Endotoxin-induced alterations in hepatic glucose-6-phosphatase activity and gene expression

The mechanisms responsible for the glycemic changes associated with endotox ic shock are not fully understood, but are known to involve the ability of the liver to produce glucose. The purpose of the present study was to deter mine whether endotoxin (LPS) influences the expression and activity of gluc ose-6-phosphatase (Glu-6-Pase) during the early hyperglycemic phase and the later hypoglycemic phase. Rats were injected with a relatively large dose of LPS (20 mg/kg) or saline (control), and sacrificed at 1 or 5 h post-inje ction. Both the plasma glucose concentration and glucose production were el evated 1 h post-LPS (2-fold) and both decreased at 5 h postinjection (50%). Compared to time-matched control values, hepatic glucose-6-phosphate and f ructose-6-phosphate levels were significantly decreased at both 1 and 5 h. Hepatic Glu-6-Pase activity and mRNA levels were moderately increased, 1 h after injection of LPS. At 5 h, an 88% decrease in mRNA abundance for Glu-6 -Pase was associated with a 30% decrease in activity of this enzyme. Plasma insulin concentrations were not different 1 h after LPS and were elevated 2-fold from control values at 5 h. Circulating levels of glucagon and corti costerone were elevated at both time points following LPS. Our data indicat e that the LPS-induced hypoglycemia and reduction in hepatic glucose produc tion were accompanied by a depression in Glu-6-Pase activity and gene expre ssion.