Normal muscle glucose uptake in mice deficient in muscle GLUT4

Abstract

Skeletal muscle insulin resistance is a major characteristic underpinning type 2 diabetes. Impairments in the insulin responsiveness of the glucose transporter, Glut4 (Slc2a4), have been suggested to be a contributing factor to this disturbance. We have produced muscle-specific Glut4 knockout (KO) mice using Cre/LoxP technology on a C57BL6/J background and shown undetectable levels of GLUT4 in both skeletal muscle and heart. Our aim was to determine whether complete deletion of muscle GLUT4 does in fact lead to perturbations in glucose homoeostasis. Glucose tolerance, glucose turnover and 2-deoxyglucose uptake into muscle and fat under basal and insulin-stimulated conditions were assessed in 12-week-old KO and control mice using the oral glucose tolerance test (OGTT) and hyperinsulinaemic/euglycaemic clamp respectively. KO mice weighed w17% less and had significantly heavier hearts compared with control mice. Basally, plasma glucose and plasma insulin were significantly lower in the KO compared with control mice, which conferred normal glucose tolerance. Despite the lack of GLUT4 in the KO mouse muscle, glucose uptake was not impaired in skeletal muscle but was reduced in heart under insulin-stimulated conditions. Neither GLUT1 nor GLUT12 protein levels were altered in the skeletal muscle or heart tissue of our KO mice. High-fat feeding did not alter glucose tolerance in the KO mice but led to elevated plasma insulin levels during the glucose tolerance test. Our study demonstrates that deletion of muscle GLUT4 does not adversely affect glucose disposal and glucose tolerance and that compensation from other transporters may contribute to this unaltered homoeostasis of glucose.

Effects of high-intensity interval training and moderate-intensity continuous training on glycaemic control and skeletal muscle mitochondrial function in db/db mice

“…Moreover, Glut4 content in soleus and gastrocnemius was significantly increased in HIIT group vs. CON and interestingly, Glut4 seems to be largely involved in whole body glucose homeostasis. Several studies using muscle-specific Glut4 KO mice have shown that Glut4 disruption can lead to hyperglycaemia 47 or impaired glucose tolerance in high fat or chow-fed mice 48, 49 . Likewise, studies dealing with the effect of a single exercise session on Glut4-deficient mice, all converge upon the conclusion that Glut4 is the major factor responsible for exercise-induced glucose uptake 50–52 .…”

Excessive training impairs the insulin signal transduction in mice skeletal muscles

“…Fam and coworkers (2012)showed that the deletion of the skeletal muscle GLUT4 on the pure C57BL6/J background strain did not impair the whole-body glucose disposal. These authors, among others (Ryder et al 1999, Charron et al 2005, Fam et al 2012, considered that other unidentified GLUTs were upregulated in an attempt to compensate the lack of GLUT4. Probably, the previous hypothesis justifies the fact that even with lower content of plasma membrane GLUT4 in EDL and soleus, the OTR/down group did not exhibit lower glycogen concentrations when compared with the CT group (Pereira et al 2014b).…”

Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats

“…This effect was significant for both exercise groups in olanzapine-treated rats, as levels of GLUT4 almost doubled compared to sedentary rats, which parallels the observation that both 1 h and 3 h of exercise were equally effective in mitigating glucose intolerance. As these findings are only correlational, the causal role of GLUT4 on olanzapineinduced glucose intolerance will require additional future study with techniques that directly modify expression of GLUT4, such as the muscle-specific GLUT4 knockout mouse (Fam et al, 2012). The role of GLUT4 is manifold, and its beneficial effects on insulin resistance and hyperglycemia may involve its translocation to the cell membrane in addition to increased gene and protein expression in skeletal muscle and other tissues.…”