No abstract

The present study examined whether a prolonged infusion of tumor necrosis factor (TNF) into rats could sustain the increased rate of whole body glucose metabolism observed with short term exposure, and whether TNF produced hepatic or peripheral insulin resistance. Basal glucose metabolism was determined with the use of [3-3H]glucose 18 h after initiating a constant infusion of recombinant human TNF (1 microgram/kg.h). Thereafter, a two-step euglycemic hyperinsulinemic clamp was performed to determine whether TNF impaired insulin action. The overnight infusion of TNF minimally elevated plasma glucose concentrations (17%), but produced large increases in the whole body rate of glucose production and utilization (133%). Under hyperinsulinemic conditions, the glucose infusion rate necessary to maintain euglycemia was 30% lower in TNF-treated rats, indicating an insulin-resistant condition. This resulted from an impaired ability of insulin to both suppress hepatic glucose production and stimulate peripheral glucose utilization in TNF-infused animals. A second series of experiments was performed, using the in vivo tracer [U-14C]2-deoxyglucose technique, to elucidate which tissues were responsible for the TNF-induced increase in basal (no exogenous insulin) glucose disposal and peripheral insulin resistance. Under basal conditions, TNF increased glucose uptake by various muscles (gastrocnemius, heart, and diaphragm) as well as nonmuscle tissues (liver, lung, spleen, gut, skin and fat). Because of their relatively large mass and/or high rate of glucose uptake, the increased uptake by skin (25%), intestine (24%), muscle (23%), and liver (15%) accounted for the majority of the TNF-induced increment in whole body glucose disposal. Under euglycemic hyperinsulinemic conditions, the increment in glucose uptake by muscle and skin (85%) accounted for the majority of the glucose disposal in control rats. However, in TNF-infused animals, hyperinsulinemia failed to increase glucose uptake by skin and blunted the insulin-mediated increase in muscle by 73%. These results suggest that sustained elevations of TNF during chronic therapy and prolonged production of TNF by patients and experimental animals with malignancies or infectious diseases may be an important mechanism for the enhanced glucose flux as well as the insulin resistance seen in these conditions.

This study examined potential mechanisms contributing to the inhibition of protein synthesis in skeletal muscle and heart after administration of tumor necrosis factor (TNF)-α. Rats had vascular catheters implanted, and TNF-α was infused continuously for 24 h. TNF-α decreased in vivo-determined rates of global protein synthesis in gastrocnemius (39%) and heart (25%). The TNF-α-induced decrease in protein synthesis in the gastrocnemius involved a reduction in the synthesis of both myofibrillar and sarcoplasmic proteins. To identify potential mechanisms responsible for regulating mRNA translation, we examined several eukaryotic initiation factors (eIFs) and elongation factors (eEFs). TNF-α decreased the activity of eIF-2B in muscle (39%) but not in heart. This diminished activity was not caused by a reduction in the content of eIF-2Bε or the content and phosphorylation state of eIF-2α. Skeletal muscle and heart from TNF-α-treated rats demonstrated 1) an increased binding of the translation repressor 4E-binding protein-1 (4E-BP1) with eIF-4E, 2) a decreased amount of eIF-4E associated with eIF-4G, and 3) a decreased content of the hyperphosphorylated γ-form of 4E-BP1. In contrast, the infusion of TNF-α did not alter the content of eEF-1α or eEF-2, or the phosphorylation state of eEF-2. In summary, these data suggest that TNF-α impairs skeletal muscle and heart protein synthesis, at least in part, by decreasing mRNA translational efficiency resulting from an impairment in translation initiation associated with alterations in eIF-4E availability.