Regulation of Glucose Metabolism in Skeletal Muscle (original) (raw)
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Metabolic control analysis of insulin-stimulated glucose disposal in rat skeletal muscle
American Journal of Physiology-Endocrinology and Metabolism, 1999
Metabolic control analysis was used to calculate the distributed control of insulin-stimulated skeletal muscle glucose disposal in awake rats. Three separate hyperinsulinemic infusion protocols were performed: 1) protocol I was a euglycemic (∼6 mM)-hyperinsulinemic (10 mU ⋅ kg−1⋅ min−1) clamp, 2) protocol II was a hyperglycemic (∼11 mM)-hyperinsulinemic (10 mU ⋅ kg−1⋅ min−1) clamp, and 3) protocol III was a euglycemic (∼6 mM)-hyperinsulinemic (10 mU ⋅ kg−1⋅ min−1)-lipid/heparin (increased plasma free fatty acid) clamp. [1-13C]glucose was administered in all three protocols for a 3-h period, during which time [1-13C]glucose label incorporation into [1-13C]glycogen, [3-13C]lactate, and [3-13C]alanine was detected in the hindlimb of awake rats via13C-NMR. Combined steady-state and kinetic data were used to calculate rates of glycogen synthesis and glycolysis. Additionally, glucose 6-phosphate (G-6- P) was measured in the hindlimb muscles with the use of in vivo31P-NMR during the three ...
General aspects of muscle glucose uptake
Anais da Academia Brasileira de Ciências, 2015
Glucose uptake in peripheral tissues is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. Studies have shown the existence of two major signaling pathways that lead to the translocation of GLUT4. The first, and widely investigated, is the insulin activated signaling pathway through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The second is the insulin-independent signaling pathway, which is activated by contractions. Individuals with type 2 diabetes mellitus have reduced insulin-stimulated glucose uptake in skeletal muscle due to the phenomenon of insulin resistance. However, those individuals have normal glucose uptake during exercise. In this context, physical exercise is one of the most important interventions that stimulates glucose uptake by insulin-independent pathways, and the main molecules involved are adenosine monophosphate-activated protein kinase, nitric oxide, bradykinin, AKT, reactive oxygen species and calcium. In...
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.
Journal of Applied Physiology, 2004
Whole body glucose disposal and skeletal muscle hexokinase, glycogen synthase (GS), pyruvate dehydrogenase (PDH), and PDH kinase (PDK) activities were measured in aerobically trained men after a standardized control diet (Con; 51% carbohydrate, 29% fat, and 20% protein of total energy intake) and a 56-h eucaloric, high-fat, low-carbohydrate diet (HF/LC; 5% carbohydrate, 73% fat, and 22% protein). An oral glucose tolerance test (OGTT; 1 g/kg) was administered after the Con and HF/LC diets with vastus lateralis muscle biopsies sampled pre-OGTT and 75 min after ingestion of the oral glucose load. The 90-min area under the blood glucose and plasma insulin concentration vs. time curves increased by 2-fold and 1.25-fold, respectively, after the HF/LC diet. The pre-OGTT fraction of GS in its active form and the maximal activity of hexokinase were not affected by the HF/LC diet. However, the HF/LC diet increased PDK activity (0.19 ± 0.05 vs. 0.08 ± 0.02 min−1) and decreased PDH activation (...
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
New England Journal of Medicine, 1999
Background Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of glycogen synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle glycogen synthesis is not known, although hexokinase activity and glucose transport have been implicated. Methods We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid. Results The time course and concentration of insulin in interstitial fluid were similar in the patients with diabetes and the normal subjects. The rates of whole-body glucose metabolism and muscle glycogen synthesis and the glucose-6-phosphate concentrations in muscle were approximately 80 percent lower in the patients with diabetes than in the normal subjects under conditions of matched plasma insulin concentrations. The mean (±SD) intracellular glucose concentration was 2.0±8.2 mg per deciliter (0.11±0.46 mmol per liter) in the normal subjects. In the patients with diabetes, the intracellular glucose concentration was 4.3±4.9 mg per deciliter (0.24±0.27 mmol per liter), a value that was 1/25 of what it would be if hexokinase were the rate-controlling enzyme in glucose metabolism. Conclusions Impaired insulin-stimulated glucose transport is responsible for the reduced rate of insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes mellitus. (
American Journal of Physiology - Endocrinology And Metabolism, 2002
We varied rates of glucose transport and glycogen synthase (GS) activity in isolated rat epitrochlearis muscle to examine the role of each process in determining the rate of glycogen accumulation. GS activity (GSI%) was maintained at or above the fasting, basal range during 3 h of incubation with 36 mM glucose and 60 µU/ml insulin. Lithium (2 mM LiCl) added to insulin increased glucose transport rate and muscle glycogen content compared with insulin alone. The glycogen synthase kinase-3β inhibitor GF109203x (10 µM, GF) maintained GSI% ~2-fold higher than insulin ± lithium but did not increase glycogen accumulation. When GSI% was lowered below the fasting range by prolonged incubation with 36 mM glucose and 2 mU/ml insulin, raising rates of glucose transport with bpV(phen) or of GSI% with GF produced additive increases in glycogen concentration. Phosphorylase activity was unaffected by GF or bpV(phen). In muscles of fed animals, GSI% was ~30% lower than in those of fasted rats, and insulin-stimulated glycogen accumulation did not occur unless GSI% was raised with GF. We conclude that the rate of glucose transport is rate limiting for glycogen accumulation unless GSI% is below the fasting range, in which case both glucose transport rate and GS activity can limit glycogen accumulation.
Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load
Journal of Clinical Investigation, 1988
Although muscle is considered to be the most important site for postprandial glucose disposal, the metabolic fate of oral glucose taken up by muscle remains unclear. We, therefore, employed the dual isotope technique (intravenous, [6-3HJglucose; oral, l1-'4Clglucose), indirect calorimetry, and forearm balance measurements of glucose, lactate, alanine, pyruvate, 02, and CO2 in nine normal volunteers to determine the relative importance of muscle glycogenic, glycolytic, and oxidative pathways in disposal of an oral glucose load. During the 5 h after glucose ingestion (1 g/kg), 37±3% (24.9±2.3 g) of the load was oxidized and 63±3% (42.8±2.7 g) was stored. At least 29% (19.4±1.3 g) was taken up by splanchnic tissues. Muscle took up 26% (17.9±2.9 g) of the oral glucose coincident with a 50% reduction in its oxidation of fat. 15% of the oral glucose taken up by muscle (2.5±0.9 g) was released as lactate, alanine, or pyruvate; 50% (8.9±1.4 g) was oxidized, and 35% (6.4±2.3 g) was available for storage. We conclude that muscle and splanchnic tissues take up a comparable percentage of an oral glucose load and that oxidation is the predominant fate of glucose taken up by muscle, with storage in muscle accounting for < 10% of the oral load. Thus, contrary to the prevailing view, muscle is neither the major site of storage nor the predominant site of disposal of an oral glucose load.