The impact of interleukin-6 on the metabolic response to endotoxin in vivo

Abstract

Inflammation and insulin resistance are characteristics of endotoxemia. While the role of interleukin-6 (IL-6) in insulin resistant states has been characterized, little is known of its role in the metabolic response to inflammation. To study the role of IL-6, conscious chronically catheterized mice were used. Five days prior to being studied, catheters were implanted in the carotid artery and jugular vein. After a 5 h fast, E.coli (250 microgram/mouse) LPS was injected in IL6-/- (KO; n=13), IL6+/- (HET; n=9), and IL-6+/+ (WT; n=10) littermates. The IL-6 response to LPS was simulated in an additional group of KO mice (KO+IL6; n=10). Glucose turnover (Ra) was assessed using 3-[3H]-D-glucose. IL-6 increased similarly in WT and HET (15±0.7 and 14±0.5 ng/ml) 4h after LPS and was undetectable in KO. IL-6 replacement in KO restored circulating IL-6 to levels observed in the WT group (14±0.3 ng/ml). WT was the only group to experience an early rise in tumor necrosis factor-alpha (TNF-alpha). Interleukin-1beta (IL-1beta) was similar in all groups. KO exhibited a more profound hyperglycemia 30 min after LPS injection and no apparent hypoglycemia at 4h (95±5 mg/dl). Glucose levels in KO+IL6, while decreased (93±4 mg/dl) at 4h, remained higher than WT. Ra was not altered. In summary, the absence of IL-6 protected against LPS induced hypoglycemia. Acute restoration of the IL-6 response to LPS did not potentiate hypoglycemia. Thus, while IL-6 promotes glucose intolerance in insulin resistant states, IL-6 promotes hypoglycemia during inflammation.