Speaker Abstract

Insulin resistance and Lipoprotein Metabolism

Gary F. Lewis, University of Toronto, Toronto, CA, M5G 2C4.

Insulin resistant states, including Type 2 diabetes, are associated with hypertriglyceridemia. and low HDL-c concentrations. This overview will focus on our studies investigating the mechanism of HDL-c lowering in hypertriglyceridemic states. We have been testing the hypothesis that triglyceride(TG)-rich HDL are susceptible to in vivo lipolysis, predominantly by the enzyme hepatic lipase. This modifies both the size as well as the chemical composition of the particles and results in HDL particles that are rapidly cleared from the circulation, resulting in a lowering of HDL-c in hypertriglyceridemic individuals. We have performed studies in the rabbit, a hepatic lipase deficient animal model, in which further in vivo modification of TG-rich HDL by hepatic lipase is minimal. Our studies have confirmed that TG-enrichment of HDL, without associated lipolytic modification of the particle, is not sufficient to enhance its clearance from the circulation. TG-enrichment, however, accompanied by in vivo or in vitro lipolysis, enhances the HDL particle clearance from the circulation, thereby contributing to a lowering of HDL-c concentration. Our studies in humans have confirmed the importance of small, physiologically relevant TG enrichment of HDL in enhancing particle clearance. Variations in the TG-content of HDL in humans may have fundamental implications for the regulation of HDL-c concentrations.