Skeletal muscle metabolism and insulin resistance during endotoxin shock in the dog

The effect of locally infused endotoxin on gracilis muscle glucose uptake was determined in anesthetized mongrel dogs. The effects of infusion of small amounts of Escherichia coli endotoxin into the arteries of isolated, innervated, constant flow perfused gracilis muscles on glucose uptake and other metabolic variables were determined. Locally infused endotoxin consistently caused a significant and substantial increase in skeletal muscle glucose uptake with no alterations in muscle arteriovenous difference of insulin, oxygen, carbon dioxode, or pH, or in venous blood hematocrit or temperature. These data demonstrate that endotoxin can act locally to increase glucose uptake by skeletal muscle, independent of the action of insulin or other metabolic factors. During natural (free flow) conditions, glucose uptake by the muscle increased markedly during six hours of shock. Increased glucose uptake occurred concomitantly with muscle ischemia and hypoxia. However, when muscle blood flow was held constant, thereby preventing local muscle ischemia and hypoxia, glucose uptake by the gracilis muscle did not change during shock. These results implicate local muscle ischemia and/or hypoxia as the mediator(s) of the increased muscle glucose uptake during shock. Further studies demonstrated that local muscle hypoxia was the stimulus for increased glucose uptake by skeletal muscle during endotoxin shock, and muscle ischemia per se did not alter muscle glucose uptake. Since approximately 50% of body mass is composed of skeletal muscle, the contribution of this organ system to the hypoglycemia of endotoxin shock in the dog may be substantial. The ability of insulin to promote glucose diffusion into skeletal muscle before and during gram-negative endotoxin shock was studied in mongrel dogs anesthetized with sodium pentobarbital. The in vivo, isolated, innervated, constant flow perfused gracilis muscle preparation was used. Prior to shock induction, close intra-arterial insulin infusion resulted in a 320% increase in muscle glucose uptake. However, at one, two, and three hours of endotoxin shock, gracilis muscle glucose uptake was unaltered by insulin infusion. This loss of responsiveness to insulin occurred with no alteration in gracilis muscle oxygen uptake, muscle venous P02, or muscle blood flow. During control experiments, however, the muscle response to intra-arterial infusion of insulin (increased glucose uptake) was unaltered during the three-hour control period. These data demonstrate that skeletal muscle insulin resistance develops early and is maintained during three hours of endotoxin shock in the dog.