Tumor necrosis factor mediates zymosan-induced increase in glucose flux and insulin resistance.
Intraperitoneal injection of sterile zymosan produces an inflammatory response ultimately resulting in multiple-organ failure. The purpose of the present study was to characterize the hormonal and metabolic alterations produced as a result of this nonbacterial nonendotoxic inflammatory agent and to determine whether these changes were mediated by enhanced production of tumor necrosis factor (TNF). Rats were injected intraperitoneally with either zymosan or saline and studied 18 h later. Under basal conditions, zymosan-injected rats were euglycemic but showed a 43% increase in hepatic glucose production and peripheral glucose uptake. The enhanced glucose flux in zymosan-treated rats was associated with elevations in plasma insulin (45%), glucagon (5-fold), corticosterone (2-fold), epinephrine (34%), and norepinephrine (115%). In vivo studies using 2-deoxyglucose (2-DG) demonstrated that the zymosan-induced increase in whole body glucose disposal resulted from an enhanced uptake by skeletal muscle (68%), diaphragm (3.7-fold), liver (144%), spleen (52%), and fat (133%). Under euglycemic hyperinsulinemic conditions, zymosan-treated rats exhibited both hepatic and peripheral insulin resistance, with the latter resulting from a decreased insulin-mediated glucose uptake by skeletal muscle, heart and diaphragm. Arterial TNF levels were increased by 1 h and remained elevated throughout the experimental protocol. Pretreatment of rats with a neutralizing anti-TNF antibody before zymosan prevented the elevation in basal glucose flux and attenuated the insulin resistance. We conclude that the inflammatory state induced by zymosan enhances basal glucose turnover and impairs insulin action and that these changes appear to be largely due to the enhanced endogenous production of TNF.
Petit
F
F
Department of Surgery, State University of New York, Stony Brook 11794-8191.
Bagby
G J
GJ
Lang
C H
CH
D000042:Absorption; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001769:Blood / Q000382:microbiology; D005947:Glucose / Q000378:metabolism*; D006439:Hemodynamics; D006728:Hormones / Q000097:blood; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015054:Zymosan / Q000494:pharmacology*
D000906:Antibodies; D006728:Hormones; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D005947:Glucose