Endotoxin tolerance diminishes endotoxin-induced alterations in carbohydrate kinetics

This study was designed to determine if attenuated mortality to a challenge dose of endotoxin was accompanied by or separated from alterations in glucose metabolism in endotoxin-tolerant rats. The in vivo effects of endotoxin were studied in catheterized endotoxin-tolerant rats and nontolerant control animals. Tolerance was induced by iv injections of 100 micrograms endotoxin/100 g BW (tolerance dose) for either 2 or 4 consecutive days; control rats received daily saline injections. On the day after the final tolerance dose, glucose kinetics were assessed by the constant infusion of [6-3H]-glucose prior to and after a challenge dose of endotoxin (1,000 micrograms/100 g) in tolerant and nontolerant rats. Following the challenge dose, 2-day tolerant animals exhibited an improved survival at 72 hr (LD 14 vs LD 92), a significantly smaller reduction in mean arterial blood pressure (20 vs 34%), and smaller increases in plasma glucose (9.4 +/- 0.6 vs 11.4 +/- 0.6 mM) and lactate (3.2 +/- 0.3 vs 8.5 +/- 1.4 mM) concentrations, compared to those in nontolerant control rats. However, increases in the rates of glucose appearance (Ra) and metabolic clearance (MCR) were not diminished. In 4-day tolerant rats, lethality to endotoxin was abolished, and no alterations in blood pressure or glucose kinetics were seen during the 4-hr period after endotoxin. However, the basal glucose Ra and MCR determined prior to endotoxin challenge were elevated in these rats compared to controls. Hyperglucagonemia was evident following the endotoxin challenge in control and 2-day tolerant rats, but not in 4-day tolerant animals. The hypothermia seen in nontolerant rats 4 hr after endotoxin was not present in either group of tolerant animals. The results show that after 2 days, tolerant animals have improved survival rates when challenged with endotoxin but still demonstrate acute changes in glucose kinetics. A complete protection against a normally lethal dose of endotoxin exists after 4 days. At this stage, rats showed no transient hemodynamic or metabolic alterations following endotoxin challenge.