RESUMEN
UNLABELLED: 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: Insulin resistance is linked to the inhibition of glucose production by the TLR4, MyD88, and NFkappaB pathway.
Asunto(s)
Hipoglucemia/metabolismo , Resistencia a la Insulina , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Glucemia , Línea Celular Tumoral , Hipoglucemia/inducido químicamente , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , RatasRESUMEN
The metabolic syndrome is currently defined by various combinations of insulin resistance, obesity, dyslipidaemia and hypertension. The tendency for these risk factors to appear simultaneously suggests a single aetiologic basis. A low level of circulating adiponectin is associated with the appearance of each metabolic syndrome risk factor. The following review summarizes a large body of evidence that suggests a low level of circulating adiponectin represents an independent risk factor and a possible biomarker for the metabolic syndrome. An association between the metabolic syndrome and low adiponectin supports the view that the development of the metabolic syndrome may be triggered by a single underlying mechanism. Clinical studies in the future may show that a low level of circulating adiponectin is a primary biomarker for a specific cluster of metabolic syndrome risk factors rather than all the possible combinations of risk factors currently used to identify the metabolic syndrome. The significance of low circulating adiponectin in risk assessment models should ultimately be compared against insulin resistance, obesity, dyslipidaemia, hypertension and other metabolic syndrome risk factors presently under consideration. Adiponectin can be measured reliably in a clinical setting; circulating values of adiponectin do not fluctuate on a diurnal basis as much as insulin, glucose, triglycerides or cholesterol and only 2-4 microl of blood are currently needed for its measurement.