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Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: role of glycogen synthase kinase-3beta inhibition.

Abstract：

OBJECTIVE: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-3beta inhibition in the protective effect of insulin on the organ injury/dysfunction associated with excessive systemic inflammation. DESIGN:Prospective, randomized study. SETTING:University-based research laboratory. SUBJECTS:Eighty-five anesthetized Wistar rats. INTERVENTIONS: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-3beta inhibitor TDZD-8 (1 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered either prophylactically or therapeutically. MEASUREMENTS AND MAIN RESULTS: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-1beta. In vitro, insulin or TDZD-8 caused similar reductions in the nuclear factor-kappaB p65 activity and similar increases in the phosphorylation of Ser9 of glycogen synthase kinase-3beta. CONCLUSIONS:Therapy with insulin or the potent and selective glycogen synthase kinase-3beta 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-3beta contributes to the protective effect of insulin against the organ injury/dysfunction caused by excessive systemic inflammation independently of any effects on blood glucose.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Dugo L,Collin M,Allen DA,Murch O,Foster SJ,Yaqoob MM,Thiemermann C

doi

10.1097/01.CCM.0000215457.83953.E3

subject

Has Abstract

pub_date

2006-05-01 00:00:00

pages

1489-96

issue

eissn

0090-3493

issn

1530-0293

journal_volume

pub_type

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Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: role of glycogen synthase kinase-3beta inhibition.