Acute and chronic signals controlling glucose transport in skeletal muscle

Abstract

Glucose transport into muscle cells occurs through facilitated diffusion mediated primarily by the GLUT1 and GLUT4 glucose transporters. These transporter proteins are controlled by acute and chronic exposure to insulin, glucose, muscle contraction, and hypoxia. We propose that acute responses occur through recruitment of pre-formed glucose transporters from an intracellular storage site to the plasma membrane. In contrast, chronic control is achieved by changes in transporter biosynthesis and protein stability. Using subcellular fractionation of rat skeletal muscle, recruitment of GLUT4 glucose transporters to the plasma membrane is demonstrated by acute exposure to insulin in vivo. The intracellular pool appears to arise from a unique organelle depleted of transverse tubule, plasma membrane, or sarcoplasmic reticulum markers. In diabetic rats, GLUT4 content in the plasma membranes and in the intracellular pool is reduced, and incomplete insulin-dependent GLUT4 recruitment is observed, possibly through a defective incorporation of transporters to the plasma membrane. The lower content of GLUT4 transporters in the muscle plasma membranes is reversed by restoration of normoglycemia with phlorizin treatment. In some muscle cells in culture, GLUT1 is the only transporter expressed yet they respond to insulin, suggesting that this transporter can also be regulated by acute mechanisms. In the L6 muscle cell line, GLUT1 transporter content diminishes during myogenesis and GLUT4 appears after cell fusion, reaching a molar ratio of about 1:1 in the plasma membrane. Prolonged exposure to high glucose diminishes the amount of GLUT1 protein in the plasma membrane by both endocytosis and reduced biosynthesis, and lowers GLUT4 protein content in the absence of changes in GLUT4 mRNA possibly through increased protein degradation. These studies suggest that the relative contribution of each transporter to transport activity, and the mechanisms by which glucose exerts control of the glucose transporters, will be key subjects of future investigations.

The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro

“…Extrapancreatic effects of sulfonylureas in vitro and in vivo. In addition to adipose tissue, prolonged expo sure to high glucose has been reported to acutely and chronically downregulate the glucose transport system in skeletal muscle, which represents the major site for insulin-dependent glucose disposal (66). It will be inter esting to see in future studies whether glimepiride will compensate the lower number of GLUT4 in PM of muscle cells in the basal and insulin-stimulated state.…”

Activation of p38 mitogen-activated protein kinase alpha and beta by insulin and contraction in rat skeletal muscle: potential role in the stimulation of glucose transport.

“…The data further suggest that activation of p38 MAPK may participate in the stimulation of glucose uptake by both stimuli in rat skeletal muscle. Diabetes 49:1794-1800, 2000 T ranslocation of glucose transporters in muscle and fat cells is a prerequisite for full stimulation of glucose uptake by insulin (1,2). Activation of several lipid and serine/threonine kinases in an orderly fashion is believed to be required for this translocation.…”

Protection Against Oxidative Stress—Induced Insulin Resistance in Rat L6 Muscle Cells by Micromolar Concentrations of α-Lipoic Acid

“…Prior studies in this cell type have demonstrated that insulin-stimulated glucose transport is mediated by the GLUT4 transporter (23,24,26), as is the case for skeletal muscle (27)(28)(29)(30). In this study, we used L6 GLUT4 cells that had been engineered to overexpress GLUT4 (23).…”