Molecular and cellular adaptations in GLUT4 -deficient mice

Abstract

Homozygous GLUT4 knockout mice are able to maintain normal glycemia. In vivo glucose clamp studies showed that they are severely insulin resistant. Fast twitch, glycolytic muscle is the major insulin resistant tissue as demonstrated by reduced 2-Deoxyglucose uptake under hyperinsulinemic clamp studies. A glycemia sensitive new glucose transport activity was identified in brown adipose tissue, diaphragm, soleus and heart, which may contribute to the maintenance of euglycemia observed in these mice. Glucose and fatty acid oxidation were increased in GLUT4 null mice skeletal muscle according to in vitro studies using isolated EDL and soleus muscle. Mitochondrial hypertrophy was observed in GLUT4 null skeletal muscle and mitochondrial oxidative capacity was also possibly increased. White adipose tissue depots were severely reduced in GLUT4 null mice with smaller adipocytes which have limited fat accumulation. However, the expression of mature adipocyte genes was activated. GLUT4 null fat pads were able to secrete leptin and ACRP30/AdipoQ and were insulin sensitive. Thus, the limited skinny fat cells of GLUT4 null mice are mostly likely differentiated. On contrary to the lack of diabetes phenotype in GLUT4 null mice, male heterozygous GLUT4 knockout mice display the full spectrum of diabetes development throughout their life. Adipocytes from normal, prediabetic, and diabetic groups were used to: study the onset and development of insulin signaling defects in adipocytes. Reduced insulin receptor tyrosine kinase activity was first observed in parallel with the onset of fed hyperinsulinemic in these mice. It was further exacerbated by the development of hyperglycemia and the expression of insulin receptor protein was reduced. Insulin stimulated IRS-1 associate P13 kinase activity was reduced starting in adipocytes of the prediabetic group and progressed to adipocytes from the diabetic group. However, the insulin signaling defects did not contribute to the reduced maximal insulin stimulated glucose uptake, which correlated with the reduced GLUT4 protein content in GLUT4(+/-) adipocytes. Cloning of mouse glucagon receptor gene and the expression and signaling of glucagon receptor in betaTC3 cells were described in the appendix.