Tissue-Specific Analysis of Glycogen Synthase Kinase-3α (GSK-3α) in Glucose Metabolism: Effect of Strain Variation

Background: Over-activity and elevated expression of glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology of insulin resistance and Type 2 diabetes. Administration of specific GSK-3 inhibitors to diabetic or obese rodent models improves glycaemic control and insulin sensitivity. However, due to the indiscriminatory nature of these inhibitors, the relative contribution of the two isoforms of GSK-3 (GSK-3 alpha and GSK-3 beta) is not known. Recently, we demonstrated that an out-bred strain of mice (ICR) lacking expression of GSK-3 alpha in all tissues displayed improved insulin sensitivity and enhanced hepatic glucose metabolism. We also found that muscle (but not liver) inactivation of GSK-3 beta conferred insulin and glucose sensitization in an in-bred strain of mice (C57BL/6). Methodology/Principal Findings: Here, we have employed tissue-specific deletion of GSK-3 alpha, to examine the relative contribution of two insulin-sensitive tissues, muscle and liver, towards the insulin sensitization phenotype originally observed in the global GSK-3 alpha KO animals. We found that mice in which GSK-3 alpha has been inactivated in either skeletal-muscle or liver displayed no differences in glucose tolerance or insulin sensitivity compared to wild type littermates. Given the strain differences in our original analyses, we examined the insulin and glucose sensitivity of global GSK-3 alpha KO animals bred onto a C57BL/6 background. These animals also revealed no significant differences in glucose metabolism/insulin sensitivity compared to their wild type littermates. Furthermore, deletion of hepatic GSK-3 alpha on the out-bred, ICR background failed to reproduce the insulin sensitivity manifested by the global deletion of this isoform. Conclusions/Significance: From these data we conclude that the improved insulin sensitivity and hepatic glucose homeostasis phenotype observed upon global inactivation of GSK-3 alpha is strain-specific. We surmise that the insulin-sensitization observed in the out-bred strain of mice lacking GSK-3 alpha is mediated by indirect means that do not require intrinsic function of GSK-3 alpha in skeletal muscle and liver tissues.