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.