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 kappaB (NFkappaB), a cell signaling pathway that mediates LPS induction of the proinflammatory
cytokine tumor necrosis factor alpha (
TNFalpha). LPS induction of
hypoglycemia was blocked in TLR4(-/-) and MyD88(-/-) mice but not in
TNFalpha(-/-) mice. Both
glucose production and
glucose utilization were decreased during
hypoglycemia.
Hypoglycemia was associated with the activation of NFkappaB 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 NFkappaB (IkappaB) mutant that interferes with NFkappaB activation. Thus, LPS-induced
hypoglycemia was mediated by the inhibition of
glucose production from the liver through the TLR4, MyD88, and NFkappaB pathway, independent of LPS-induced
TNFalpha. 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: