title: Lipid-induced insulin resistance is associated with increased monocyte expression of scavenger receptor CD36 and internalization of oxidized LDL.
abstract: Elevated free fatty acids (FFAs) contribute to the development of insulin resistance, type 2 diabetes mellitus (T2DM), and may be atherogenic. We tested the relationship among lipid-induced insulin resistance, endothelial dysfunction, and monocyte capacity to form foam cells through scavenger receptor A (SRA) and CD36. Ten healthy subjects underwent 24-h infusion of Intralipid/heparin and saline (0.5 ml/min) on two separate occasions followed by brachial artery reactivity testing and a euglycemic hyperinsulinemic (80 mU/(kg.min)) clamp study to determine insulin sensitivity. Isolation of blood monocytes was performed 24 h after infusion. Surface expression and function of CD36 and SRA to take up oxidized low-density lipoprotein (oxLDL) was determined by flow cytometry and quantitative confocal imaging. Lipid infusion resulted in a twofold increase in serum FFA levels, reduced whole-body glucose disposal by approximately 20% (P < 0.05), and possibly impaired endothelial-dependent vasodilation (P = 0.1). Blood monocytes obtained during lipid infusion demonstrated a approximately 25% increase in cell surface expression of CD36 (P < 0.05) but no change in SRA expression. Enhanced CD36 expression was associated with a 50% increase in internalization of oxLDL (P < 0.05). The increase in CD36 surface expression during lipid infusion correlated inversely with glucose disposal (P < 0.05) and not with FFA levels or brachial artery dilation. These data support a role for FFAs in induction of insulin resistance and provide a link to atherogenic mechanisms mediated by expression of scavenger receptor CD36.
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Endocrinology Institute, Lerner Research Institute; Cleveland Clinic Foundation, Cleveland, Ohio, USA. kashyas@ccf.org
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Kashyap
authors.forename: Adriana G
authors.initials: AG
authors.lastname: Ioachimescu
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gornik
authors.forename: Thottathil
authors.initials: T
authors.lastname: Gopan
authors.forename: Michael B
authors.initials: MB
authors.lastname: Davidson
authors.forename: Antonie
authors.initials: A
authors.lastname: Makdissi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Major
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology; D001916:Brachial Artery / Q000187:drug effects; D018955:CD36 Antigens / Q000097:blood*; D004727:Endothelium; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005434:Flow Cytometry; D005487:Foam Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007333:Insulin Resistance / Q000276:immunology / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D012016:Reference Values; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000925:Anticoagulants; D018955:CD36 Antigens; D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D008077:Lipoproteins, LDL; D051117:Scavenger Receptors, Class A; C099252:oxidized low density lipoprotein; D006493:Heparin; D005947:Glucose