Lipopolysaccharide inhibition of glucose production through the Toll‐like receptor‐4, myeloid differentiation factor 88, and nuclear factor κb pathway†

Abstract

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␣

GLP-1 Secretion Is Increased by Inflammatory Stimuli in an IL-6–Dependent Manner, Leading to Hyperinsulinemia and Blood Glucose Lowering

“…Any blood glucose lowering, also if done to the normal range, might however increase the vulnerability of the organism to other hypoglycemic stimuli. Endotoxin is thereby known to suppress hepatic gluconeogenesis via activation of TLR4, MyD88, and NF-kB, enhance systemic glucose consumption, and deplete glycogen stores, which in conjunction can lead to hypoglycemia (13)(14)(15). Indeed, blockade of the GLP-1 system by use of GLP-1 receptor antagonists or IL-6 knockouts markedly blunted endotoxin-dependent hyperinsulinemia in our experiments but only modestly and temporarily counteracted the glucose-lowering effects of LPS.…”

“…Whereas this secondary raise can be attributed to the occurrence of insulin resistance, a variety of mechanisms contribute to the early drop of blood glucose (11,12). These include hyperinsulinemia, enhanced systemic glucose consumption, depletion of glycogen stores, and suppression of gluconeogenesis (13)(14)(15). Relevance of inflammation-dependent hyperinsulinemia has consistently been found in mice, rats, dogs, cows, and men (15)(16)(17)(18)(19), with inhibition of insulin secretion being able to prevent hypoglycemia in the inflammatory setting (20).…”

Mechanisms of intrinsic resistance to antimicrobial peptides of Edwardsiella ictaluri and its influence on fish gut inflammation and virulence

“…UDP-GlcA is found in several capsular polysaccharides (K-antigens) and in colanic acid (M-antigen), an extracellular polysaccharide produced by many Escherichia coli strains (Whitfield, 2006). Also, UDPGlcA participates in the synthesis of UDP-L-Ara4N (Breazeale et al, 2002;Raetz & Whitfield, 2002;Strominger, 1957), which is a crucial element in bacterial resistance to antibiotics such as polymyxin B and cationic peptides of the innate immune system (Guo et al, 1998;Raetzsch et al, 2009;Trent et al, 2001).…”

Stimulation of autophagy in the liver by lipopolysaccharide-induced systemic inflammation in a rat model of diabetes mellitus

“…We previously reported that LPSinduced systemic inflammation reduced serum glucose levels (16). Recent studies have demonstrated that interleukin (IL)-6 promotes hypoglycemia during acute inflammation (29) and that the TLR4/ MyD88/NF-κB pathway inhibits glucose production (24). Through these mechanisms, hypoglycemia was induced in systemic inflammation in normal rats.…”