Proinflammatory Endothelial Activation Detected by Molecular Imaging in Obese Nonhuman Primates Coincides With Onset of Insulin Resistance and Progressively Increases With Duration of Insulin Resistance

Abstract

Background— Inflammation and insulin resistance (IR) are associated processes that potentiate risk for cardiovascular disease in obesity. The temporal relation between IR and inflammation is not completely characterized. We hypothesized that endothelial cell adhesion molecule expression in large arteries is an early event that coincides with diet-induced obesity and IR in primates. Methods and Results— Ten adult male rhesus macaques were studied at baseline and every 4 to 6 months on a high-fat diet for 2 years. Truncal fat, carotid intima-media thickness, plasma inflammatory biomarkers, and carotid P-selectin and vascular cell adhesion molecule-1 expression by contrast-enhanced ultrasound molecular imaging were assessed. Intravenous glucose tolerance test was performed at baseline and at 4 and 18 months. A high-fat diet produced a rapid increase ( P <0.01) in weight, truncal fat, and degree of IR indicated by the insulin area under the curve and glucose disappearance rate on intravenous glucose tolerance test, all of which worsened minimally thereafter. Molecular imaging detected a progressive increase in endothelial cell adhesion molecule expression over time (5- to 7-fold greater than control agent signal at 2 years; P <0.01). Changes in intima-media thickness were not detected until 2 years and, although there was a trend toward an increase in plasma markers of inflammation (monocyte chemotactic protein-1, C-reactive protein), the pattern of increase varied considerably over time. Conclusions— In primates with diet-induced obesity, endothelial inflammatory activation is an early event that occurs coincident with the development of IR and long before any measurable change in carotid intima-media thickness. Endothelial activation is related more to the duration rather than to the severity of IR and is not mirrored by changes in plasma biomarkers.