inflammation in Association With Excess Body Fat and Insulin Resistance Diabetes Care, March 1, 2008; 31(3): 576 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Ivey, A. S. Ryan, C. E. Hafer-Macko, A. P. Goldberg, and R. F. Macko Treadmill Aerobic Training Improves Glucose Tolerance and Indices of Insulin Sensitivity in Disabled Stroke Survivors: A Preliminary Report Stroke, October 1, 2007; 38(10): 2752 - 2758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Muscari, S. Antonelli, G. Bianchi, G. Cavrini, S. Dapporto, A. Ligabue, C. Ludovico, D. Magalotti, G. Poggiopollini, M. Zoli, et al. Serum C3 Is a Stronger Inflammatory Marker of Insulin Resistance Than C-Reactive Protein, Leukocyte Count, and Erythrocyte Sedimentation Rate: Comparison study in an elderly population Diabetes Care, September 1, 2007; 30(9): 2362 - 2368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Kahn, B. Zinman, S. M. Haffner, M. C. O'Neill, B. G. Kravitz, D. Yu, M. I. Freed, W. H. Herman, R. R. Holman, N. P. Jones, et al. Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes. Diabetes, August 1, 2006; 55(8): 2357 - 2364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Festa, K. Williams, R. P. Tracy, L. E. Wagenknecht, and S. M. Haffner Progression of Plasminogen Activator Inhibitor-1 and Fibrinogen Levels in Relation to Incident Type 2 Diabetes Circulation, April 11, 2006; 113(14): 1753 - 1759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-J. Kim and E. Barrett-Connor Association of serum proinsulin with hormone replacement therapy in nondiabetic older women: the rancho bernardo study. Diabetes Care, March 1, 2006; 29(3): 618 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Kanaya, C. Wassel Fyr, E. Vittinghoff, T. B. Harris, S. W. Park, B. H. Goodpaster, F. Tylavsky, and S. R. Cummings Adipocytokines and incident diabetes mellitus in older adults: the independent effect of plasminogen activator inhibitor 1. Arch Intern Med, February 13, 2006; 166(3): 350 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Quyyumi Women and Ischemic Heart Disease: Pathophysiologic Implications From the Women's Ischemia Syndrome Evaluation (WISE) Study and Future Research Steps J. Am. Coll. Cardiol., February 7, 2006; 47(3_Suppl_S): S66 - S71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Blaschke, Y. Takata, E. Caglayan, R. E. Law, and W. A. Hsueh Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 28 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
the Diabetes Prevention Program Research Group Lipid, Lipoproteins, C-Reactive Protein, and Hemostatic Factors at Baseline in the Diabetes Prevention Program Diabetes Care, October 1, 2005; 28(10): 2472 - 2479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kahn, J. Buse, E. Ferrannini, and M. Stern The Metabolic Syndrome: Time for a Critical Appraisal: Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes Diabetes Care, September 1, 2005; 28(9): 2289 - 2304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
The Diabetes Prevention Program Research Group Intensive Lifestyle Intervention or Metformin on Inflammation and Coagulation in Participants With Impaired Glucose Tolerance Diabetes, May 1, 2005; 54(5): 1566 - 1572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Walcher and N. Marx Insulin resistance and cardiovascular disease: the role of PPAR{gamma} activators beyond their anti-diabetic action Diabetes and Vascular Disease Research, October 1, 2004; 1(2): 76 - 81. [Abstract] [PDF]
|
|
|
|
|
|
A. J.G. Hanley, A. Festa, R. B. D'Agostino, L. E. Wagenknecht, P. J. Savage, R. P. Tracy, M. F. Saad, and S. M. Haffner Metabolic and Inflammation Variable Clusters and Prediction of Type 2 Diabetes: Factor Analysis Using Directly Measured Insulin Sensitivity Diabetes, July 1, 2004; 53(7): 1773 - 1781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Festa, R. D'Agostino Jr., A. J.G. Hanley, A. J. Karter, M. F. Saad, and S. M. Haffner Differences in Insulin Resistance in Nondiabetic Subjects With Isolated Impaired Glucose Tolerance or Isolated Impaired Fasting Glucose Diabetes, June 1, 2004; 53(6): 1549 - 1555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. V. de Courten, C. Weyer, N. Stefan, M. Horton, A. DelParigi, P. Havel, C. Bogardus, and P. A. Tataranni Parasympathetic Blockade Attenuates Augmented Pancreatic Polypeptide But Not Insulin Secretion in Pima Indians Diabetes, March 1, 2004; 53(3): 663 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-J. Ma, S.-L. Mao, K. L. Taylor, T. Kanjanabuch, Y. Guan, Y. Zhang, N. J. Brown, L. L. Swift, O. P. McGuinness, D. H. Wasserman, et al. Prevention of Obesity and Insulin Resistance in Mice Lacking Plasminogen Activator Inhibitor 1 Diabetes, February 1, 2004; 53(2): 336 - 346. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Romano, M. T. Guagnano, G. Pacini, S. Vigneri, A. Falco, M. Marinopiccoli, M. R. Manigrasso, S. Basili, and G. Davi Association of Inflammation Markers with Impaired Insulin Sensitivity and Coagulative Activation in Obese Healthy Women J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5321 - 5326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Sobel, D. J. Taatjes, and D. J. Schneider Intramural Plasminogen Activator Inhibitor Type-1 and Coronary Atherosclerosis Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 1979 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Festa, R. D'Agostino Jr, S. S. Rich, N. S. Jenny, R. P. Tracy, and S. M. Haffner Promoter (4G/5G) Plasminogen Activator Inhibitor-1 Genotype and Plasminogen Activator Inhibitor-1 Levels in Blacks, Hispanics, and Non-Hispanic Whites: The Insulin Resistance Atherosclerosis Study Circulation, May 20, 2003; 107(19): 2422 - 2427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Viberti, S. E. Kahn, D. A. Greene, W. H. Herman, B. Zinman, R. R. Holman, S. M. Haffner, D. Levy, J. M. Lachin, R. A. Berry, et al. A Diabetes Outcome Progression Trial (ADOPT): An international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes Diabetes Care, October 1, 2002; 25(10): 1737 - 1743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Roffi, D. J. Moliterno, B. Meier, E. R. Powers, C. L. Grines, P. M. DiBattiste, H. C. Herrmann, M. Bertrand, K. E. Harris, L. A. Demopoulos, et al. Impact of Different Platelet Glycoprotein IIb/IIIa Receptor Inhibitors Among Diabetic Patients Undergoing Percutaneous Coronary Intervention: Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) 1-Year Follow-Up Circulation, June 11, 2002; 105(23): 2730 - 2736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Festa, R. D'Agostino Jr, R. P. Tracy, and S. M. Haffner Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study Diabetes, April 1, 2002; 51(4): 1131 - 1137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Devaraj, A. V. C. Chan Jr., and I. Jialal {alpha}-Tocopherol Supplementation Decreases Plasminogen Activator Inhibitor-1 and P-Selectin Levels in Type 2 Diabetic Patients Diabetes Care, March 1, 2002; 25(3): 524 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Wu, J. P. Dorn, R. P. Donahue, C. T. Sempos, and M. Trevisan Associations of Serum C-reactive Protein with Fasting Insulin, Glucose, and Glycosylated Hemoglobin : The Third National Health and Nutrition Examination Survey, 1988-1994 Am. J. Epidemiol., January 1, 2002; 155(1): 65 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pandolfi, D. Cetrullo, R. Polishuck, M. M. Alberta, A. Calafiore, G. Pellegrini, E. Vitacolonna, F. Capani, and A. Consoli Plasminogen Activator Inhibitor Type 1 Is Increased in the Arterial Wall of Type II Diabetic Subjects Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1378 - 1382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. Vinik, T. Erbas, T. S. Park, R. Nolan, and G. L. Pittenger Platelet Dysfunction in Type 2 Diabetes Diabetes Care, August 1, 2001; 24(8): 1476 - 1485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F. Geffken, M. Cushman, G. L. Burke, J. F. Polak, P. A. Sakkinen, and R. P. Tracy Association between Physical Activity and Markers of Inflammation in a Healthy Elderly Population Am. J. Epidemiol., February 1, 2001; 153(3): 242 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. T. Cefalu Insulin Resistance: Cellular and Clinical Concepts Experimental Biology and Medicine, January 1, 2001; 226(1): 13 - 26. [Abstract] [Full Text]
|
|
|
|
|
|
A. Festa, R. D'Agostino Jr, G. Howard, L. Mykkanen, R. P. Tracy, and S. M. Haffner Chronic Subclinical Inflammation as Part of the Insulin Resistance Syndrome : The Insulin Resistance Atherosclerosis Study (IRAS) Circulation, July 4, 2000; 102(1): 42 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Muscari, G Massarelli, L Bastagli, G Poggiopollini, V Tomassetti, G Drago, C Martignani, P Pacilli, P Boni, and P Puddu Relationship of serum C3 to fasting insulin, risk factors and previous ischaemic events in middle-aged men Eur. Heart J., July 1, 2000; 21(13): 1081 - 1090. [Abstract] [PDF]
|
|
|
|
|
|
J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zethelius, L. Byberg, C. N. Hales, H. Lithell, and C. Berne Proinsulin Is an Independent Predictor of Coronary Heart Disease: Report From a 27-Year Follow-Up Study Circulation, May 7, 2002; 105(18): 2153 - 2158. [Abstract] [Full Text] [PDF]
|
|