AJP - Endocrinology and Metabolism, Vol 268, Issue 2 E219-E228, Copyright © 1995 by American Physiological Society
Tumor necrosis factor mediates zymosan-induced increase in glucose flux and insulin resistance
F. Petit, G. J. Bagby and C. H. Lang
Department of Surgery, State University of New York, Stony Brook 11794-8191.
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.
