Insulin-stimulated α-(methyl)aminoisobutyric acid uptake in skeletal muscle. Evidence for a short-term activation of uptake independent of Na + electrochemical gradient and protein synthesis (original) (raw)
Related papers
Metabolism-clinical and Experimental, 1991
Amino acid (AA) transport systems A and L, which transfer preferentially small neutral AA (SNAA) and large neutral AA (LNAA), respectively, were studied in the isolated soleus muscle with the specific models, Z-(methylamino)isobutyrate (MeAIB) and 2-aminobicyclo[2,2,1]heptane-2-carboxylate (BCH). Affinity for MeAlB was greater than for BCH (Km = 3.2 2 0.2 and 8.7 -+ 0.2 mm, respectively).
Effect of insulin on the activity of amino acid transport systems in cultured human fibroblasts
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1985
The regulation of amino acid transport by insulin has been studied in cultured human fibroblasts. Among the six amino acid transport systems operating in cultured human fibroblasts, two systems (A and xc) are strongly stimulated by insulin and four (ASC, XAC , y + and L) are essentially not sensitive to the presence of the hormone in the incubation medium. The hormonal stimulation of system A and system x c became significant after 3 h of incubation and increased up to 12 h. The stimulatory effect was related to insulin concentration, with a half-maximal stimulation at 10 -9 M hormone concentration. Insulin enhanced transport activity by increasing the maximal velocity (Vma x ) of transport, without significant changes in K~, values.
Insulin action on skeletal muscle protein metabolism during catabolic states
Reproduction Nutrition Development, 1999
Insulin plays a major role in the regulation of skeletal muscle protein turnover but its mechanism of action is not fully understood, especially in vivo during catabolic states. These aspects are presently reviewed. Insulin inhibits the ATP-ubiquitin proteasome proteolytic pathway which is presumably the predominant pathway involved in the breakdown of muscle protein. Evidence of the ability of insulin to stimulate muscle protein synthesis in vivo was also presented. Many catabolic states in rats, e.g. streptozotocin diabetes, glucocorticoid excess or sepsis-induced cytokines, resulted in a decrease in insulin action on protein synthesis or degradation. The effect of catabolic factors would therefore be facilitated. In contrast, the antiproteolytic action of insulin was improved during hyperthyroidism in man and early lactation in goats. Excessive muscle protein breakdown should therefore be prevented. In other words, the anabolic hormone insulin partly controlled the 'catabolic drive'. Advances in the understanding of insulin signalling pathways and targets should provide information on the interactions between insulin action, muscle protein turnover and catabolic factors. © Inra/ Elsevier, Paris. insulin / skeletal muscle / protein synthesis / protein breakdown / catabolic states Résumé ― Action de l'insuline sur le métabolisme protéique musculaire au cours des états cataboliques. L'insuline joue un rôle majeur dans la régulation du métabolisme protéique musculaire mais son mécanisme d'action n'est pas complétement connu, notamment in vivo durant les états cataboliques. Nous avons rapporté dans cette revue les données récentes qui démontrent que l'insuline inhibe la protéolyse ATP-ubiquitine-protéasome dépendante dans le muscle. Cette voie protéolytique joue un rôle fondamental dans la dégradation des protéines musculaires. Nous avons aussi apporté la preuve que l'insuline est capable de stimuler la synthèse des protéines musculaires in vivo. Dans de nombreux états cataboliques comme le diabète induit par la streptozotocine, l'hyper-* Correspondence and reprints
System A transport activity is stimulated in skeletal muscle in response to diabetes
FEBS Letters, 1992
We have studied the activity of system A transport in skeletal muscle during experimental diabetes. Five days after streptozotocin injection, rats showed a marked hyperglycemia and a substantial decrease in the content of GLUT-4 protein in skeletal muscle and adipose tissut¢, Under these conditions, basal uptake of 2-(methyl)aminoisobutyric acid (MeAl B), an index of system A transport activity, was enhanced in cxt~msor digitorum longus (EDL) muscles from diabetic rats compared to controls. Furthermore, insulin-stimulated MeAl13 uptake by the incubated EDL and soleus muscles was markedly greater in diabetic than in control rats. The derepressiv¢ phase of adaptive regulation was partially blocked in the diabetic muscle, and incubation of muscles for 3 h in the absence of amino acids led to a lower stimulation of system A tnmsport activity in muscles from diabetic groups compared to controls, We propose that the activated system A might participate in the enhanced alanine release from muscle cells that occurs in diabetes.
Glucose Transport in Human Skeletal Muscle: The In Vivo Response to Insulin
Diabetes, 1993
Transmembrane glucose transport plays a key role in determining insulin sensitivity. We have measured in vivo WBGU, FGU, and K ln and K out of 3-O-methyl-D-glucose in forearm skeletal muscle by combining the euglycemic clamp technique, the forearm-balance technique, and a novel dual-tracer (1-[ 3 H]-L-glucose and 3-O-[ 14 C]-methyl-D-glucose) technique for measuring in vivo transmembrane transport. Twenty-seven healthy, lean subjects were studied. During saline infusion, insulin concentration, FGU (n = 6), K ln , and K out (n = 4) were similar to baseline. During SRIF-induced hypoinsulinemia (insulin <15 pM, n = 4) WBGU was close to 0, and FGU, K ln , and K out were unchanged from basal (insulin = 48 pM) values. During insulin clamps at plasma insulin levels of-1 8 0 (n = 4),-4 2 0 (n = 5),-3000 (n = 4), and-9500 pM (n = 4), WBGU was 14.2 ± 1.3, 34.2 ± 4.1 (P < 0.05 vs. previous step), 55.8 ± 1.8 (P < 0.05 vs. previous step), and 56.1 ± 6.3 ixmol • min~1 • kg" 1 of body weight (NS vs. previous step), respectively. Graded hyperinsulinemia concomitantly increased FGU from a basal value of 4.7 ± 0.5 jimol • rnin" 1 • kg" 1 up to 10.9 ± 2.3 (P < 0.05 vs. basal value), 26.6 ± 4.5 (P < 0.05 vs. previous step), 54.8 ± 4.3 (P < 0.05 vs. previous step), and 61.1 ± 10.8 junol • min" 1 • kg" 1 of forearm tissues (NS vs. previous step), respectively. K ln of 3-O-methyl-D-glucose in forearm skeletal muscle was increased by hyperinsulinemia from a basal value of 6.6 • 10" 2 ± 0.38 • 10" 2 to 10.0 • 10" 2 ± 1.4 • 10" 2
Regulation of System A Amino Acid Transport in 3T3-L1 Adipocytes by Insulin
Journal of Biological Chemistry, 1998
The insulin-stimulated uptake of 2-(methylamino) isobutyric acid (MeAIB), a nonmetabolizable substrate for system A, in 3T3-L1 adipocytes was investigated. As cells took on a more adipogenic phenotype, the insulinstimulated versus the saturable basal MeAIB uptake increased by 5-fold. The induced transport activity showed properties characteristic of system A, with a K m value of 190 M. The half-life of the induced system A activity was independent of de novo mRNA and protein synthesis and was not accelerated by ambient amino acids, therefore, it was mechanistically distinct from the previously described adaptive and hormonal regulation of system A. Inhibition of mitogen-activated protein kinase kinase by PD98059, Ras farnesylation by PD152440 and B581, p70 S6K by rapamycin, and phosphatidylinositol 3-kinase (PI 3-K) by wortmannin and LY294002 revealed that only wortmannin and LY294002 inhibited the insulin-induced MeAIB uptake with IC 50 values close to that previously reported for inhibition of PI 3-K. These results suggest that the Ras/mitogenactivated protein kinase and pp70 S6K insulin signaling pathways are neither required nor sufficient for insulin stimulation of MeAIB uptake, and activation of PI 3-K or a wortmannin/LY294002-sensitive pathway may play an important role in regulation of system A transport by insulin in 3T3-L1 cells.
Effect of insulin and contraction up on glucose transport in skeletal muscle
Progress in Biophysics & Molecular Biology, 2004
The major glucose transporter protein expressed in skeletal muscle is GLUT4. Both muscle contraction and insulin induce translocation of GLUT4 from the intracellular pool to the plasma membrane. The intracellular pathways that lead to contraction- and insulin-stimulated GLUT4 translocation seem to be different, allowing the attainment of a maximal effect when acting together. Insulin utilizes a phosphatidylinositol 3-kinase-dependent mechanism, whereas the exercise signal may be initiated by calcium release from the sarcoplasmic reticulum or from autocrine- or paracrine-mediated activation of glucose transport. During exercise skeletal muscle utilizes more glucose than when at rest. However, endurance training leads to decreased glucose utilization during sub-maximal exercise, in spite of a large increase in the total GLUT4 content associated with training. The mechanisms involved in this reduction have not been totally elucidated, but appear to cause the decrease of the amount of GLUT4 translocated to the plasma membrane by altering the exercise-induced enhancement of glucose transport capacity. On the other hand, the effect of resistance training is controversial. Recent studies, however, demonstrated the improvement in insulin sensitivity correlated with increasing muscle mass. New studies should be designed to define the molecular basis for these important adaptations to skeletal muscle. Since during exercise the muscle may utilize insulin-independent mechanisms to increase glucose uptake, the mechanisms involved should provide important knowledge to the understanding and managing peripheral insulin resistance.
Mechanism of Amino Acid-Induced Skeletal Muscle Insulin Resistance in Humans
Diabetes, 2002
Plasma concentrations of amino acids are frequently elevated in insulin-resistant states, and a protein-enriched diet can impair glucose metabolism. This study examined effects of short-term plasma amino acid (AA) elevation on whole-body glucose disposal and cellular insulin action in skeletal muscle. Seven healthy men were studied for 5.5 h during euglycemic (5.5 mmol/l), hyperinsulinemic (430 pmol/l), fasting glucagon (65 ng/l), and growth hormone (0.4 μg/l) somatostatin clamp tests in the presence of low (∼1.6 mmol/l) and increased (∼4.6 mmol/l) plasma AA concentrations. Glucose turnover was measured with d-[6,6-2H2]glucose. Intramuscular concentrations of glycogen and glucose-6-phosphate (G6P) were monitored using 13C and 31P nuclear magnetic resonance spectroscopy, respectively. A ∼2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% (P < 0.01). Rates of muscle glycogen synthesis decreased by 64% (180–315 min, 24 ± 3; control, 67 ± 10 μmol · l−1 · min−...