Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans Nehal N. Mehta 1 , 2 , 3 , Fiona C. McGillicuddy 1 , 2 , Paul D. Anderson 4 , Christine C. Hinkle 1 , 2 , Rachana Shah 3 , Leticia Pruscino 1 , 2 , Jennifer Tabita-Martinez 1 , Kim F. Sellers 5 , Michael R. Rickels 2 , 3 and Muredach P. Reilly 1 , 2 , 3 1 the Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 2 the Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 3 Institute for Diabetes Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 4 Department of Medicine, Darthmouth Hitchcock Medical Center, Lebanon, New Hampshire; 5 Department of Biostatistics, Georgetown University Medical School, Washington, D.C. Corresponding author: Muredach P. Reilly, muredach{at}spirit.gcrc.upenn.edu . Abstract OBJECTIVE An emerging model of metabolic syndrome and type 2 diabetes is of adipose dysfunction with leukocyte recruitment into adipose leading to chronic inflammation and insulin resistance (IR). This study sought to explore potential mechanisms of inflammatory-induced IR in humans with a focus on adipose tissue. RESEARCH DESIGN AND METHODS We performed a 60-h endotoxemia protocol (3 ng/kg intravenous bolus) in healthy adults ( n = 20, 50% male, 80% Caucasian, aged 27.3 ± 4.8 years). Before and after endotoxin, whole-blood sampling, subcutaneous adipose biopsies, and frequently sampled intravenous glucose tolerance (FSIGT) testing were performed. The primary outcome was the FSIGT insulin sensitivity index ( S i ). Secondary measures included inflammatory and metabolic markers and whole-blood and adipose mRNA and protein expression. RESULTS Endotoxemia induced systemic IR as demonstrated by a 35% decrease in S i (3.17 ± 1.66 to 2.06 ± 0.73 × 10 −4 [μU · ml −1 · min −1 ], P < 0.005), while there was no effect on pancreatic β-cell function. In adipose, endotoxemia suppressed insulin receptor substrate-1 and markedly induced suppressor of cytokine signaling proteins (1 and 3) coincident with local activation of innate (interleukin-6, tumor necrosis factor) and adaptive (monocyte chemoattractant protein-1 and CXCL10 chemokines) inflammation. These changes are known to attenuate insulin receptor signaling in model systems. CONCLUSIONS We demonstrate, for the first time in humans, that acute inflammation induces