Original Article Obesity Is a Major Determinant of the Association of C-Reactive Protein Levels and the Metabolic Syndrome in Type 2 Diabetes Steven E. Kahn, 1 Bernard Zinman, 2 Steven M. Haffner, 3 M. Colleen O’Neill, 4 Barbara G. Kravitz, 4 Dahong Yu, 4 Martin I. Freed, 4 William H. Herman, 5 Rury R. Holman, 6 Nigel P. Jones, 4 John M. Lachin, 7 Giancarlo C. Viberti, 8 and the ADOPT Study Group* The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activa- tor-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA 1c [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (<3 years), drug-naive, type 2 diabetic subjects (fasting plasma glucose <10 mmol/ l), we examined a representative subgroup (n  921) of the U.S. cohort in ADOPT (A Diabetes Outcome Progression Trial). The relationship between levels of CRP, fibrinogen, PAI-1 antigen and PAI-1 activity, and baseline variables including National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome phenotype were explored. All four factors increased significantly with in- creasing numbers of metabolic syndrome components (P  0.0136 to P < 0.0001). BMI (P < 0.0001) and HOMA-IR (P < 0.0001) but not A1C (P  0.65) increased with increasing numbers of metabolic syndrome components. Adjustment of CRP levels for BMI eliminated the associa- tion between CRP and the number of metabolic syndrome components, while adjusting for HOMA-IR did not (P  0.0028). The relationships of PAI-1 antigen and PAI-1 activity with the number of metabolic syndrome compo- nents were maintained after adjusting for BMI (P  0.0002 and P  <0.0001, respectively) or HOMA-IR (P  0.0008 and P  <0.0001, respectively), whereas that with fibrin- ogen was eliminated after adjusting for BMI but not after adjusting for HOMA-IR (P  0.013). Adjustment for A1C had no effect on any of the relationships between the inflammatory and fibrinolytic factors and the metabolic syndrome. We conclude that in recently diagnosed, drug- naive type 2 diabetic subjects, markers of inflammation and fibrinolysis are strongly related to the number of metabolic syndrome components. Further, for CRP and fibrinogen this relationship is determined by body adipos- ity and not by insulin sensitivity or glucose control. Diabetes 55:2357–2364, 2006 I ncreased levels of the nontraditional cardiovascular disease (CVD) risk factors C-reactive protein (CRP), plasminogen activator-1 (PAI-1), and fibrinogen have been associated with increased CVD in the general population (1– 4). Type 2 diabetes is also associated with increased levels of these nontraditional CVD risk factors (5,6). In the nondiabetic population, insulin resistance and obesity are important determinants of increases in these inflammatory and fibrinolytic variables (5–9). However, the role of obesity and insulin resistance relative to worsening glycemia as determinants of these risk factors has not been extensively explored in subjects with type 2 diabetes. The metabolic syndrome (10), which comprises the more traditional CVD risk factors such as blood pressure, lipids, and central obesity, has been shown to be a risk factor for the development of both CVD and diabetes (11–13). The vast majority of subjects with type 2 diabetes have the metabolic syndrome, and these individuals are at higher risk of CVD than subjects with type 2 diabetes who do not have the metabolic syndrome (12,13). Furthermore, in nondiabetic subjects the metabolic syndrome has been associated with higher levels of CRP as well as PAI-1 and fibrinogen (7,11). However, the relationship between the presence or absence of the metabolic syndrome and concentrations of CRP, PAI-1, and fibrinogen has not been explored in a large cohort of type 2 diabetic subjects who are drug naive. The interpretation of analyses of nontraditional CVD risk factors in subjects with type 2 diabetes has been complicated by the fact that many subjects with the disease have been treated with glucose-lowering pharma- cological therapies at the time of investigation, and these From the 1 Division of Metabolism, Endocrinology and Nutrition, Department of Internal Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington; the 2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Ontario, Canada; the 3 Uni- versity of Texas Health Science Center at San Antonio, San Antonio, Texas; 4 GlaxoSmithKline, King of Prussia, Pennsylvania; the 5 Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, Michigan; the 6 Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metab- olism, Oxford, U.K.; the 7 Biostatistics Center, George Washington University, Rockville, Maryland; and the 8 King’s College London School of Medicine, King’s College London, London, U.K. Address correspondence and reprint requests to Steven E. Kahn, MB, ChB, VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA 98108. E-mail: skahn@u.washington.edu. Received for publication 25 January 2006 and accepted in revised form 22 May 2006. *A list of members of the ADOPT Study Group appears in Diabetes 53:3193–3200, 2004 S.E.K., B.Z., S.M.H., W.H.H., R.R.H., J.M.L., and G.C.V. have received honoraria, consulting fees, and/or grant/research support from GlaxoSmithK- line. ADOPT, A Diabetes Outcome Progression Trial; CRP, C-reactive protein; CVD, cardiovascular disease; HOMA-IR, homeostasis model assessment of insulin resistance; PAI-1, plasminogen activator-1. DOI: 10.2337/db06-0116 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES, VOL. 55, AUGUST 2006 2357