title: Chronic low-dose lipid infusion in healthy patients induces markers of endothelial activation independent of its metabolic effects.
abstract: 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.
authors.affiliation: Division of Diabetes, University of Texas Health Science Center, San Antonio, TX 78284-3900, USA.
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Kashyap
authors.forename: Renata
authors.initials: R
authors.lastname: Belfort
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cersosimo
authors.forename: Shuko
authors.initials: S
authors.lastname: Lee
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cusi
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D001786:Blood Glucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000097:blood*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D005951:Glucose Tolerance Test; D006801:Humans; D007262:Infusions, Intravenous; D007333:Insulin Resistance / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood*; D008055:Lipids / Q000008:administration & dosage*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000209:etiology; D011379:Prognosis; D012016:Reference Values; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D019332:Endothelin-1; D008055:Lipids; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1