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Insulin reduces morbidity and mortality among critically ill patients, but the molecular mechanisms of its effect remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3, which may play an important role in systemic inflammation and shock. Here we investigate the role of blood glucose and glycogen synthase kinase-3β inhibition in the protective effect of insulin on the organ injury/dysfunction associated with excessive systemic inflammation.Prospective, randomized study.University-based research laboratory.Eighty-five anesthetized Wistar rats.Rats received Escherichia coli lipopolysaccharide (1 mg/kg) and Staphylococcus aureus peptidoglycan (0.3 mg/kg) or vehicle intravenously. Insulin (1.4 units/kg intravenously) was administered in the absence or presence of continuous glucose administration (4.5 mg/kg/hr intravenously) either prophylactically or therapeutically. The potent and selective glycogen synthase kinase-3β inhibitor TDZD-8 (1 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered either prophylactically or therapeutically.Coadministration of lipopolysaccharide and peptidoglycan resulted in increases in the serum levels of creatinine (indicator of renal dysfunction), alanine aminotransferase, and aspartate aminotransferase (indicators of liver injury) at 6 hrs. Insulin or TDZD-8 similarly attenuated the organ injury/dysfunction caused by lipopolysaccharide and peptidoglycan when given either prophylactically or therapeutically. Continuous glucose administration had no effect on blood glucose levels or organ injury/dysfunction at 6 hrs. Treatment with insulin or TDZD-8 reduced the plasma levels of the proinflammatory cytokine interleukin-1β. In vitro, insulin or TDZD-8 caused similar reductions in the nuclear factor-κB p65 activity and similar increases in the phosphorylation of Ser9 of glycogen synthase kinase-3β.Therapy with insulin or the potent and selective glycogen synthase kinase-3β inhibitor TDZD-8 reduced the organ injury/dysfunction caused by lipopolysaccharide and peptidoglycan in the rat. We propose that the inhibitory effect of insulin on the activity of glycogen synthase kinase-3β contributes to the protective effect of insulin against the organ injury/dysfunction caused by excessive systemic inflammation independently of any effects on blood glucose.