Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Skeletal muscle-specific glycogen synthase 1 gene (gys1) deletion in mice results in insulin resistance associated with reduced GLUT4 levels (#139)

Chrysovalantou Xirouchaki 1 , Salv Mangiafico 1 , Zheng Ruan 1 , Joseph Proietto 1 , Sof Andrikopoulos 1
  1. University of Melbourne, Heidelberg, Vic, Australia
Impaired glucose storage is considered to be a contributing defect to peripheral insulin resistance, a principal characteristic underpinning type 2 Diabetes. The aim of the present study was to examine the effects of gys1 muscle-specific deletion on glucose metabolism, using a tamoxifen-inducible muscle-specific knockout (KO) mouse model with C57/BL6 background. Ten week-old mice were fed a diet containing 1 mg/g tamoxifen for 8 weeks followed by a recovery period of up to 4 weeks on tamoxifen-free chow diet. KO mice displayed >90% deletion of muscle gys1 protein levels, preserved for 1-4 weeks following tamoxifen withdrawal. We have previously shown at this meeting that 18-22 week old gys1 KO animals are characterized by impaired glucose tolerance when challenged with an OGTT as well as by decreased glucose infusion rate, reduced rate of glucose disappearance and decreased skeletal-muscle and white adipose tissue glucose uptake, under hyperinsulinaemic-euglycaemic conditions, suggestive of insulin resistance. After establishing the phenotype, we are currently carrying out further mechanistic studies via glycogen assays and immunoblotting, in order to identify a potential pathway linking gys1 deletion and insulin resistance. Our preliminary results indicate that muscle-specific gys1 deletion leads to reduced skeletal muscle glycogen phosphorylase and GLUT-4 protein levels associated with the reduced muscle glycogen concentration. In addition, there was no difference in Glucose-6-phosphate isomerase protein levels between the two groups of mice as expected. We are currently investigating other enzymes and metabolites including hexokinase II and glucose-6-phosphate levels in order to get a clear picture of the mechanism. We conclude that our study demonstrates that a muscle-specific gys1 deletion could modify the glucose metabolism pathway, resulting in glucose intolerance and reduced glucose uptake in skeletal muscle and adipose tissue.