Partial or complete loss of GLUT4: Close-up on skeletal muscle glucose transport

Abstract

Oxidative skeletal muscles from whole body homozygous (GLUT4 null) or heterozygous GLUT4+/- mice were studied to determine their glucose uptake profile and signal transduction pathways regulating it. Previously, it has been shown that genetic ablation of GLUT4 leads to a novel 2-deoxyglucose (2-DOG) transport activity in several tissues including a 2 fold increase in the oxidative soleus muscle.;Biochemical characterization of the in vitro 2-DOG uptake in GLUT4 null soleus was conducted using various inhibitors of the insulin signaling pathway. 2-DOG transport activity in GLUT4 null soleus does not depend on PI3 kinase as wortmannin, a potent inhibitor of PI3 kinase, did not alter this glucose transport activity. The results demonstrate a dependence of the compensatory glucose transport activity in GLUT4 null soleus muscle on constitutive activation of Akt that is independent of PI3 kinase activity.;To further characterize the glucose transport activity of oxidative soleus muscle, streptozotocin (STZ) was administered to induce diabetes in GLUT4 null mice. GLUT4 null mice developed hyperglycemia and hyperlipidemia. A dramatic decrease of in vitro GLUT4 null soleus 2-DOG uptake has occurred following 8 days diabetes. Moreover, fasting, that is usually associated with elevation of circulating free fatty acids and low blood glucose, led to a similar decrease in GLUT4 null soleus glucose uptake pointing to the possible inhibitory effect of fatty acids and not high glucose on glucose uptake activity. This study demonstrates the susceptibility of the compensatory glucose transport system of the GLUT4 null soleus to STZ induced diabetes and fasting and suggests that this transport activity could be regulated by the availability of circulating lipids leading to an increased activity of PP2A and inhibition of Akt.;GLUT8 expression and regulation was studied in liver from different developmental stages; normal and STZ diabetic mice; and diabetic GLUT4+/- mice. Hepatic GLUT8 mRNA and protein expression was differentially regulated depending on the pre and postnatal developmental stage of the mice. These data demonstrate that GLUT8 mRNA and protein are differentially regulated in liver in response to physiologic and pathologic milieu and suggests that GLUT8 is intimately linked to glucose homeostasis.;The potential of antidiabetic compounds, antioxidant-lipoic acid and insulin sensitizer-BRL, in hyperglycemic/hyperinsulinemic GLUT4+/- mice was addressed. Short term treatment of GLUT4+/- mice with lipoic acid or BRL resulted in improved insulin tolerance. (Abstract shortened by UMI.).