Local histamine H1- and H2-receptor blockade reduces postexercise skeletal muscle interstitial glucose concentrations in humans

2010 ◽  
Vol 35 (5) ◽  
pp. 617-626 ◽  
Author(s):  
Thomas K. Pellinger ◽  
Grant H. Simmons ◽  
David A. MacLean ◽  
John R. Halliwill
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Vastus Lateralis ◽  
Receptor Activation ◽  
Peak Oxygen Uptake ◽  
Vastus Lateralis Muscle ◽  
Receptor Blockade ◽  
Glucose Levels ◽  
Interstitial Glucose ◽  
The Impact

Elevated blood flow can potentially influence skeletal muscle glucose uptake, but the impact of postexercise hyperemia on glucose availability to skeletal muscle remains unknown. Because postexercise hyperemia is mediated by histamine H1- and H2-receptors, we tested the hypothesis that postexercise interstitial glucose concentrations would be lower in the presence of combined H1- and H2-receptor blockade. To this end, 4 microdialysis probes were inserted into the vastus lateralis muscle of 14 healthy subjects (21–27 years old) immediately after 60 min of either upright cycling at 60% peak oxygen uptake (exercise, n = 7) or quiet rest (sham, n = 7). Microdialysis probes were perfused with a modified Ringer’s solution containing 3 mmol·L–1 glucose, 5 mmol·L–1 ethanol, and [6-3H] glucose (200 disintegrations·min–1·μL–1). Two sites (blockade) received both H1- and H2-receptor antagonists (1 mmol·L–1 pyrilamine and 3 mmol·L–1 cimetidine) and 2 sites (control) did not receive antagonists. Ethanol outflow/inflow ratios (an inverse surrogate of local blood flow) were higher in blockade sites than in control sites following exercise (p < 0.05), whereas blockade had no effect on ethanol outflow/inflow ratios following sham (p = 0.80). Consistent with our hypothesis, during 3 of the 5 dialysate collection periods, interstitial glucose concentrations were lower in blockade sites vs. control sites following exercise (p < 0.05), whereas blockade had no effect on interstitial glucose concentrations following sham (p = 0.79). These findings indicate that local H1- and H2-receptor activation modulates skeletal muscle interstitial glucose levels during recovery from exercise in humans and suggest that the availability of glucose to skeletal muscle is enhanced by postexercise hyperemia.

Muscle interstitial glucose and lactate levels during dynamic exercise in humans determined by microdialysis

1999 ◽  
Vol 87 (4) ◽  
pp. 1483-1490 ◽  
Author(s):  
Dave A. MacLean ◽  
Jens Bangsbo ◽  
Bengt Saltin
Keyword(s):  
Skeletal Muscle ◽  
Vastus Lateralis ◽  
Lactate Concentration ◽  
Reference Method ◽  
Vastus Lateralis Muscle ◽  
Glucose Levels ◽  
Interstitial Glucose ◽  
Lactate Levels ◽  
Exercise In Humans ◽  
Venous Plasma

The purpose of the present study was to use the microdialysis technique to determine skeletal muscle interstitial glucose and lactate concentrations during dynamic incremental exercise in humans. Microdialysis probes were inserted into the vastus lateralis muscle, and subjects performed knee extensor exercise at workloads of 10, 20, 30, 40, and 50 W. The in vivo probe recoveries determined at rest by the internal reference method for glucose and lactate were 28.7 ± 2.5 and 32.0 ± 2.7%, respectively. As exercise intensity increased, probe recovery also increased, and at the highest workload probe recovery for glucose (61.0 ± 3.9%) and lactate (66.3 ± 3.6%) had more than doubled. At rest the interstitial glucose concentration (3.5 ± 0.2 mM) was lower than both the arterial (5.6 ± 0.2 mM) and venous (5.3 ± 0.3 mM) plasma water glucose levels. The interstitial glucose levels remained lower ( P < 0.05) than the arterial and venous plasma water glucose concentrations during exercise at all intensities and at 10, 20, 30, and 50 W, respectively. At rest the interstitial lactate concentration (2.5 ± 0.2 mM) was higher ( P < 0.05) than both the arterial (0.9 ± 0.2 mM) and venous (1.1 ± 0.2 mM) plasma water lactate levels. This relationship was maintained ( P < 0.05) during exercise at workloads of 10, 20, and 30 W. These data suggest that interstitial glucose delivery at rest is flow limited and that during exercise changes in the interstitial concentrations of glucose and lactate mirror the changes observed in the venous plasma water compartments. Furthermore, skeletal muscle contraction results in an increase in the diffusion coefficient of glucose and lactate within the interstitial space as reflected by an elevation in probe recovery during exercise.

Muscle blood flow during exercise in sedentary and trained hypothyroid rats

1995 ◽  
Vol 269 (6) ◽  
pp. H1949-H1954 ◽  
Author(s):  
R. M. McAllister ◽  
M. D. Delp ◽  
K. A. Thayer ◽  
M. H. Laughlin
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Citrate Synthase ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Treadmill Running ◽  
Exercise Intolerance ◽  
Vastus Lateralis Muscle ◽  
Blood Flows ◽  
Vastus Intermedius

Hypothyroidism is characterized by exercise intolerance. We hypothesized that active muscle blood flow during in vivo exercise is inadequate in the hypothyroid state. Additionally, we hypothesized that endurance exercise training would restore normal blood flow during acute exercise. To test these hypotheses, rats were made hypothyroid (Hypo) over 3-4 mo with propylthiouracil. A subset of Hypo rats was trained (THypo) on a treadmill at 30 m/min (15% grade) for 60 min/day 5 days/wk over 10-15 wk. Hypothyroidism was evidenced by approximately 80% reductions in plasma triiodothyronine levels in Hypo and THypo and by 40-50% reductions in citrate synthase activities in high oxidative muscles in Hypo compared with euthyroid (Eut) rats. Training efficacy was indicated by increased (25-100%) citrate synthase activities in muscles of THypo vs. Hypo. Regional blood flows were determined by the radiolabeled microsphere method before exercise and at 1-2 min of treadmill running at 15 m/min (0% grade). Preexercise muscle blood flows were generally similar among groups. During exercise, however, flows were lower in Hypo than in Eut for high oxidative muscles such as the red section of vastus lateralis [277 +/- 24 and 153 +/- 13 (SE) ml.min-1.100 g-1 for Eut and Hypo, respectively; P < 0.01] and vastus intermedius (317 +/- 32 and 187 +/- 20 ml.min-1.100 g-1 for Eut and Hypo, respectively; P < 0.01) muscles. Training (THypo) did not normalize these flows (168 +/- 24 and 181 +/- 24 ml.min-1.100 g-1 for red section of vastus lateralis and vastus intermedius muscles, respectively). Blood flows to low oxidative muscle, such as the white section of vastus lateralis muscle, were similar among groups (21 +/- 5, 25 +/- 4, and 34 +/- 7 ml.min-1.100 g-1 for Eut, Hypo, and THypo, respectively; P = NS). These findings indicate that hypothyroidism is associated with reduced blood flow to skeletal muscle during exercise, suggesting that impaired delivery of nutrients to and/or removal of metabolites from skeletal muscle contributes to the poor exercise tolerance characteristic of hypothyroidism.

ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine

2009 ◽  
Vol 296 (4) ◽  
pp. R1140-R1148 ◽  
Author(s):  
Stefan P. Mortensen ◽  
José González-Alonso ◽  
Laurids T. Bune ◽  
Bengt Saltin ◽  
Henriette Pilegaard ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Human Skeletal Muscle ◽  
Purinergic Receptors ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Pcr Analysis ◽  
Receptor Subtypes ◽  
Vastus Lateralis Muscle

Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P2 receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5–7 min of femoral intra-arterial infusion of ATP [0.45–2.45 μmol/min] in 19 healthy male subjects with and without coinfusion of NG-monomethyl-l-arginine (l-NMMA; NO formation inhibitor; 12.3 ± 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 ± 12 μg/min), and/or theophylline (adenosine receptor blocker; 400 ± 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 ± 0.14 l/min. When ATP was coinfused with either l-NMMA, INDO, or l-NMMA + INDO combined, the increase in LBF was reduced by 14 ± 6, 15 ± 9, and 39 ± 8%, respectively (all P < 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O2 extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of P2Y2 receptors of the 10 investigated P2 receptor subtypes. Immunohistochemistry showed that P2Y2 receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P2X1 receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression and localization of the nucleotide selective P2Y2 and P2X1 receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle.

Muscle glycogen utilization during shivering thermogenesis in humans

1988 ◽  
Vol 65 (5) ◽  
pp. 2046-2050 ◽  
Author(s):  
L. Martineau ◽  
I. Jacobs
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Cold Water ◽  
Vastus Lateralis ◽  
Water Immersion ◽  
Venous Blood ◽  
Cold Water Immersion ◽  
Vastus Lateralis Muscle ◽  
Glucose Levels ◽  
Shivering Thermogenesis

The purpose of the present study was to clarify the importance of skeletal muscle glycogen as a fuel for shivering thermogenesis in humans during cold-water immersion. Fourteen seminude subjects were immersed to the shoulders in 18 degrees C water for 90 min or until rectal temperature (Tre) decreased to 35.5 degrees C. Biopsies from the vastus lateralis muscle and venous blood samples were obtained before and immediately after the immersion. Metabolic rate increased during the immersion to 3.5 +/- 0.3 (SE) times resting values, whereas Tre decreased by 0.9 degrees C to approximately 35.8 degrees C at the end of the immersion. Intramuscular glycogen concentration in the vastus lateralis decreased from 410 +/- 15 to 332 +/- 18 mmol glucose/kg dry muscle, with each subject showing a decrease (P less than 0.001). Plasma volume decreased (P less than 0.001) markedly during the immersion (-24 +/- 1%). After correcting for this decrease, blood lactate and plasma glycerol levels increased by 60 (P less than 0.05) and 38% (P less than 0.01), respectively, whereas plasma glucose levels were reduced by 20% after the immersion (P less than 0.001). The mean expiratory exchange ratio showed a biphasic pattern, increasing initially during the first 30 min of the immersion from 0.80 +/- 0.06 to 0.85 +/- 0.05 (P less than 0.01) and decreasing thereafter toward basal values. The results demonstrate clearly that intramuscular glycogen reserves are used as a metabolic substrate to fuel intensive thermogenic shivering activity of human skeletal muscle.

scholarly journals Activation of the erythropoietin receptor in human skeletal muscle

2009 ◽  
Vol 161 (3) ◽  
pp. 427-434 ◽  
Author(s):  
Helene Rundqvist ◽  
Eric Rullman ◽  
Carl Johan Sundberg ◽  
Helene Fischer ◽  
Katarina Eisleitner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Vastus Lateralis ◽  
Muscle Fibers ◽  
Receptor Activation ◽  
Erythropoietin Receptor ◽  
Muscle Performance ◽  
Vastus Lateralis Muscle

Objective:Erythropoietin receptor (EPOR) expression in non-hematological tissues has been shown to be activated by locally produced and/or systemically delivered EPO. Improved oxygen homeostasis, a well-established consequence of EPOR activation, is very important for human skeletal muscle performance. In the present study we investigate whether human skeletal muscle fibers and satellite cells express EPOR and if it is activated by exercise.Design and methodsTen healthy males performed 65 min of cycle exercise. Biopsies were obtained from the vastus lateralis muscle and femoral arterio-venous differences in EPO concentrations were estimated.ResultsThe EPOR protein was localized in areas corresponding to the sarcolemma and capillaries. Laser dissection identified EPOR mRNA expression in muscle fibers. Also, EPOR mRNA and protein were both detected in human skeletal muscle satellite cells. In the initial part of the exercise bout there was a release of EPO from the exercising leg to the circulation, possibly corresponding to an increased bioavailability of EPO. After exercise, EPOR mRNA and EPOR-associated JAK2 phosphorylation were increased.ConclusionsInteraction with JAK2 is required for EPOR signaling and the increase found in phosphorylation is therefore closely linked to the activation of EPOR. The receptor activation by acute exercise suggests that signaling through EPOR is involved in exercise-induced skeletal muscle adaptation, thus extending the biological role of EPO into the skeletal muscle.

Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow

2006 ◽  
Vol 291 (3) ◽  
pp. R803-R809 ◽  
Author(s):  
Kari K. Kalliokoski ◽  
Henning Langberg ◽  
Ann Kathrine Ryberg ◽  
Celena Scheede-Bergdahl ◽  
Simon Doessing ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Vastus Lateralis Muscle ◽  
Substrate Uptake ◽  
Skeletal Muscle Blood Flow ◽  
Lateralis Muscle

Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising skeletal muscle. Skeletal muscle blood flow was measured in seven healthy young men using near-infrared spectroscopy and indocyanine green and muscle glucose uptake using positron emission tomography and 2-fluoro-2-deoxy-d-[18F]glucose without and with local blockade of NO and PG at rest and during one-legged dynamic knee-extension exercise. Local blockade was produced by infusing nitro-l-arginine methyl ester and indomethacin directly in the muscle via a microdialysis catheter. Blood flow and glucose uptake were measured in the region of blockade and in two additional regions of vastus lateralis muscle 1 and 4 cm away from the infusion of blockers. Local blockade during exercise at 25 and 40 watts significantly decreased blood flow in the infusion region and in the region 1 cm away from the site of infusion but not in the region 4 cm away. During exercise, muscle glucose uptake did not show any regional differences in response to blockade. These results show that NO and PG synergistically contribute to the local regulation of blood flow in skeletal muscle independently of muscle glucose uptake in healthy young men. Thus these vasodilators can play a role in regulating microvascular blood flow in localized regions of vastus lateralis muscle but do not influence regional glucose uptake. The findings suggest that local substrate uptake in skeletal muscle can be regulated independently of regional changes in blood flow.

Microdialysis ethanol removal reflects probe recovery rather than local blood flow in skeletal muscle

1998 ◽  
Vol 85 (2) ◽  
pp. 751-757 ◽  
Author(s):  
G. Rådegran ◽  
H. Pilegaard ◽  
J. J. Nielsen ◽  
J. Bangsbo
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Femoral Artery ◽  
Vastus Lateralis ◽  
Molecular Transport ◽  
Thigh Muscle ◽  
High Dose ◽  
Vastus Lateralis Muscle ◽  
Acetate Solution ◽  
Induced Changes

The present study compared the microdialysis ethanol outflow-inflow technique for estimating blood flow (BF) in skeletal muscle of humans with measurements by Doppler ultrasound of femoral artery inflow to the limb (BFFA). The microdialysis probes were inserted in the vastus lateralis muscle and perfused with a Ringer acetate solution containing ethanol, [2-3H]adenosine (Ado), andd-[14C(U)]glucose. BFFA at rest increased from 0.16 ± 0.02 to 1.80 ± 0.26 and 4.86 ± 0.53 l/min with femoral artery infusion of Ado (AdoFA,i) at 125 and 1,000 μg ⋅ min−1 ⋅ l−1thigh volume (low dose and high dose, respectively; P < 0.05) and to 3.79 ± 0.37 and 6.13 ± 0.65 l/min during one-legged, dynamic, thigh muscle exercise without and with high AdoFA,i, respectively ( P < 0.05). The ethanol outflow-to-inflow ratio (38.3 ± 2.3%) and the probe recoveries (PR) for [2-3H]Ado (35.4 ± 1.6%) and ford-[14C(U)]glucose (15.9 ± 1.1%) did not change with AdoFA,i at rest ( P = not significant). During exercise without and with AdoFA,i, the ethanol outflow-to-inflow ratio decreased ( P < 0.05) to a similar level of 17.5 ± 3.4 and 20.6 ± 3.2%, respectively ( P = not significant), respectively, while the PR increased ( P < 0.05) to a similar level ( P = not significant) of 55.8 ± 2.8 and 61.2 ± 2.5% for [2-3H]Ado and to 42.8 ± 3.9 and 45.2 ± 5.1% ford-[14C(U)]glucose. Whereas the ethanol outflow-to-inflow ratio and PR correlated inversely and positively, respectively, to the changes in BF during muscular contractions, neither of the ratio nor PR correlated to the AdoFA,i-induced BF increase. Thus the ethanol outflow-to-inflow ratio does not represent skeletal muscle BF but rather contraction-induced changes in molecular transport in the interstitium or over the microdialysis membrane.

scholarly journals The influence of physical training on the angiopoietin and VEGF-A systems in human skeletal muscle

2007 ◽  
Vol 103 (3) ◽  
pp. 1012-1020 ◽  
Author(s):  
T. Gustafsson ◽  
H. Rundqvist ◽  
J. Norrbom ◽  
E. Rullman ◽  
E. Jansson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Vastus Lateralis ◽  
Exercise Bout ◽  
Voluntary Exercise ◽  
Vastus Lateralis Muscle ◽  
Mrna Levels ◽  
Ki 67

Eleven subjects performed one-legged exercise four times per week for 5 wk. The subjects exercised one leg for 45 min with restricted blood flow (R leg), followed by exercise with the other leg at the same absolute workload with unrestricted blood flow (UR leg). mRNA and protein expression were measured in biopsies from the vastus lateralis muscle obtained at rest before the training period, after 10 days, and after 5 wk of training, as well as 120 min after the first and last exercise bouts. Basal Ang-2 and Tie-1 mRNA levels increased in both legs with training. The Ang-2-to-Ang-1 ratio increased to a greater extent in the R leg. The changes in Ang-2 mRNA were followed by similar changes at the protein level. In the R leg, VEGF-A mRNA expression responded transiently after acute exercise both before and after the 5-wk training program. Over the course of the exercise program, there was a concurrent increase in basal VEGF-A protein and VEGFR-2 mRNA in the R leg. Ki-67 mRNA showed a greater increase in the R leg and the protein was localized to the endothelial cells. In summary, the increased translation of VEGF-A is suggested to be caused by the short mRNA burst induced by each exercise bout. The concurrent increase in the Ang-2-to-Ang-1 ratio and the VEGF-expression combined with the higher level of Ki-67 mRNA in the R leg indicate that changes in these systems are of importance also in nonpathological angiogenic condition such as voluntary exercise in humans. It further establish that hypoxia/ischemia-related metabolic perturbation is likely to be involved as stimuli in this process in human skeletal muscle.

Skeletal muscle blood flow and flow heterogeneity during dynamic and isometric exercise in humans

2003 ◽  
Vol 284 (3) ◽  
pp. H979-H986 ◽  
Author(s):  
Marko S. Laaksonen ◽  
Kari K. Kalliokoski ◽  
Heikki Kyröläinen ◽  
Jukka Kemppainen ◽  
Mika Teräs ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Vastus Lateralis ◽  
Muscle Blood Flow ◽  
Isometric Exercise ◽  
Dynamic Exercise ◽  
Emg Activity ◽  
Vastus Lateralis Muscle ◽  
Skeletal Muscle Blood Flow ◽  
Flow Heterogeneity

The effects of dynamic and intermittent isometric knee extension exercises on skeletal muscle blood flow and flow heterogeneity were studied in seven healthy endurance-trained men. Regional muscle blood flow was measured using positron emission tomography (PET) and an [15O]H2O tracer, and electromyographic (EMG) activity was recorded in the quadriceps femoris (QF) muscle during submaximal intermittent isometric and dynamic exercises. QF blood flow was 61% ( P = 0.002) higher during dynamic exercise. Interestingly, flow heterogeneity was 13% ( P = 0.024) lower during dynamic compared with intermittent isometric exercise. EMG activity was significantly higher ( P < 0.001) during dynamic exercise, and the change in EMG activity from isometric to dynamic exercise was tightly related to the change in blood flow in the vastus lateralis muscle ( r = 0.98, P < 0.001) but not in the rectus femoris muscle ( r = −0.09, P = 0.942). In conclusion, dynamic exercise causes higher and less heterogeneous blood flow than intermittent isometric exercise at the same exercise intensity. These responses are, at least partly, related to the increased EMG activity.

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

2017 ◽  
Vol 122 (1) ◽  
pp. 38-47 ◽  
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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