Regulation of Liver and Kidney Glucose‐6‐phosphatase Gene Expression in Hemorrhage and Resuscitation

Abstract

Abstract.The authors have recently demonstrated that increased gene expression of glucose-6-phosphatase (Glu-6-Pase) in hemorrhagic hypotension (HH) and following lactated Ringer's resuscitation (LR) is associated with a decrease in insulin and an increase in corticosterone concentrations. Objective: To evaluate the in-vivo role of hormones the authors used insulin (IN), phentolamine and propranolol (PP) as an adrenergic blocker, and cyclic somatostatin (CS) as a glucagon blocker to prevent the induction of Glu-6-Pase gene expression in liver and kidney following HH and LR. Methods: Hemorrhage was induced in fasted anesthetized rats, and the reduction of blood pressure to 40 mm Hg for a duration of 30 minutes was accomplished by withdrawal or infusion of shed blood. The resuscitated group underwent hemorrhage followed by fluid resuscitation with lactated Ringer's solution. Results: Neither PP nor CS treatment could block the induction of Glu-6-Pase messenger ribonucleic acid (mRNA) following either HH or LR. However, the administration of IN significantly prevented the increase of Glu-6-Pase mRNA level and activity in both liver and kidney following HH and LR. This was associated with a normalization of plasma glucose, corticosterone, and glucagon levels and glucose-6-phosphate concentrations in liver and kidney toward prehemorrhage levels. Conclusions: These results indicate that in-vivo treatment with insulin during hemorrhagic hypotension and resuscitation is capable of preventing the increase in Glu-6-Pase gene expression in liver and kidney responsible for the observed hyperglycemia.

Hemorrhage induces the rapid development of hepatic insulin resistance

“…Previous studies suggest that hepatic glycogen content is reduced over 90% following a 20-to 24-h fast (28). In support of this contention, data from Maitra et al (33) suggest that adrenergic blockers and inhibition of glucagon had no effect on hemorrhage-induced hyperglycemia in rats fasted for 20 h. However, breakdown of liver or muscle glycogen may have contributed to the increase in blood glucose. Hyperglycemia, when combined with the severe hyperinsulinemia obtained following trauma and hemorrhage, is strongly suggestive of a rapid development of insulin.…”

“…Hyperglycemia occurs following sepsis (11,33), surgery (35,37,45), and hemorrhage (33). This injury/ infection-induced hyperglycemia, often referred to as "stress diabetes," could be readily explained by either insulin deficiency or insulin resistance.…”

“…In less severe forms of injury or very early following hemorrhage, serum insulin concentrations were sometimes found to decrease or not increase (13,33,45). However, in the later stages of the hemorrhage period or following resuscitation, there is a uniform responsiveness of pancreatic beta cells to glucose and plasma insulin concentrations rise in an attempt to control the hyperglycemia.…”

“…However, little is known about hepatic insulin resistance following injury, and if it becomes resistant to insulin, the liver may contribute to the hyperglycemia. There is evidence that soon after hemorrhage and resuscitation, hepatic expression of the gluconeogenic gene glucose-6-phosphatase increases, suggesting insulin resistance in the liver (33); but this might be due to rising glucocorticoids, another regulator of glucose-6-phosphatase expression (32). Therefore, a direct examination of hepatic insulin signaling and any changes following hemorrhage was necessary to characterize hepatic insulin resistance.…”

“…However, if the liver becomes resistant to insulin, the increased hepatic glucose output can contribute to the hyperglycemia. Recently, there is evidence that expression of at least one hepatic gluconeogenic gene (glucose-6-phosphatase) is altered following hemorrhage or sepsis (1,31,33), but the relationship between the development of hepatic insulin resistance and altered expression of this gene is unknown.…”