Expression of glucose transporters in critical illness

Abstract

Stress-induced hyperglycemia is a significant problem in critically ill patients, for whom the severity of hyperglycemia and insulin resistance reflects the risk of death. We recently demonstrated that strict maintenance of normoglycemia with intensive insulin therapy during intensive care reduced the morbidity and mortality of surgical ICU patients [1]. Normal cells respond to hyperglycemia by downregulating the insulin-independent glucose transporters (GLUT1, GLUT2 and GLUT3), thereby protecting themselves against passive glucose overload. Insulin is known to upregulate muscle GLUT4 expression, required for controlled glucose uptake in the muscle. We investigated expression levels of these four GLUTs in critical illness and assessed the impact of intensive insulin therapy. We examined mRNA expression levels with real-time RT-PCR in muscle and liver tissue of 36 nonsurvivors, who had been randomized to intensive (normoglycemic) or conventional (hyper-glycemic) insulin therapy and who were comparable for age and severity, duration and type of critical illness. The mean blood glucose levels were 5.6 ± 0.4 and 9.9 ± 0.9 mmol/l (P < 0.001) on a median daily insulin dose of 44.2 and 14.4 IU (P = 0.005), respectively. For comparison, we studied tissue harvested from patients undergoing acute surgical stress as well as tissue from healthy controls. We demonstrated that in both the liver and muscle of patients with prolonged critical illness, the high-affinity insulin-independent glucose transporters GLUT1 and GLUT3 are substantially up-regulated. In muscle the GLUT4 expression is reduced, reflecting insulin resistance. In liver, intensive insulin therapy suppresses GLUT2 with no effect on the other GLUTs. In muscle, intensive insulin therapy downregulates GLUT1 and GLUT3 expression whereas GLUT4 expression is normalized. In conclusion, expression of GLUT1 and GLUT3 is upregulated and GLUT2 expression is normal in prolonged critical illness, a constellation that may predispose cells to glucose overload and toxicity, and that can be beneficially affected by intensive insulin therapy. Expression of GLUT4, by far the most dominantly expressed transporter in muscle, is low in the critically ill and is normalized by intensive insulin therapy. Together, these findings may offer an explanation for the high vulnerability to glucose toxicity during critical illness and how intensive insulin therapy may prevent this.