Direct Administration of Insulin Into Skeletal Muscle Reveals That the Transport of Insulin Across the Capillary Endothelium Limits the Time Course of Insulin to Activate Glucose Disposal

To better define the time course of skeletal muscle glucose uptake and its modulation by changes in perfusion, we performed systemic euglycemic-hyperinsulinemic clamps (40 mU.m-2.min-1) for a 90-min period in a group of lean, insulin-sensitive subjects (n = 9) on two occasions (approximately 4 wk apart) with insulin-mediated vasodilation intact or inhibited. Insulin-mediated vasodilation was inhibited by an intrafemoral artery infusion of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthase. During the study, leg blood flow (LBF) and arteriovenous glucose difference (AVG delta) were measured every 10 min; leg glucose uptake (LGU) was calculated as LGU = LBF x AVG delta. The systemic insulin infusion caused a time-dependent increase in LBF from 0.194 +/- 0.024 to 0.349 +/- 0.046 l/min (P < 0.01). The intrafemoral artery infusion of L-NMMA completely inhibited this increase in LBF. AVG delta, LGU, and whole body glucose disposal rates increased in a time-dependent manner in both studies. The maximum AVG delta was lower with insulin-mediated vasodilation intact than when inhibited (25.9 +/- 2.5 vs. 35.0 +/- 1.6 mg/dl, P < 0.001). The time to achieve half-maximal (T1/2) AVG delta was somewhat longer with insulin-mediated vasodilation intact compared with inhibited (35.6 +/- 4.1 vs. 29.7 +/- 1.6 min, P < 0.01). Maximal LGU was 93.9 +/- 26.8 and 57.2 +/- 11.6 mg/min (P < 0.005), and the T1/2 LGU was 50.2 +/- 16.0 and 36.3 +/- 8.8 min (P = 0.1) during intact and inhibited insulin-mediated vasodilation, respectively. Thus insulin-mediated vasodilation has a modest effect in slowing the time course at which insulin stimulates glucose uptake but has a marked effect in augmenting the maximal rate of insulin-stimulated glucose uptake in skeletal muscle. Impaired insulin-mediated vasodilation, as observed in patients with essential hypertension, may explain, at least in part, the insulin resistance observed in these patients.

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UPTAKE OF OXYTOCIN IN TISSUES AFTER INTRAVENOUS ADMINISTRATION OF TRITIATED OXYTOCIN IN RATS

Acta Endocrinologica ◽

10.1530/acta.0.0610432 ◽

1969 ◽

Vol 61 (3) ◽

pp. 432-440 ◽

Cited By ~ 7

Author(s):

Ingvar Sjöholm ◽

Gunnar Rydén

Keyword(s):

Skeletal Muscle ◽

Distribution Pattern ◽

Intravenous Injection ◽

Intravenous Administration ◽

Time Course ◽

Tritiated Water ◽

Preferential Distribution ◽

Time Period ◽

Initial Uptake

ABSTRACT The distribution of oxytocin in the kidneys, liver, uterus and skeletal muscle of the rat was followed during 10 min after intravenous injection of tritium labelled oxytocin. Oxytocin was found to be taken up and degraded mainly in the kidneys and the liver. After 150 seconds no intact oxytocin could be detected in these organs. The time course of the distribution of the radioactivity in the liver and the skeletal muscle showed no noteworthy characteristics, whereas a different course was found in the kidneys and in the uterus. In the kidneys, the radioactivity increased continuously from 60 to 200 seconds after the injection, indicating an accumulation of oxytocin or its metabolites in the kidneys. In the uterus a high initial uptake was observed, followed by a decrease of the radioactivity from 60 to 100 seconds after the injection. This distribution pattern was specific to oxytocin, since the uptake of tritiated tyrosine and tritiated water was almost constant during the same time period. These findings may indicate a preferential distribution of oxytocin to the uterus.

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Neural control of glucose uptake by skeletal muscle after central administration of NMDA

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.268.2.r492 ◽

1995 ◽

Vol 268 (2) ◽

pp. R492-R497 ◽

Cited By ~ 1

Author(s):

C. H. Lang ◽

M. Ajmal ◽

A. G. Baillie

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Glucose Uptake ◽

Neural Control ◽

Plasma Insulin ◽

Regional Blood Flow ◽

Muscle Blood Flow ◽

Whole Body ◽

Glucose Disposal ◽

Central Administration

Intracerebroventricular injection of N-methyl-D-aspartate (NMDA) produces hyperglycemia and increases whole body glucose uptake. The purpose of the present study was to determine in rats which tissues are responsible for the elevated rate of glucose disposal. NMDA was injected intracerebroventricularly, and the glucose metabolic rate (Rg) was determined for individual tissues 20-60 min later using 2-deoxy-D-[U-14C]glucose. NMDA decreased Rg in skin, ileum, lung, and liver (30-35%) compared with time-matched control animals. In contrast, Rg in skeletal muscle and heart was increased 150-160%. This increased Rg was not due to an elevation in plasma insulin concentrations. In subsequent studies, the sciatic nerve in one leg was cut 4 h before injection of NMDA. NMDA increased Rg in the gastrocnemius (149%) and soleus (220%) in the innervated leg. However, Rg was not increased after NMDA in contralateral muscles from the denervated limb. Data from a third series of experiments indicated that the NMDA-induced increase in Rg by innervated muscle and its abolition in the denervated muscle were not due to changes in muscle blood flow. The results of the present study indicate that 1) central administration of NMDA increases whole body glucose uptake by preferentially stimulating glucose uptake by skeletal muscle, and 2) the enhanced glucose uptake by muscle is neurally mediated and independent of changes in either the plasma insulin concentration or regional blood flow.

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A Time-Course Comparison of Skeletal Muscle Metabolomic Alterations in Walker-256 Tumour-Bearing Rats at Different Stages of Life

Metabolites ◽

10.3390/metabo11060404 ◽

2021 ◽

Vol 11 (6) ◽

pp. 404

Author(s):

Gabriela de Matuoka e Chiocchetti ◽

Leisa Lopes-Aguiar ◽

Natália Angelo da Silva Miyaguti ◽

Lais Rosa Viana ◽

Carla de Moraes Salgado ◽

...

Keyword(s):

Skeletal Muscle ◽

Time Course ◽

Cancer Cachexia ◽

Tumour Bearing ◽

Walker 256 Tumour ◽

Walker 256 ◽

Muscle Changes ◽

The Right ◽

Biomarker Research ◽

Host Metabolism

Cancer cachexia is a severe wasting condition that needs further study to find ways to minimise the effects of damage and poor prognosis. Skeletal muscle is the most impacted tissue in cancer cachexia; thus, elucidation of its metabolic alterations could provide a direct clue for biomarker research and be applied to detect this syndrome earlier. In addition, concerning the significant changes in the host metabolism across life, this study aimed to compare the metabolic muscle changes in cachectic tumour-bearing hosts at different ages. We performed 1H-NMR metabolomics in the gastrocnemius muscle in weanling and young adult Walker-256 tumour-bearing rats at different stages of tumour evolution (initial, intermediate, and advanced). Among the 49 metabolites identified, 24 were significantly affected throughout tumour evolution and 21 were significantly affected regarding animal age. The altered metabolites were mainly related to increased amino acid levels and changed energetic metabolism in the skeletal muscle, suggesting an expressive catabolic process and diverted energy production, especially in advanced tumour stages in both groups. Moreover, these changes were more severe in weanling hosts throughout tumour evolution, suggesting the distinct impact of cancer cachexia regarding the host’s age, highlighting the need to adopting the right animal age when studying cancer cachexia.

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Effect of α-Lipoic Acid Combined with Creatine Monohydrate on Human Skeletal Muscle Creatine and Phosphagen Concentration

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.13.3.294 ◽

2003 ◽

Vol 13 (3) ◽

pp. 294-302 ◽

Cited By ~ 25

Author(s):

Darren G. Burke ◽

Philip D. Chilibeck ◽

Gianni Parise ◽

Mark A. Tarnopolsky ◽

Darren G. Candow

Keyword(s):

Skeletal Muscle ◽

Lipoic Acid ◽

Human Skeletal Muscle ◽

Vastus Lateralis ◽

Creatine Supplementation ◽

Creatine Monohydrate ◽

Glucose Disposal ◽

Creatine Uptake ◽

Total Creatine ◽

Muscle Creatine

α-lipoic acid has been found to enhance glucose uptake into skeletal muscle in animal models. Studies have also found that the co-ingestion of carbohydrate along with creatine increases muscle creatine uptake by a process related to insulin-stimulated glucose disposal. The purpose of this study was to determine the effect of α-lipoic acid on human skeletal muscle creatine uptake by directly measuring intramuscular concentrations of creatine, phosphocreatine, and ad-enosine triphosphate when creatine monohydrate was co-ingested with α-lipoic acid. Muscle biopsies were acquired from the vastus lateralis m. of 16 male subjects (18–32 y) before and after the experimental intervention. After the initial biopsy, subjects ingested 20 g · d−1 of creatine monohydrate, 20 g · d−1 of creatine monohydrate + 100 g · d−1 of sucrose, or 20 g · d−1 of creatine monohydrate + 100 g · d−1 of sucrose + 1000 mg · d−1 of α-lipoic acid for 5 days. Subjects refrained from exercise and consumed the same balanced diet for 7 days. Body weight increased by 2.1% following the nutritional intervention, with no differences between the groups. There was a significant increase in total creatine concentration following creatine supplementation, with the group ingesting α-lipoic acid showing a significantly greater increase (p < .05) in phosphocreatine (87.6 → 106.2 mmol · kg−1 dry mass [dm]) and total creatine (137.8 → 156.8 mmol · kg−1 dm). These findings indicate that co-ingestion of α-lipoic acid with creatine and a small amount of sucrose can enhance muscle total creatine content as compared to the ingestion of creatine and sucrose or creatine alone.

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Prep1 Deficiency Induces Protection from Diabetes and Increased Insulin Sensitivity through a p160-Mediated Mechanism

Molecular and Cellular Biology ◽

10.1128/mcb.00117-08 ◽

2008 ◽

Vol 28 (18) ◽

pp. 5634-5645 ◽

Cited By ~ 35

Author(s):

Francesco Oriente ◽

Luis Cesar Fernandez Diaz ◽

Claudia Miele ◽

Salvatore Iovino ◽

Silvia Mori ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Normal Glucose Tolerance ◽

Glucose Disposal ◽

Protein Levels ◽

Normal Glucose ◽

Enhanced Expression ◽

The Stability

ABSTRACT We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1 i / i ) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1 i / i muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1α, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1 i / i mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.

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Time course of skeletal muscle loss and oxidative stress in rats with walker 256 solid tumor

Muscle & Nerve ◽

10.1002/mus.21798 ◽

2010 ◽

Vol 42 (6) ◽

pp. 950-958 ◽

Cited By ~ 38

Author(s):

Flávia A. Guarnier ◽

Alessandra L. Cecchini ◽

Andréia A. Suzukawa ◽

Ana Leticia G.C. Maragno ◽

Andréa N.C. Simão ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Solid Tumor ◽

Time Course ◽

Muscle Loss ◽

Skeletal Muscle Loss ◽

Walker 256 ◽

And Oxidative Stress

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Localization of Rate-Limiting Defect for Glucose Disposal in Skeletal Muscle of Insulin-Resistant Type I Diabetic Patients

Diabetes ◽

10.2337/diab.39.2.157 ◽

1990 ◽

Vol 39 (2) ◽

pp. 157-167 ◽

Cited By ~ 51

Author(s):

H. Yki-Jarvinen ◽

K. Sahlin ◽

J. M. Ren ◽

V. A. Koivisto

Keyword(s):

Skeletal Muscle ◽

Glucose Disposal ◽

Diabetic Patients ◽

Type I ◽

Insulin Resistant ◽

Rate Limiting

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Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1

Journal of Applied Physiology ◽

10.1152/japplphysiol.00286.2016 ◽

2017 ◽

Vol 122 (1) ◽

pp. 38-47 ◽

Cited By ~ 30

Author(s):

Leryn J. Reynolds ◽

Daniel P. Credeur ◽

Camila Manrique ◽

Jaume Padilla ◽

Paul J. Fadel ◽

...

Keyword(s):

Nitric Oxide ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Blood Flow ◽

Vastus Lateralis ◽

Glucose Disposal ◽

Endothelin 1 ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)−1·min−1] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM−1·min−1) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P < 0.05). peNOS/eNOS content was higher in Lean under basal conditions and, although not increased by insulin, remained higher in Lean during the insulin clamp than in obese T2D ( P < 0.05). ET-1 mRNA and peptide were 2.25 ± 0.50- and 1.52 ± 0.11-fold higher in obese T2D compared with Lean at baseline, and ET-1 peptide remained 2.02 ± 1.9-fold elevated in obese T2D after insulin infusion ( P < 0.05) but did not increase with insulin in either group ( P > 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 ( P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients. NEW & NOTEWORTHY Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.

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Pulsatile Pressure and Flow in the Skeletal Muscle Microcirculation

Journal of Biomechanical Engineering ◽

10.1115/1.2891208 ◽

1990 ◽

Vol 112 (4) ◽

pp. 437-443 ◽

Cited By ~ 5

Author(s):

Shou-Yan Lee ◽

G. W. Schmid-Scho¨nbein

Keyword(s):

Skeletal Muscle ◽

Arterial Pressure ◽

Time Course ◽

Venous Pressure ◽

Time Dependent ◽

Physiological Importance ◽

Pulsatile Pressure ◽

Theoretical Predictions ◽

Skeletal Muscle Microcirculation

Although blood flow in the microcirculation of the rat skeletal muscle has negligible inertia forces with very low Reynolds number and Womersley parameter, time-dependent pressure and flow variations can be observed. Such phenomena include, for example, arterial flow overshoot following a step arterial pressure, a gradual arterial pressure reduction for a step flow, or hysteresis between pressure and flow when a pulsatile pressure is applied. Arterial and venous flows do not follow the same time course during such transients. A theoretical analysis is presented for these phenomena using a microvessel with distensible viscoelastic walls and purely viscous flow subject to time variant arterial pressures. The results indicate that the vessel distensibility plays an important role in such time-dependent microvascular flow and the effects are of central physiological importance during normal muscle perfusion. In-vivo whole organ pressure-flow data in the dilated rat gracilis muscle agree in the time course with the theoretical predictions. Hemodynamic impedances of the skeletal muscle microcirculation are investigated for small arterial and venous pressure amplitudes superimposed on an initial steady flow and pressure drop along the vessel.

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