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 B (NF B), a cell signaling pathway that mediates LPS induction of the proinflammatory cytokine tumor necrosis factor alpha (TNF␣). LPS induction of hypoglycemia was blocked in TLR4 ؊/؊ and MyD88 ؊/؊ mice but not in TNF␣ ؊/؊ mice. Both glucose production and glucose utilization were decreased during hypoglycemia. Hypoglycemia was associated with the activation of NF 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 B (I B) mutant that interferes with NF B activation. Thus, LPS-induced hypoglycemia was mediated by the inhibition of glucose production from the liver through the TLR4, MyD88, and NF B pathway, independent of LPS-induced TNF␣. 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 B pathway. (HEPATOLOGY 2009;50:592-600.) L ipopolysaccharide (LPS) from Gram-negative bacterial infection can cause hypoglycemia and insulin resistance in both humans and mice; however, the underlying mechanisms are unclear. 1-5 Low levels of LPS exposure through gastrointestinal tract and airborne particles can also lead to insulin resistance. 6-8 Thus, insulin resistance is decreased in mice by antibiotic treatment or housing in germ-free facilities. 9,10 Insulin resistance is also decreased by gene deletion of Toll-like receptor-4 (TLR4) or cluster of differentiation 14 (CD14), a glycoprotein that binds to the extracellular portion of TLR4. [11][12][13] TLR4 is a plasma membrane protein that mediates LPS induction of inflammatory cytokines such as tumor necrosis factor alpha (TNF␣) and interleukin-1 beta (IL-1␤). 14 The main goals of this study were to (1) determine whether TLR4 and its downstream signaling targets mediate the induction of hypoglycemia by LPS and, if so, (2) determine whether the induction of hypoglycemia by TLR4 is linked to the development of insulin resistance.LPS was postulated to cause hypoglycemia through the induction of the cytokines TNF␣ and IL-1␤. 15 Given that LPS does not induce hypoglycemia in IL-1␣ Ϫ/Ϫ and IL-1␤ Ϫ/Ϫ "double-knockout" mice, LPS induction of IL-1␤ is essential. 16 Whether LPS induction of TNF␣

Glucose metabolism is altered in long-lived people and mice. Although it is clear that there is an association between altered glucose metabolism and longevity, it is not known whether this link is causal or not. Our current hypothesis is that decreased fasting glucose utilization may increase longevity by reducing oxygen radical production, a potential cause of aging. We observed that whole body fasting glucose utilization was lower in the Snell dwarf, a long-lived mutant mouse. Whole body fasting glucose utilization may be reduced by a decrease in the production of circulating glucose. Our isotope labeling analysis indicated both gluconeogenesis and glycogenolysis were suppressed in Snell dwarfs. Elevated circulating adiponectin may contribute to the reduction of glucose production in Snell dwarfs. Adiponectin lowered the appearance of glucose in the media over hepatoma cells by suppressing gluconeogenesis and glycogenolysis. The suppression of glucose production by adiponectin in vitro depended on AMP-activated protein kinase, a cell mediator of fatty acid oxidation. Elevated fatty acid oxidation was indicated in Snell dwarfs by increased utilization of circulating oleic acid, reduced intracellular triglyceride content, and increased phosphorylation of acetyl-CoA carboxylase. Finally, protein carbonyl content, a marker of oxygen radical damage, was decreased in Snell dwarfs. The correlation between high glucose utilization and elevated oxygen radical production was also observed in vitro by altering the concentrations of glucose and fatty acids in the media or pharmacologic inhibition of glucose and fatty acid oxidation with 4-hydroxycyanocinnamic acid and etomoxir, respectively.Glucose metabolism is altered in centenarians and long-lived mice (1-8). Our current hypothesis is that a decrease in fasting glucose utilization may increase longevity by lowering oxygen radical production, a potential cause of aging. Changes in glucose metabolism have been indicated in long-lived rodents by (a) oral glucose tolerance test, (b) insulin tolerance test, (c) inhibition of glucose production and stimulation of glucose disposal under euglycemic clamp conditions, and (d) the levels of circulating glucose and insulin under physiologic conditions (9 -13). These methods suggest that glucose utilization is elevated in long-lived mice during feeding. However, they do not reveal whether glucose utilization is lower in long-lived mice during fasting, a period of the day when glucose utilization is relatively low and fatty acid utilization is high.During fasting (a) the appearance in the circulation of glucose from the gastrointestinal tract is low, (b) the concentrations of circulating glucose and insulin are low, (c) circulating glucose is used for energy rather than storage, and (d) the circulating glucose used is replenished largely by liver glucose production, via gluconeogenesis and glycogenolysis. Thus, whole body glucose utilization may be lowered during fasting by decreasing glucose production. Whether fasting glucose pro...

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