Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

被引:291
作者
Mehta, Nehal N. [1 ,2 ,3 ]
McGillicuddy, Fiona C. [1 ,2 ]
Anderson, Paul D. [4 ]
Hinkle, Christine C. [1 ,2 ]
Shah, Rachana [3 ]
Pruscino, Leticia [1 ,2 ]
Tabita-Martinez, Jennifer [1 ]
Sellers, Kim F. [5 ]
Rickels, Michael R. [2 ,3 ]
Reilly, Muredach P. [1 ,2 ,3 ]
机构
[1] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA
[4] Dartmouth Hitchcock Med Ctr, Dept Med, Lebanon, NH 03766 USA
[5] Georgetown Univ, Sch Med, Dept Biostat, Washington, DC USA
基金
美国国家卫生研究院;
关键词
PHOSPHATIDYLINOSITOL; 3-KINASE; OBESITY; RECEPTOR; SENSITIVITY; PROTEINS; TISSUE; MICE; PHOSPHORYLATION; TRANSPORT;
D O I
10.2337/db09-0367
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 x 10(-4) [mu U.ml(-1). min(-1)], P < 0.005), while there was no effect on pancreatic P-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. Diabetes 59:172-181, 2010
引用
收藏
页码:172 / 181
页数:10
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