Experimental endotoxemia induces adipose inflammation and insulin resistance in humans.
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.


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 x 10(-4) [microU * ml(-1) * min(-1)], P < 0.005), while there was no effect on pancreatic beta-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 systemic IR following modulation of specific adipose inflammatory and insulin signaling pathways. It also provides a rationale for focused mechanistic studies and a model for human proof-of-concept trials of novel therapeutics targeting adipose inflammation in IR and related consequences in humans.
Mehta
Nehal N
NN
Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
McGillicuddy
Fiona C
FC
Anderson
Paul D
PD
Hinkle
Christine C
CC
Shah
Rachana
R
Pruscino
Leticia
L
Tabita-Martinez
Jennifer
J
Sellers
Kim F
KF
Rickels
Michael R
MR
Reilly
Muredach P
MP
D015502:Absorptiometry, Photon; D000208:Acute Disease; D000273:Adipose Tissue / Q000503:physiopathology; D000328:Adult; D001794:Blood Pressure; D001798:Blood Proteins / Q000235:genetics; D018925:Chemokines / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D016207:Cytokines / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology; D019446:Endotoxemia / Q000503:physiopathology*; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000097:blood; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics; D055815:Young Adult
D001798:Blood Proteins; D018925:Chemokines; D008076:Cholesterol, HDL; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors