Abstract-Upregulation of endothelial adhesion molecules is the earliest step of atherogenesis. Whether obesity induces endothelial adhesin upregulation is unknown. To address this topic, circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and von Willebrand factor (vWF) Obesity and central body fat disposition have been correlated with a higher prevalence of cardiovascular death in low-risk subjects. 4 The relative risk of cardiovascular death associated with an increment of 1 kg/m 2 in body mass index (BMI) is 1.10 and 1.08 for adult men and women, respectively. 1 Thus, although the influence of other risk factors such as low physical activity and excess alcohol intake 2 cannot be excluded, obesity acts as an independent cardiovascular risk factor.Upregulation of endothelial adhesins of the selectin family 5 (E-selectin and P-selectin) and of the immunoglobulin superfamily 6 [intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)] allows the attachment of circulating cells to the endothelium and represents the initiating event in atherogenesis. 7,8 Upregulation of adhesin genes leads to the expression of membraneassociated adhesins and release of their soluble forms. Thus, circulating soluble adhesin levels act as markers of in vivo adhesin expression. 8 -11 Accordingly, plasma soluble E-selectin concentrations were found to be elevated in conditions associated with increased risk for developing atherosclerosis, ie, type 2 diabetes 12,13 and hypertension. 14 Similarly, plasma soluble VCAM-1, ICAM-1, and E-selectin concentrations were found to be elevated in glucoseintolerant hypertensives. 15 Augmented levels of circulating von Willebrand factor (vWF), a marker of in vivo endothelial damage, 16 were found in nonatherosclerotic obese persons. 17 Furthermore, circulating levels of endothelin-1 18 and tissue plasminogen activator-1 19 were increased while endotheliumdependent vasodilation 20 was reduced in normotensive obese individuals.Taken together, the above data support the concept that obesity per se might induce early endothelial activation in humans. In view of the possible relationship between such endothelial activation and obesity, we evaluated circulating

Endothelin-1 (ET-1) is a potent vasoactive and mitogenic peptide produced by the vascular endothelium. In this study, we evaluated whether insulin stimulates ET-1 secretion by human endothelial cells derived from umbilical cord veins and by human permanent endothelial hybrid cells Ea.hy 926. Moreover, to provide evidence that insulin may stimulate ET-1 secretion in vivo, plasma ET-1 levels were evaluated in 7 type II diabetic normotensive males (mean age, 54.3 +/- 4.0 yr) during 2-h hyperinsulinemic euglycemic clamps (287 pmol insulin/m2.min-1) as well as in 12 obese hypertensive males (mean age, 44.2 +/- 4.6 yr) before and after a 12-week period of caloric restriction. Our results showed that insulin stimulated ET-1 release from cultured endothelial cells in a dose-dependent fashion. ET-1 release persisted for 24 h and was also observed at physiological insulin concentrations (10(-9) mol/L). The insulin-induced ET-1 secretion was inhibited by genistein, a tyrosine kinase inhibitor, and by cycloheximide, a protein synthesis inhibitor, suggesting that it requires de novo protein synthesis rather than ET-1 release from intracellular stores. In the in vivo experiments, plasma ET-1 levels rapidly increased during euglycemic hyperinsulinemic clamps (from 0.76 +/- 0.18 pg/mL at time zero to 1.65 +/- 0.21 pg/mL at 60 min; P < 0.05) and persisted elevated until the end of insulin infusion (1.37 +/- 0.37 pg/mL at 120 min; P < 0.05 vs. time zero). In obese hypertensives, plasma ET-1 levels significantly decreased after 12 weeks of caloric restriction (from 0.85 +/- 0.51 to 0.48 +/- 0.28 pg/mL; P < 0.04). The decrease in body weight induced by caloric restriction was accompanied by a significant reduction in fasting insulin levels (from 167.2 +/- 94.0 to 98.9 +/- 44.9 pmol/L; P < 0.05) which correlated with the reduction in plasma ET-1 levels (r = 0.78; P < 0.003). In conclusion, our data show that insulin stimulates both in vitro and in vivo ET-1 secretion. Such interaction could play a significant role in the development of atherosclerotic lesions in hyperinsulinemic conditions.

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Isotype restriction and polyclonality O R I G I N A L A R T I C L EO B J E C T I V E -To determine the isotypes and clonality of antibodies to GAD (GADA) and IA-2 (IA-2A) in patients with type 1 and type 2 diabetes.RESEARCH DESIGN AND METHODS -We studied the following consecutive series of patients who attended a diabetes center for antibodies to GADA and IA-2A: 52 newly diagnosed type 1 diabetic patients, 199 type 2 diabetic patients, 200 control patients, and a cohort of 34 nondiabetic identical twins of patients with type 1 diabetes (15 of whom developed diabetes) who were followed pro s p e c t i v e l y.R E S U LT S -GADA or IA-2A were detected in 37 (71%) type 1 diabetic patients compare d with only 10 (5%) type 2 diabetic patients (P 0.0001). Both GAD and IA-2 antibodies, re g a rdless of the type of diabetes, were usually subclass restricted to IgG1 and were polyclonal. IgM, IgG3, and IgE isotypes were also detected, but all isotypes of GADA and IA-2A were less p revalent than IgG1 (P 0.017 for either antibody). There was no evidence of spreading or switching of isotypes before the onset of type 1 diabetes.C O N C L U S I O N S -These observations suggest that the pathogenesis of antigen-specific antibodies in type 1 and type 2 diabetes is similar and probably involves a chronic nonrandom antigen-driven polyclonal B-cell activation that is consistent with a Th1-type immune re s p o n s e .