Atherosclerosis 161 (2002) 233 – 242 Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians Christian Weyer a, *, John S. Yudkin b , Coen D.A. Stehouwer c , Casper G. Schalkwijk c , Richard E. Pratley a , P. Antonio Tataranni a a Clinical Diabetes and Nutrition Section, National Institutes of Diabetes and Digestie and Kidney Diseases, National Institutes of Health, 4212 N 16th Street Rm. 5 -41, Phoenix, AZ 85016, USA b Diabetes and Cardioascular Disease Academic Unit, Uniersity College London Medical School, Whittington Hospital, London, UK c Department of Medicine, Academic Hospital and Institute for Cardioascular Research, Vrije Uniersiteit, Amsterdam, The Netherlands Received 21 November 2000; received in revised form 21 May 2001; accepted 30 May 2001 Abstract Several studies have shown that humoral markers of inflammation and endothelial dysfunction are predictive of macrovascular events, and correlated with indirect measures of adiposity and insulin action, thus providing a possible link between obesity, insulin resistance and atherosclerosis. We examined the relationship between humoral markers of inflammation and endothelial dysfunction and direct measures of adiposity and insulin action in Pima Indians, a population with a very high prevalence of obesity and insulin resistance, but a relatively low propensity for atherosclerotic disease. Fasting plasma concentrations of the inflammatory markers C-reactive protein (CRP), secretory phospholipase A2 (sPLA2) and soluble intercellular adhesion molecule-1 (sICAM-1) and of the endothelial markers E-selectin and von Willebrand factor (vWF) were measured in 32 non-diabetic Pima Indians (18 M/14 F, age 27 1 years) in whom percent body fat and insulin-stimulated glucose disposal (M) were assessed by DEXA and a hyperinsulinemic clamp, respectively. CRP, sPLA2, and sICAM-1 were all positively correlated with percent body fat (r =0.71, 0.57, and 0.51, all P 0.01). E-selectin and vWF were not correlated with percent body fat, but were negatively correlated with M (r =-0.65 and -0.46, both P 0.001) and positively correlated with CRP (r =0.46, and 0.33, both P 0.05). These findings indicate that humoral markers of inflammation increase with increasing adiposity in Pima Indians whereas humoral markers of endothelial dysfunction increase primarily in proportion to the degree of insulin resistance and inflammation. Thus, obesity and insulin resistance appear to be associated with low-grade inflammation and endothelial dysfunction, respectively, even in an obesity- and diabetes-prone population with relatively low propensity for atherosclerosis. Published by Elsevier Science Ireland Ltd. Keywords: Insulin resistance; Obesity; Atherosclerosis; Glucose clamp; Ethnicity www.elsevier.com/locate/atherosclerosis 1. Introduction In recent years, there has been growing recognition that obesity is associated with a state of chronic low- grade inflammation [1 – 6]. Although the pathophysio- logical basis for this association remains incompletely understood, it is known that adipose tissue expresses a variety of pro-inflammatory cytokines such as IL-6, TNF-, and complement C3 [1,3–5], which stimulate the production of acute-phase proteins such as C-reac- tive protein (CRP) [7]. Accordingly, plasma concentra- tions of pro-inflammatory cytokines and acute-phase proteins are elevated in people with obesity [1–6]. Inflammatory processes, in turn, are known to be involved in the early stages of atherogenesis [8,9] and, more recently, have also been proposed to play a role in the pathogenesis of insulin resistance [5,6,10 – 12]. This is supported by several lines of evidence. First, experi- mental studies have shown that IL-6 and TNF- stimu- late the in vitro expression [13–16] and in vivo release [17] of endothelial adhesion molecules and, in the case of TNF-, to impair in vitro insulin action by interfer- * Corresponding author. Tel.: +1-858-642-7076; fax: +1-858-558- 0257. E-mail address: cweyer@amylin.com (C. Weyer). 0021-9150/02/$ - see front matter. Published by Elsevier Science Ireland Ltd. PII:S0021-9150(01)00626-8