Glucose kinetics in rats infused with endotoxin-induced monokines or tumor necrosis factor

This study was conducted to determine if macrophage elaborated monokines in general, and human recombinant tumor necrosis factor (hrTNFα) in particular alter glucose metabolism in a manner analogous to that observed in endotoxin-treated animals. Endotoxin-tolerant rats were infused for 3 hr with saline, E. coli endotoxin (100 μg/l weight) or monokines contained in conditioned media from endotoxin-stimulated RAW 264.7 cells (1 μg/ml). Compared to saline- and endotoxin-infused rats, animals receiving the monokine mixture had no change in mean arterial blood pressure or heart rate but exhibited overt signs of morbidity including stupor and diarrhea. Monokine-infused rats remained euglycemic but had elevated lactate concentrations and a 15-30% increase in glucose rate of appearance (Ra). Nontolerant rats received a 3 hr infusion of saline, hrTNFα (15 μg/100 g), or heat-treated hrTNFα. HrTNFα infusion increased glucose Ra about 25% compared to the two control groups but did so without producing signs of morbidity seen in the monokine infused animals. Serum TNF levels were 6-fold higher in rats infused with the monokine mixture levels of TNF contained in the monokine mixture and hrTNFα infusates. Plasma insulin, glucagon, and catecholamine concentrations were increased in rats infused with either the monokine mixture of hrTNFα, but the increases were more pronounced in rats receiving the monokine mixture. The results demonstrate that monokines and hrTNFα increase glucose production in vivo, and that the effect may be mediated by endocrine changes known to influence glucose homeostasis.