Lipopolysaccharide (LPS) Impairs Insulin‐Stimulated Glucose Uptake in vivo Despite Enhancing AKT Phosphorylation

Abstract

LPS is known to impair insulin stimulated glucose metabolism in vitro. Central to this defect is the release of inflammatory cytokines, leading to impairments in insulin signaling. However this relationship has not been directly tested in vivo. In this study, 12‐week old chronically catheterized conscious male mice (C57BL6/j) received either LPS (10ug/g body weight) or saline. After 4hrs, a 2hr euglycemic (120mg/dl) hyperinsulinemic clamp was performed. 2‐deoxy [14C]‐glucose was given to determine tissue‐specific glucose uptake. Despite similar insulin concentrations (4.2±1.5 vs 2.4±0.3 ng/ml; LPS vs saline), the glucose infusion rate was decreased in LPS (38±6 vs 54±3 mg/kg/min). LPS decreased (p<0.05) insulin‐stimulated glucose uptake in the heart (32%), gastrocnemius (53%), vastus lateralis (57%), and soleus (31%). LPS increased plasma cytokine levels (TNF‐α, ~6‐fold; IL‐6, ~20‐fold; IL‐1β, ~9‐fold and IL‐10, ~2‐fold). Yet, in the gastrocnemius AKT phosphorylation was increased 39% at Thr308 and 23% at Ser473 in LPS vs saline. GSK phosphorylation was similar in both groups. This data was recapitulated in the liver and heart. In conclusion, while LPS impairs insulin‐stimulated muscle glucose uptake in vivo, it does not disrupt the classical insulin signaling pathway. Thus, a decrement of insulin‐stimulated muscle glucose uptake due to acute inflammation may not occur through an AKT dependent pathway. Funding: DK43748, DK078188, and DK59637