Effects of systemic infusions of endotoxin, tumor necrosis factor, and interleukin-1 on glucose metabolism in the rat: relationship to endogenous glucose production and peripheral tissue glucose uptake

Abstract

This study was performed to characterize and compare the actions of insulin on hepatic glucose production and peripheral glucose utilization during infusions of endotoxin, tumor necrosis factor (TNF), interleukin-1 (IL-1), and a combination of IL-1 and TNF in the rat. The euglycemic hyperinsulinemic clamp technique was combined with a primed-constant tracer infusion of high-performance liquid chromatography (HPLC)-purified 3H-3-glucose for estimation of whole-body glucose appearance and utilization rates; 14C-deoxyglucose (14C-DG) uptake was also measured in specific tissues following intravenous bolus administration. As expected, acute endotoxemia resulted in a significant reduction of glucose infusion during the clamp procedure (insulin concentration, 100 microU/mL), suggesting decreased insulin action. Similarly, infusion of TNF decreased the rate of glucose infusion necessary to maintain euglycemia. However, differences between endotoxin- and cytokine-treated rats were noted in whole-body glucose appearance (or disappearance) rates. Whereas endotoxin infusion predominantly decreased whole-body glucose uptake, suggesting diminished utilization in skeletal muscles, cytokine infusions were associated with a measurable hepatic glucose output despite hyperinsulinemia. In contrast, both cytokine and endotoxin administration decreased the rate of 14C-DG uptake by muscle tissue. These results demonstrate that TNF, IL-1, and endotoxin can induce a state of insulin resistance when infused continuously; the results also emphasize the complexity of regulation of glucose homeostasis during infection and sepsis.