Lipid-induced insulin resistance is associated with increased monocyte expression of scavenger receptor CD36 and internalization of oxidized LDL.
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.
Kashyap
Sangeeta R
SR
Department of Endocrinology, Diabetes and Metabolism, Endocrinology Institute, Lerner Research Institute; Cleveland Clinic Foundation, Cleveland, Ohio, USA. kashyas@ccf.org
Ioachimescu
Adriana G
AG
Gornik
Heather L
HL
Gopan
Thottathil
T
Davidson
Michael B
MB
Makdissi
Antonie
A
Major
Jennifer
J
Febbraio
Maria
M
Silverstein
Roy L
RL
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
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