Lipopolysaccharide Inhibition of Glucose Production Through the Toll-Like Receptor-4, Myeloid Differentiation Factor 88, and Nuclear Factor κB Pathway

Acute exposure to lipopolysaccharide (LPS) can cause hypoglycemia and insulin resistance; the underlying mechanisms, however, are unclear. We set out to determine whether insulin resistance is linked to hypoglycemia through Toll-like receptor-4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF kappa B), a cell signaling pathway that mediates LPS induction of the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha). LPS induction of hypoglycemia was blocked in TLR4(-/-) and MyD88(-/-) mice but not in TNF alpha(-/-) mice. Both glucose production and glucose utilization were decreased during hypoglycemia. Hypoglycemia was associated with the activation of NF kappa B in the liver. LPS inhibition of glucose production was blocked in hepatocytes isolated from TLR4(-/-) and MyD88(-/-) mice and hepatoma cells expressing an inhibitor of NF kappa B (I kappa B) mutant that interferes with NF kappa B activation. Thus, LPS-induced hypoglycemia was mediated by the inhibition of glucose production from the liver through the TLR4, MyD88, and NF kappa B pathway, independent of LPS-induced TNF alpha. LPS suppression of glucose production was not blocked by pharmacologic inhibition of the insulin signaling intermediate phosphatidylinositol 3-kinase in hepatoma cells. Insulin injection caused a similar reduction of circulating glucose in TLR4(-/-) and TLR4(+/+) mice. These two results suggest that LPS and insulin inhibit glucose production by separate pathways. Recovery from LPS-induced hypoglycemia was linked to glucose intolerance and hyperinsulinemia in TLR4(+/+) mice, but not in TLR4(-/-) mice. Conclusion: Insulin resistance is linked to the inhibition of glucose production by the TLR4, MyD88, and NF kappa B pathway. (HEPATOLOGY 2009;50:592-600.)