Chronic Low-Dose Lipid Infusion in Healthy Patients Induces Markers of Endothelial Activation Independent of Its Metabolic Effects

Elevated plasma triglyceride/free fatty acid (FFA) levels and insulin resistance may promote atherosclerosis through endothelial activation (ie, increased expression of intercellular adhesion molecule 1 [ICAM-1]/vascular adhesion molecule 1 [VCAM-1], and endothelin-1 [ET-1]) in patients with the metabolic syndrome, but this has never been directly tested. The authors measured endothelial activation and insulin sensitivity (euglycemic insulin clamp with [3- ³ H]-glucose) after a 4-day low-dose lipid infusion that elevated plasma FFA to levels observed in the metabolic syndrome in 20 lean, non-diabetic insulin-resistant subjects with a strong family history of type 2 diabetes mellitus (FH ⁺ ) and 10 insulin-sensitive volunteers without a family history of type 2 diabetes mellitus (FH ⁻ ). Low-dose lipid infusion reduced insulin sensitivity by approximately 25% in insulin-sensitive FH ⁻ controls but did not worsen preexisting insulin resistance in FH ⁺ . Low-dose lipid infusion elevated plasma ICAM and VCAM levels similarly in both groups (approximately 12%–18%; P<.01 vs baseline), while plasma ET-1 levels increased more in FH⁺vs FH⁻(46% vs 10%; P=.005). Increased plasma FFA levels closely correlated with elevated ICAM (r=0.60; P<.01), VCAM, and ET-1 levels (r=0.39 and r=0.42, respectively; P<.05). Low-dose lipid infusion induces endothelial activation in both lean insulin-resistant (FH⁺) and insulin-sensitive (FH⁻) healthy patients, regardless of changes in insulin sensitivity. These results prove that even a modest lipid oversupply may be sufficient to trigger a deleterious endothelial response.