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Glucose transport across the cell surface is a key regulatory step for glucose metabolism in skeletal muscle. Both insulin and exercise increase glucose transport into myofibers through glucose transporter (GLUT) proteins. Skeletal muscle expresses several members of the GLUT family but the GLUT4 glucose transporter is considered the main "regulatable" isoform that is modulated by insulin and contraction. Glucose transport rate can be stimulated either by recruitment of GLUT4 units from intracellular storage vesicles or through activation of cell surface transporters. Insulin activates GLUT4 translocation through a complex signaling cascade involving both the lipid kinase phosphatidylinositol 3-kinase and the proto-oncoprotein c-Cbl. Contraction, on the other hand, appears to trigger GLUT4 translocation at least in part through activation of the metabolite-sensing 5'-AMP-activated protein kinase. Furthermore, recent studies suggest that p38 MAP kinase activation represents a point of convergence of the signaling pathways utilized by insulin and contraction to increase GLUT4 activation at the cell surface. This review will summarize our current knowledge of these alternative pathways of GLUT4 regulation in skeletal muscle.

Investigates whether the AMP-activated protein kinase activator AICAR increases glucose uptake by inducing the translocation of GLUT4. Result that occurs from the contraction on muscle glucose uptake; Manner in which muscle contraction increases glucose uptake and utilization; Events that activate p38 MAPK in rat skeletal muscle.

The stress-activated p38 mitogen-activated protein kinase (MAPK) was recently shown to be activated by insulin in muscle and adipose cells in culture. Here, we explore whether such stimulation is observed in rat skeletal muscle and whether muscle contraction can also affect the enzyme. Insulin injection (2 U over 3.5 min) resulted in increases in p38 MAPK phosphorylation measured in soleus (3.2-fold) and quadriceps (2.2-fold) muscles. Increased phosphorylation (3.5-fold) of an endogenous substrate of p38 MAPK, cAMP response element binder (CREB), was also observed. After in vivo insulin treatment, p38 MAPKalpha and p38 MAPKbeta isoforms were found to be activated (2.1- and 2.4-fold, respectively), using an in vitro kinase assay, in immunoprecipitates from quadriceps muscle extracts. In vitro insulin treatment (1 nmol/l over 4 min) and electrically-induced contraction of isolated extensor digitorum longus (EDL) muscle also doubled the kinase activity of p38 MAPKalpha and p38 MAPKbeta. The activity of both isoforms was inhibited in vitro by 10 micromol/l SB203580 in all muscles. To explore the possible participation of p38 MAPK in the stimulation of glucose uptake, EDL and soleus muscles were exposed to increasing doses of SB203580 before and during stimulation by insulin or contraction. SB203580 caused a significant reduction in the insulin- or contraction-stimulated 2-deoxyglucose uptake. Maximal inhibition (50-60%) occurred with 10 micromol/l SB203580. These results show that p38 MAPKalpha and -beta isoforms are activated by insulin and contraction in skeletal muscle. The data further suggest that activation of p38 MAPK may participate in the stimulation of glucose uptake by both stimuli in rat skeletal muscle. [ABSTRACT FROM AUTHOR]

Insulin and contraction increase glucose transport in an additive fashion in skeletal muscle. However, it is still unclear whether they do so by inducing the recruitment of GLUT4 transporters from the same or distinct intracellular compartments to the plasma membrane and the T-tubules. Using the transferrin receptor as a recognized marker of recycling endosomes, we have examined whether insulin and/or contraction recruit GLUT4 from this pool to either the plasma membranes or T-tubules, isolated by subcellular fractionation of perfused hindlimb muscles. Either stimulus independently increased GLUT4 translocation from an intracellular fraction to both the plasma membrane and T-tubules. The combination of insulin and contraction induced a marked (approximately threefold) and almost fully additive increase in GLUT4 content, but only in the plasma membrane. Insulin did not stimulate transferrin receptor recruitment from the GLUT4-containing intracellular fraction to either the plasma membrane or the T-tubules. In contrast, contraction stimulated the recruitment of the transferrin receptor from the same GLUT4-containing intracellular fraction to the plasma membrane but not to the T-tubules. Contraction-induced recruitment of the transferrin receptor was also observed from immunopurified GLUT4 vesicles. It is concluded that muscle contraction stimulates translocation of GLUT4 from two distinct intracellular compartments: 1) a population of recycling endosomes that is selectively recruited to the plasma membrane and 2) from GLUT4 storage vesicles that are also insulin-responsive and recruited to both the plasma membrane and the T-tubules. The lack of additive translocation of GLUT4 to the T-tubules may be linked to the failure of GLUT4-containing recycling endosomes to be recruited to these structures. [ABSTRACT FROM AUTHOR]