ORCID Profile
0000-0003-4214-7628
Current Organisation
Deakin University
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Medical Biotechnology | Systems Physiology | Endocrinology | Medical Physiology
Diagnostics | Endocrine organs and diseases (incl. diabetes) | Treatments (e.g. chemicals, antibiotics) |
Publisher: American Physiological Society
Date: 15-05-2015
DOI: 10.1152/AJPREGU.00412.2014
Abstract: Nitric oxide (NO) has been shown to be involved in skeletal muscle glucose uptake during contraction/exercise, especially in in iduals with Type 2 diabetes (T2D). To examine the potential mechanisms, we examined the effect of local NO synthase (NOS) inhibition on muscle glucose uptake and muscle capillary blood flow during contraction in healthy and T2D rats. T2D was induced in Sprague-Dawley rats using a combined high-fat diet (23% fat wt/wt for 4 wk) and low-dose streptozotocin injections (35 mg/kg). Anesthetized animals had one hindlimb stimulated to contract in situ for 30 min (2 Hz, 0.1 ms, 35 V) with the contralateral hindlimb rested. After 10 min, the NOS inhibitor, N G -nitro-l-arginine methyl ester (l-NAME 5 μM) or saline was continuously infused into the femoral artery of the contracting hindlimb until the end of contraction. Surprisingly, there was no increase in skeletal muscle NOS activity during contraction in either group. Local NOS inhibition had no effect on systemic blood pressure or muscle contraction force, but it did cause a significant attenuation of the increase in femoral artery blood flow in control and T2D rats. However, NOS inhibition did not attenuate the increase in muscle capillary recruitment during contraction in these rats. Muscle glucose uptake during contraction was significantly higher in T2D rats compared with controls but, unlike our previous findings in hooded Wistar rats, NOS inhibition had no effect on glucose uptake during contraction. In conclusion, NOS inhibition did not affect muscle glucose uptake during contraction in control or T2D Sprague-Dawley rats, and this may have been because there was no increase in NOS activity during contraction.
Publisher: American Physiological Society
Date: 15-09-2013
DOI: 10.1152/AJPENDO.00289.2013
Abstract: Insulin stimulates microvascular recruitment in skeletal muscle, and this vascular action augments muscle glucose disposal by ∼40%. The aim of the current study was to determine the contribution of local nitric oxide synthase (NOS) to the vascular actions of insulin in muscle. Hooded Wistar rats were infused with the NOS inhibitor N ω -nitro-l-arginine methylester (l-NAME, 10 μM) retrogradely via the epigastric artery in one leg during a systemic hyperinsulinemic-euglycemic cl (3 mU·min −1 ·kg −1 × 60 min) or saline infusion. Femoral artery blood flow, microvascular blood flow (assessed from 1-methylxanthine metabolism), and muscle glucose uptake (2-deoxyglucose uptake) were measured in both legs. Local l-NAME infusion did not have any systemic actions on blood pressure or heart rate. Local l-NAME blocked insulin-stimulated changes in femoral artery blood flow (84%, P 0.05) and microvascular recruitment (98%, P 0.05), and partially blocked insulin-mediated glucose uptake in muscle (reduced by 34%, P 0.05). l-NAME alone did not have any metabolic effects in the hindleg. We conclude that insulin-mediated microvascular recruitment is dependent on local activation of NOS in muscle and that this action is important for insulin's metabolic actions.
Publisher: American Diabetes Association
Date: 09-2007
DOI: 10.2337/DB07-0020
Abstract: We examined whether contraction-induced muscle microvascular recruitment would expand the surface area for insulin and nutrient exchange and thereby contribute to insulin-mediated glucose disposal. We measured in vivo rat hindlimb microvascular blood volume (MBV) using contrast ultrasound and femoral blood flow (FBF) using Doppler ultrasound in response to a stimulation frequency range. Ten minutes of 0.1-Hz isometric contraction more than doubled MBV (P & 0.05 n = 6) without affecting FBF (n = 7), whereas frequencies & .5 Hz increased both. Specific inhibition of nitric oxide (NO) synthase with Nω-l-nitro-arginine-methyl ester (n = 5) significantly elevated mean arterial pressure by ∼30 mmHg but had no effect on basal FBF or MBV. We next examined whether selectively elevating MBV without increasing FBF (0.1-Hz contractions) increased muscle uptake of albumin-bound Evans blue dye (EBD). Stimulation at 0.1 Hz (10 min) elicited more than twofold increases in EBD content (micrograms EBD per gram dry tissue) in stimulated versus contralateral muscle (n = 8 52.2 ± 3.8 vs. 20 ± 2.5, respectively P & 0.001). We then measured muscle uptake of EBD and 125I-labeled insulin (dpm per gram dry tissue) with 0.1-Hz stimulation (n = 6). Uptake of EBD (19.1 ± 3.8 vs. 9.9 ± 1 P & 0.05) and 125I-insulin (5,300 ± 800 vs. 4,244 ± 903 P & 0.05) was greater in stimulated muscle versus control. Low-frequency contraction increases muscle MBV by a NO-independent pathway and facilitates muscle uptake of albumin and insulin in the absence of blood flow increases. This microvascular response may, in part, explain enhanced insulin action in exercising skeletal muscle.
Publisher: Wiley
Date: 03-03-2022
DOI: 10.1111/DOM.14669
Abstract: To investigate the effects of mitochondrial-targeted antioxidants (mitoAOXs) on glycaemic control, cardiovascular health, and oxidative stress outcomes in humans. Randomized controlled trials investigating mitoAOX interventions in humans were searched for in databases (MEDLINE-PubMed, Scopus, EMBASE and Cochrane Library) and clinical trial registries up to 10 June 2021. The Cochrane Collaboration's tool for assessing risk of bias and Grading of Recommendations, Assessment, Development and Evaluations were used to assess trial quality and evidence certainty, respectively. Nineteen studies (n = 884 participants) using mitoAOXs (including Elamipretide, MitoQ and MitoTEMPO) were included in the systematic review. There were limited studies investigating the effects of mitoAOXs on glycaemic control and outcomes and population groups in studies focusing on cardiovascular health were erse. MitoAOXs significantly improved brachial flow-mediated dilation (n = 3 trials standardized mean difference: 1.19, 95% CI: 0.28, 2.16 I While short-term studies indicate that mitoAOXs are generally well tolerated, there is currently limited evidence to support the use of mitoAOXs in the management of glycaemic control and cardiovascular health. Review findings suggest that future research should focus on the effects of mitoAOXs on glycaemic control and endothelial function in target clinical population groups.
Publisher: Elsevier BV
Date: 2001
Publisher: Wiley
Date: 03-04-2021
Publisher: Wiley
Date: 27-12-2017
Abstract: Skeletal muscle is an important site for insulin to regulate blood glucose levels. It is estimated that skeletal muscle is responsible for ~80% of insulin-mediated glucose disposal in the post-prandial period. The classical action of insulin to increase muscle glucose uptake involves insulin binding to insulin receptors on myocytes to stimulate glucose transporter 4 (GLUT 4) translocation to the cell surface membrane, enhancing glucose uptake. However, an additional role of insulin that is often under-appreciated is its action to increase muscle perfusion thereby improving insulin and glucose delivery to myocytes. Either of these responses (myocyte and/or vascular) may be impaired in insulin resistance, and both impairments are apparent in type 2 diabetes, resulting in diminished glucose disposal by muscle. The aim of this review is to report on the growing body of literature suggesting that insulin-mediated control of skeletal muscle perfusion is an important regulator of muscle glucose uptake and that impairment of microvascular insulin action has important physiological consequences early in the pathogenesis of insulin resistance. This work was discussed at the 2015 Australian Physiological Society Symposium "Physiological mechanisms controlling microvascular flow and muscle metabolism".
Publisher: American Diabetes Association
Date: 13-01-2021
DOI: 10.2337/DC20-1893
Abstract: Evidence suggests that vitamin C supplementation could be a potential therapy in type 2 diabetes. However, its effectiveness and evidence quality require further evaluation. To investigate the efficacy of oral vitamin C supplementation in improving glycemic control, cardiovascular risk factors, and oxidative stress in people with type 2 diabetes. Databases (PubMed, Embase, Scopus, Cochrane Library) and clinical trial registries were searched for randomized controlled trials up to 8 September 2020. Trials in adults with type 2 diabetes were included. Trials were excluded if supplements were not exclusive to vitamin C and if & weeks in duration. Primary outcomes were HbA1c, glucose, cholesterol, triglycerides, and blood pressure (BP). Data were extracted for changes in outcomes between vitamin C and control groups. Evidence certainty was assessed using Grading of Recommendations, Assessment, Development, and Evaluation methods. Twenty-eight studies (N = 1,574 participants) were included in the review. Outcomes that changed to a statistically and clinically significant extent with vitamin C were systolic BP (mean difference −6.27 [95% CI −9.60, −2.96] mmHg P = 0.0002), with moderate evidence certainty, and HbA1c (−0.54% [−0.90, −0.17] P = 0.004) and diastolic BP (−3.77 [−6.13, −1.42] mmHg P = 0.002) with very low evidence certainty. Studies were predominantly short term (& months) with a small number of participants (n & 100). While evidence from short-term studies suggests that vitamin C supplementation may improve glycemic control and BP in people with type 2 diabetes, vitamin C supplementation cannot currently be recommended as a therapy until larger, long-term, and high-quality trials confirm these findings.
Publisher: Wiley
Date: 12-2000
Publisher: Wiley
Date: 27-01-2005
DOI: 10.1002/NBM.950
Abstract: This work discusses the strengths, limitations and validity of a novel arterial spin labeling technique when used specifically to measure perfusion in limb skeletal muscle. The technique, flow-driven arterial water stimulation with elimination of tissue signal (FAWSETS), offers several advantages over existing arterial spin labeling techniques. The primary goal of this study was to determine the perfusion signal response to changes in net hind limb flow that were independently verifiable. The range of perfusate flow was relevant to skeletal muscle during mild to moderate exercise. Localized, single voxel measurements were acquired from a 5 mm-thick slice in the isolated perfused rat hind limb at variable net flow rates. The results show that the perfusion signal is linearly proportional to net hind limb flow with a correlation coefficient of 0.974 (p = 0.0013). FAWSETS is especially well suited for studies of skeletal muscle perfusion, where it eliminates the need to compensate for magnetization transfer and arterial transit time effects. A conceptual discussion of the basic principles underlying these advantages is presented.
Publisher: Springer Science and Business Media LLC
Date: 12-09-2014
DOI: 10.1007/S00125-014-3373-Y
Abstract: High sodium (HS) effects on hypertension are well established. Recent evidence implicates a relationship between HS intake and insulin resistance, even in the absence of hypertension. The aim of the current study was to determine whether loss of the vascular actions of insulin may be the driving factor linking HS intake to insulin resistance. Sprague Dawley rats were fed a control (0.31% wt/wt NaCl) or HS (8.00% wt/wt NaCl) diet for 4 weeks and subjected to euglycaemic-hyperinsulinaemic cl (10 mU min(-1) kg(-1)) or constant-flow pump-perfused hindlimb studies following an overnight fast. A separate group of HS rats was given quinapril during the dietary intervention and subjected to euglycaemic-hyperinsulinaemic cl as above. HS intake had no effect on body weight or fat mass or on fasting glucose, insulin, endothelin-1 or NEFA concentrations. However, HS impaired whole body and skeletal muscle glucose uptake, in addition to a loss of insulin-stimulated microvascular recruitment. These effects were present despite enhanced insulin signalling (Akt) in both liver and skeletal muscle. Constant-flow pump-perfused hindlimb experiments revealed normal insulin-stimulated myocyte glucose uptake in HS-fed rats. Quinapril treatment restored insulin-mediated microvascular recruitment and muscle glucose uptake in vivo. HS-induced insulin resistance is driven by impaired microvascular responsiveness to insulin, and is not due to metabolic or signalling defects within myocytes or liver. These results imply that reducing sodium intake may be important not only for management of hypertension but also for insulin resistance, and highlight the vasculature as a potential therapeutic target in the prevention of insulin resistance.
Publisher: Wiley
Date: 08-1999
DOI: 10.1046/J.1365-201X.1999.00572.X
Abstract: Exogenous substrates for capillary endothelial enzymes have potential as markers for changes in capillary recruitment (albeit nutritive flow). The metabolism of infused 1-methylxanthine (1-MX) to 1-methylurate (1-MU) by capillary endothelial xanthine oxidase of the constant-flow perfused rat hindlimb was shown previously to decrease with oxygen uptake (VO2) when nutritive flow was decreased. In the present study, the metabolism of 1-MX was investigated under conditions when VO2 and nutritive flow are known to increase during muscle contraction. The constant-flow red blood cell-perfused rat hindlimb at 37 degrees C was used with sciatic nerve stimulation, and perfusate s les from whole hindlimb and working muscles taken for analysis of oxygen, lactate, 1-MX and 1-MU. Flow to muscle was assessed separately using fluorescent microspheres and was found to increase 2.3-fold to the working muscles while flow to the non-working leg muscles decreased to compensate. The activity of xanthine oxidase of whole muscle extracts was not altered by contraction. S les from the vein draining the working muscles, and microsphere measurements of flow, indicated increased VO2 (5.5-fold to 249.2 +/- 43.1 micromol h-1 g-1, P < 0.001), and 1-MX conversion (2.5-fold to 1.87 +/- 0.25 micromol h-1 g-1, P < 0.01) (SEM are shown). It is concluded that as 1-MX metabolism parallels VO2, this substrate may be a useful indicator of changes in capillary (nutritive) surface area in muscle.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2022
Abstract: Although the impact of dietary fats on cardiovascular disease (CVD) risk is widely researched, longitudinal associations between dietary patterns (DPs) based on fat type and early markers of CVD risk remain unclear. UK Biobank participants (46.9% men, mean age 55 years) with data on early markers of CVD risk (n=12 706) were followed longitudinally (2014–2020 mean 8.4 years). Two DPs (DP1, DP2) were derived using reduced rank regression (response variables: monounsaturated fat, polyunsaturated fat, and saturated fat based on two 24‐hour dietary assessments. Multivariable logistic and linear regression were used to investigate associations between DPs and odds of elevated CVD risk (using the nonlaboratory Framingham Risk Score) and changes in early CVD markers, respectively. DP1 (characterized by higher nuts and seeds and lower fruit and legumes intake) was positively correlated with saturated fat, monounsaturated fat, and polyunsaturated fat DP2 (characterized by higher butter and high‐fat cheese, lower nuts and seeds intake) was positively correlated with saturated fat and negatively with polyunsaturated fat and monounsaturated fat. DP2 was associated with slightly higher odds of elevated CVD risk (odds ratio, 1.04 [95% CI, 1.00–1.07]). DP1 was associated with higher diastolic blood pressure (β, 0.20 [95% CI, 0.01–0.37]) and lower cardiac index (β, −0.02 [95% CI, −0.04 to −0.01]) DP2 was associated with higher carotid intima medial thickness (β, 1.80 [95% CI, 0.01–3.59]) and lower left ventricular ejection fraction (β, −0.15 [95% CI, −0.24 to −0.07]) and cardiac index (β, −0.01 [95% CI, −0.02 to −0.01]). This study suggests small but statistically significant associations between DPs based on fat type and some early markers of CVD risk. Further research is needed to confirm these associations.
Publisher: Bioscientifica
Date: 11-2019
DOI: 10.1530/JOE-19-0067
Abstract: Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow, and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin-resistant rats. Sprague–Dawley rats were fed a normal (ND) or high-fat (HFD) diet for 4 weeks. A separate HFD group was given metformin in drinking water (HFD + MF, 150 mg/kg/day) during the final 2 weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-h euglycaemic–hyperinsulinaemic cl (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser 473 -AKT and Thr 172 -AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole-body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser 473 -AKT phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and free fatty acid concentrations and lowered body weight and adiposity. During euglycaemic-hyperinsulinaemic cl , metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser 473 -AKT phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr 172 -AMPK phosphorylation. We conclude that 2-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin-resistant rats.
Publisher: Wiley
Date: 14-06-2010
DOI: 10.1096/FJ.09-150177
Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: American Diabetes Association
Date: 06-2009
DOI: 10.2337/DC09-0206
Abstract: Ingestion of a mixed meal recruits flow to muscle capillaries and increases total forearm blood flow in healthy young lean people. We examined whether these vascular responses are blunted by obesity. We fed eight middle-aged lean and eight obese overnight-fasted volunteers a liquid mixed meal (480 kcal). Plasma glucose and insulin were measured every 30 min, and brachial artery flow and muscle microvascular recruitment (contrast ultrasound) were assessed every 60 min over 2 h after the meal. By 30 min, plasma glucose rose in both the lean (5.1 ± 0.1 vs. 6.7 ± 0.4 mmol/l, P & 0.05) and the obese groups (5.4 ± 0.2 vs. 6.7 ± 0.4 mmol/l, P & 0.05). Plasma insulin rose (28 ± 4 vs. 241 ± 30 pmol/l, P & 0.05) by 30 min in the lean group and remained elevated for 2 h. The obese group had higher fasting plasma insulin levels (65 ± 8 pmol/l, P & 0.001) and a greater postmeal area under the insulin-time curve (P & 0.05). Brachial artery flow was increased at 120 min after the meal in the lean group (38 ± 6 vs. 83 ± 16 ml/min, P & 0.05) but not in the obese group. Muscle microvascular blood volume rose by 120 min in the lean group (14.4 ± 2.2 vs. 24.4 ± 4.2 units, P & 0.05) but not in the obese group. A mixed meal recruits muscle microvasculature in lean subjects, and this effect is blunted by obesity. This impaired vascular recruitment lessens the endothelial surface available and may thereby impair postprandial glucose disposal.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2020
DOI: 10.1249/MSS.0000000000002463
Abstract: Whole-body vibration (WBV) therapy has been reported to potentially act as an exercise mimetic by improving muscle function and exercise capacity in a variety of healthy and clinical populations. Considering the important role that microvascular blood flow plays in muscle metabolism and exercise capacity, we investigated the muscle microvascular responses of acute WBV to knee extension exercise (KEX) in healthy in iduals. Eleven healthy adults (age: 33 ± 2 yr body mass index: 23.6 ± 1.1 kg·m −2 ) underwent 3 min of WBV, or 3 min of KEX at 25% of one-repetition maximum, in a randomized order separated by a minimum of 72 h. Femoral arterial blood flow was measured via Doppler ultrasound, and thigh muscle microvascular blood flow was measured via contrast-enhanced ultrasound at baseline and throughout the 3-min postintervention recovery period. Both WBV and KEX significantly increased peak microvascular blood flow (WBV, 5.6-fold KEX, 21-fold both P 0.05) during the 3-min recovery period. Despite a similar increase in femoral arterial blood flow (~4-fold both P 0.05 vs baseline) and whole-body oxygen consumption measured by indirect calorimetry (WBV, 48% KEX, 60% both P 0.05 vs baseline) in both conditions, microvascular blood flow was stimulated to a greater extent after KEX. A single 3-min session of WBV in healthy in iduals is sufficient to significantly enhance muscle microvascular blood flow. Despite KEX providing a more potent stimulus, WBV may be an effective method for improving microvascular blood flow in populations reported to exhibit microvascular dysfunction such as patients with type 2 diabetes.
Publisher: American Diabetes Association
Date: 05-2006
DOI: 10.2337/DB05-1373
Abstract: We have previously shown that skeletal muscle capillaries are rapidly recruited by physiological doses of insulin in both humans and animals. This facilitates glucose and insulin delivery to muscle, thus augmenting glucose uptake. In obese rats, both insulin-mediated microvascular recruitment and glucose uptake are diminished however, this action of insulin has not been studied in obese humans. Here we used contrast ultrasound to measure microvascular blood volume (MBV) (an index of microvascular recruitment) in the forearm flexor muscles of lean and obese adults before and after a 120-min euglycemic-hyperinsulinemic (1 mU · min−1 · kg−1) cl . We also measured brachial artery flow, fasting lipid profile, and anthropomorphic variables. Fasting plasma glucose (5.4 ± 0.1 vs. 5.1 ± 0.1 mmol/l, P = 0.05), insulin (79 ± 11 vs. 38 ± 6 pmol/l, P = 0.003), and percent body fat (44 ± 2 vs. 25 ± 2%, P = 0.001) were higher in the obese than the lean adults. After 2 h of insulin infusion, whole-body glucose infusion rate was significantly lower in the obese versus lean group (19.3 ± 3.2 and 37.4 ± 2.6 μmol · min−1 · kg−1 respectively, P & 0.001). Compared with baseline, insulin increased MBV in the lean (18.7 ± 3.3 to 25.0 ± 4.1, P = 0.019) but not in the obese group (20.4 ± 3.6 to 18.8 ± 3.8, NS). Insulin increased brachial artery diameter and flow in the lean but not in the obese group. We observed a significant, negative correlation between ΔMBV and BMI (R = −0.482, P = 0.027) in response to insulin. In conclusion, obesity eliminated the insulin-stimulated muscle microvascular recruitment and increased brachial artery blood flow seen in lean in iduals.
Publisher: Wiley
Date: 04-2005
DOI: 10.1111/J.1440-1681.2005.04188.X
Abstract: 1. In the 80+ years since insulin's discovery, an enormous amount of literature has accumulated relating to its actions on body fat, glucose and protein metabolism. In particular, skeletal muscle has been extensively studied because of its major role as a site of insulin-mediated glucose disposal. Liver and adipose tissue are two other extensively studied sites of insulin action. Much less investigation has been directed towards delineating insulin's actions on cells other than myocytes, adipocytes and hepatocytes. 2. Over the past 5-10 years it has become increasingly evident that insulin exerts important actions on vascular cells. Here, we review evidence that insulin's action within muscle may be very much regulated by its ability to transit the vasculature to access the interstitial fluid (and hence the myocyte insulin receptor). Surprisingly little is known regarding the regulation of vascular events that first bring insulin to the capillary endothelium within muscle, whence presumably it transits from the vascular to the interstitial space. Recent studies suggest that insulin can increase blood flow and also influence the distribution of blood flow within skeletal muscle, potentially therefore regulating its own delivery to the capillary endothelium. Beyond insulin's ability to access the vascular lumen within skeletal muscle microvasculature lies the issue of its passing the endothelial barrier. Even less is known about the processes involved in insulin's actual transit across the endothelium. Available data do not clearly indicate whether this is a saturable, receptor-mediated process or a passive-diffusion pathway. Also, whether insulin in any manner regulates its own transit across the endothelium or its clearance via the lymphatic system is entirely unknown. 3. The aim of the present review is to identify areas where knowledge is deficient and highlight hypotheses which may lead to a better understanding of the coordinated relationship between insulin's vascular actions within muscle and its metabolic actions in that tissue. Even so, there is now sufficient evidence to indicate that insulin's vascular action within skeletal muscle is a major regulatory locus for its insulin mediated glucose disposal.
Publisher: Wiley
Date: 15-11-2020
DOI: 10.1113/JP280651
Abstract: Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high‐glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism. We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high‐glucose mixed‐nutrient meal ingested 3 and 24 h post‐exercise. Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high‐glucose mixed meal ingested 3 h post‐exercise, and to a lesser extent 24 h post‐exercise. High‐glucose ingestion 3 h post‐exercise leads to greater postprandial blood glucose, non‐esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control. Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion lead to increased muscle microvascular blood flow (MBF), whereas high‐glucose ingestion impairs MBF. We investigated whether prior cycling exercise could enhance postprandial muscle MBF and prevent MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion. In a randomized cross‐over design, eight healthy young men ingested a high‐glucose mixed‐nutrient meal (1.1 g glucose/kg body weight 45% carbohydrate, 20% protein and 35% fat) after an overnight fast (no‐exercise control) and 3 h and 24 h after moderate‐intensity cycling exercise (1 h at 70–75% ). Skeletal muscle MBF, measured directly by contrast‐enhanced ultrasound, was lower at 60 min and 120 min postprandially compared to baseline in all conditions ( P 0.05), with a greater decrease occurring from 60 min to 120 min in the control (no‐exercise) condition only ( P 0.001). Despite this meal‐induced decrease, MBF was still markedly higher compared to control in the 3 h post‐exercise condition at 0 min (pre‐meal 74%, P = 0.004), 60 min (112%, P = 0.002) and 120 min (223%, P 0.001), and in the 24 h post‐exercise condition at 120 min postprandially (132%, P 0.001). We also report that in the 3 h post‐exercise condition postprandial blood glucose, non‐esterified fatty acids (NEFAs), and fat oxidation were substantially elevated, and the insulin response to the meal delayed compared to control. This probably reflects a combination of increased post‐exercise exogenous glucose appearance, substrate competition, and NEFA‐induced insulin resistance. We conclude that prior cycling exercise elicits long‐lasting effects on muscle MBF and partially mitigates MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion.
Publisher: American Physiological Society
Date: 03-2008
Publisher: Wiley
Date: 21-11-2020
Abstract: The matching of capillary blood flow to metabolic rate of the cells within organs and tissues is a critical microvascular function which ensures appropriate delivery of hormones and nutrients, and the removal of waste products. This relationship is particularly important in tissues where local metabolism, and hence capillary blood flow, must be regulated to avoid a mismatch between nutrient demand and supply that would compromise normal function. The consequences of a mismatch in microvascular blood flow and metabolism are acutely apparent in the brain and heart, where a sudden cessation of blood flow, for ex le following an embolism, acutely manifests as stroke or myocardial infarction. Even in more resilient tissues such as skeletal muscle, a short-term mismatch reduces muscle performance and exercise tolerance, and can cause intermittent claudication. In the longer-term, a microvascular-metabolic mismatch in skeletal muscle reduces insulin-mediated muscle glucose uptake, leading to disturbances in whole-body metabolic homeostasis. While the notion that capillary blood flow is fine-tuned to meet cellular metabolism is well accepted, the mechanisms that control this function and where and how different parts of the vascular tree contribute to capillary blood flow regulation remain poorly understood. Here, we discuss the emerging evidence implicating pericytes, mural cells that surround capillaries, as key mediators that match tissue metabolic demand with adequate capillary blood flow in a number of organs, including skeletal muscle.
Publisher: Oxford University Press (OUP)
Date: 05-09-2019
DOI: 10.1093/CVR/CVY225
Abstract: Angiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin’s microvascular and metabolic actions in skeletal muscle. Adult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic cl ), or insulin (hyperinsulinaemic euglycaemic cl ) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic cl ) infusion. In all animals’ systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic cl inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin’s effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake. Acute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin’s microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects.
Publisher: Elsevier BV
Date: 11-2001
Publisher: American Physiological Society
Date: 08-2018
DOI: 10.1152/AJPENDO.00448.2017
Abstract: Skeletal muscle microvascular (capillary) blood flow increases in the postprandial state or during insulin infusion due to dilation of precapillary arterioles to augment glucose disposal. This effect occurs independently of changes in large artery function. However, acute hyperglycemia impairs vascular function, causes insulin to vasoconstrict precapillary arterioles, and causes muscle insulin resistance in vivo. We hypothesized that acute hyperglycemia impairs postprandial muscle microvascular perfusion, without disrupting normal large artery hemodynamics, in healthy humans. Fifteen healthy people (5 F/10 M) underwent an oral glucose challenge (OGC, 50 g glucose) and a mixed-meal challenge (MMC) on two separate occasions (randomized, crossover design). At 1 h, both challenges produced a comparable increase (6-fold) in plasma insulin levels. However, the OGC produced a 1.5-fold higher increase in blood glucose compared with the MMC 1 h postingestion. Forearm muscle microvascular blood volume and flow (contrast-enhanced ultrasound) were increased during the MMC (1.3- and 1.9-fold from baseline, respectively, P 0.05 for both) but decreased during the OGC (0.7- and 0.6-fold from baseline, respectively, P 0.05 for both) despite a similar hyperinsulinemia. Both challenges stimulated brachial artery flow (ultrasound) and heart rate to a similar extent, as well as yielding comparable decreases in diastolic blood pressure and total vascular resistance. Systolic blood pressure and aortic stiffness remained unaltered by either challenge. Independently of large artery hemodynamics, hyperglycemia impairs muscle microvascular blood flow, potentially limiting glucose disposal into skeletal muscle. The OGC reduced microvascular blood flow in muscle peripherally and therefore may underestimate the importance of skeletal muscle in postprandial glucose disposal.
Publisher: Oxford University Press (OUP)
Date: 23-01-2013
DOI: 10.1093/CVR/CVT015
Abstract: Enhanced microvascular perfusion of skeletal muscle is important for nutrient exchange and contributes ∼40% insulin-mediated muscle glucose disposal. High fat-fed (36% fat wt./wt.) rats are a commonly used model of insulin-resistance that exhibit impairment of insulin-mediated microvascular recruitment and muscle glucose uptake, which is accompanied by myocyte insulin-resistance. Distinguishing the contribution of impaired microvascular recruitment and impaired insulin action in the myocyte to decreased muscle glucose uptake in these high-fat models is difficult. It is unclear whether microvascular and myocyte insulin-resistance develop simultaneously. To assess this, we used a rat diet model with a moderate increase (two-fold) in dietary fat. Sprague Dawley rats fed normal (4.8% fat wt./wt., 5FD) or high (9.0% fat wt./wt., 9FD) fat diets for 4 weeks were subject to euglycaemic hyperinsulinemic cl (10 mU/min/kg insulin or saline) or isolated hindlimb perfusion (1.5 or 15 nM insulin or saline). Body weight, epididymal fat mass, and fasting plasma glucose were unaffected by diet. Fasting plasma insulin and non-esterified fatty acid concentrations were significantly elevated in 9FD. Glucose infusion rate and muscle glucose uptake were significantly impaired during insulin cl s in 9FD. Insulin-stimulated microvascular recruitment was significantly blunted in 9FD. Insulin-mediated muscle glucose uptake between 5FD and 9FD were not different during hindlimb perfusion. Impaired insulin-mediated muscle glucose uptake in vivo can be the direct result of reduced microvascular blood flow responses to insulin, and can result from small (two-fold) increases in dietary fat. Thus, microvascular insulin-resistance can occur independently to the development of myocyte insulin-resistance.
Publisher: American Diabetes Association
Date: 06-2004
DOI: 10.2337/DIABETES.53.6.1418
Abstract: Insulin increases glucose disposal into muscle. In addition, in vivo insulin elicits distinct nitric oxide synthase-dependent vascular responses to increase total skeletal muscle blood flow and to recruit muscle capillaries (by relaxing resistance and terminal arterioles, respectively). In the current study, we compared the temporal sequence of vascular and metabolic responses to a 30-min physiological infusion of insulin (3 mU · min−1 · kg−1, euglycemic cl ) or saline in rat skeletal muscle in vivo. We used contrast-enhanced ultrasound to continuously quantify microvascular volume. Insulin recruited microvasculature within 5–10 min (P & 0.05), and this preceded both activation of insulin-signaling pathways and increases in glucose disposal in muscle, as well as changes in total leg blood flow. Moreover, l-NAME (Nω-nitro-l-arginine-methyl ester), a specific inhibitor of nitric oxide synthase, blocked this early microvascular recruitment (P & 0.05) and at least partially inhibited early increases in muscle glucose uptake (P & 0.05). We conclude that insulin rapidly recruits skeletal muscle capillaries in vivo by a nitric oxide-dependent action, and the increase in capillary recruitment may contribute to the subsequent glucose uptake.
Publisher: American Physiological Society
Date: 03-2008
Publisher: American Physiological Society
Date: 12-2018
DOI: 10.1152/AJPENDO.00234.2018
Abstract: The microcirculation in adipose tissue is markedly impaired in type 2 diabetes (T2D). Resistance training (RT) often increases muscle mass and promotes a favorable metabolic profile in people with T2D, even in the absence of fat loss. Whether the metabolic benefits of RT in T2D are linked to improvements in adipose tissue microvascular blood flow is unknown. Eighteen sedentary people with T2D (7 women/11 men, 52 ± 7 yr) completed 6 wk of RT. Before and after RT, overnight-fasted participants had blood s led for clinical chemistries (glucose, insulin, lipids, HbA1c, and proinflammatory markers) and underwent an oral glucose challenge (OGC 50 g glucose × 2 h) and a DEXA scan to assess body composition. Adipose tissue microvascular blood volume and flow were assessed at rest and 1 h post-OGC using contrast-enhanced ultrasound. RT significantly reduced fasting blood glucose ( P = 0.006), HbA1c ( P = 0.007), 2-h glucose area under the time curve post-OGC ( P = 0.014), and homeostatic model assessment of insulin resistance ( P = 0.005). This was accompanied by a small reduction in total body fat ( P = 0.002), trunk fat ( P = 0.023), and fasting triglyceride levels ( P = 0.029). Lean mass ( P = 0.003), circulating TNF-α ( P = 0.006), and soluble VCAM-1 ( P 0.001) increased post-RT. There were no significant changes in adipose tissue microvascular blood volume or flow following RT however those who did have a higher baseline microvascular blood flow post-RT also had lower fasting triglyceride levels ( r = −0.476, P = 0.045). The anthropometric, glycemic, and insulin-sensitizing benefits of 6 wk of RT in people with T2D are not associated with an improvement in adipose tissue microvascular responses however, there may be an adipose tissue microvascular-linked benefit to fasting triglyceride levels.
Publisher: Wiley
Date: 22-09-2021
DOI: 10.1002/EHF2.13620
Abstract: Weight excess and insulin resistance predispose to heart failure. High sodium consumption may contribute to the development of cardiac impairment in insulin‐resistant in iduals by promoting inadequate skeletal muscle microvascular perfusion response to insulin. We sought to investigate the association of dietary sodium reduction with muscle perfusion, insulin sensitivity, and cardiac function in overweight/obese insulin‐resistant (O‐IR) normotensive subjects. Fifty O‐IR in iduals with higher than recommended sodium intake were randomized to usual or reduced sodium diet for 8 weeks 25 lean, healthy subjects served as controls for pre‐intervention measurements. Echocardiography and muscle perfusion were performed during fasting and under stable euglycaemic–hyperinsulinaemic cl conditions. O‐IR patients demonstrated subclinical cardiac dysfunction as evidenced by lower left ventricular global longitudinal strain (GLS), e′ tissue velocity, and left atrial strain and reduced muscle perfusion. The intervention arm showed improvements in insulin resistance [glucose infusion rate (GIR)], GLS, e′, atrial strain, and muscle perfusion in fasting conditions, as well as improved responses of GLS and muscle perfusion to insulin during cl . Significant interactions were found between the allocation to low‐salt diet and improvement in muscle perfusion on change in GIR at follow‐up ( P = 0.030), and between improvement in muscle perfusion and change in GIR on change in GLS response to insulin at follow‐up ( P = 0.026). Mediation analysis revealed that the relationship between the reduction of sodium intake and improvement in GLS was mediated by improvements in muscle perfusion and GIR (decrease in beta coefficient from −0.29 to −0.16 after the inclusion of mediator variables to the model). The reduction of dietary sodium in the normotensive O‐IR population improves cardiac function, and this effect may be associated with the concomitant improvements in skeletal muscle perfusion and insulin resistance. These findings might contribute to refining heart failure preventive strategies.
Publisher: Springer Science and Business Media LLC
Date: 07-2003
DOI: 10.1007/S11892-003-0018-9
Abstract: Insulin has important vascular actions that regulate blood flow, in addition to its classical actions to coordinate glucose homeostasis. Insulin-stimulated production of nitric oxide in vascular endothelium results in capillary recruitment and vasodilation that erts and increases blood flow to skeletal muscle and consequently increases glucose disposal. Thus, vascular actions of insulin may be essential for coupling hemodynamic and metabolic homeostasis. A complete biochemical signaling pathway linking the insulin receptor to activation of endothelial nitric oxide synthase in vascular endothelium has recently been elucidated. Moreover, the time course and dose response for capillary recruitment in response to physiologic concentrations of insulin parallels that of insulin-mediated glucose uptake in vivo. Taken together, these observations suggest a molecular mechanism that may help to explain how insulin resistance contributes to cardiovascular components of the metabolic syndrome and vascular complications of diabetes.
Publisher: American Diabetes Association
Date: 2002
Abstract: Supraphysiological doses of insulin enhance total limb blood flow and recruit capillaries in skeletal muscle. Whether these processes change in response to physiological hyperinsulinemia is uncertain. To examine this, we infused either saline (n = 6) or insulin (euglycemic cl , 3.0 mU · min−1 · kg−1, n = 9) into anesthetized rats for 120 min. Femoral artery flow was monitored continuously using a Doppler flow probe, and muscle microvascular recruitment was assessed by metabolism of infused 1-methylxanthine (1-MX) and by contrast-enhanced ultrasound (CEU). Insulin infusion raised plasma insulin concentrations by ∼10-fold. Compared with saline, physiological hyperinsulinemia increased femoral artery flow (1.02 ± 0.10 vs. 0.68 ± 0.09 ml/min P & 0.05), microvascular recruitment (measured by 1-MX metabolism [6.6 ± 0.5 vs. 4.5 ± 0.48 nmol/min P & 0.05] as well as by CEU [167.0 ± 39.8 vs. 28.2 ± 13.8% P & 0.01]), and microvascular flow velocity (β, 0.14 ± 0.02 vs. 0.09 ± 0.02 s−1). Subsequently, we studied the time dependency of insulin’s vascular action in a second group (n = 5) of animals. Using CEU, microvascular volume was measured at 0, 30, and 90 min of insulin infusion. Insulin augmented microvascular perfusion within 30 min (52.8 ± 14.8%), and this persisted at 90 min (64.6 ± 9.9%). Microvascular recruitment occurred without changes to femoral artery flow or β. We conclude that insulin increases tissue perfusion by recruiting microvascular beds, and at physiological concentrations this precedes increases in total muscle blood flow by 60–90 min.
Publisher: Springer Science and Business Media LLC
Date: 22-07-2015
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 18-03-2021
DOI: 10.1038/S42255-021-00369-9
Abstract: Both obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we show that systemic alanine metabolism is linked to glycaemic control. We find that expression of alanine aminotransferases is increased in the liver in mice with obesity and diabetes, as well as in humans with type 2 diabetes. Hepatocyte-selective silencing of both alanine aminotransferase enzymes in mice with obesity and diabetes retards hyperglycaemia and reverses skeletal muscle atrophy through restoration of skeletal muscle protein synthesis. Mechanistically, liver alanine catabolism driven by chronic glucocorticoid and glucagon signalling promotes hyperglycaemia and skeletal muscle wasting. We further provide evidence for amino acid-induced metabolic cross-talk between the liver and skeletal muscle in ex vivo experiments. Taken together, we reveal a metabolic inter-tissue cross-talk that links skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.
Publisher: Wiley
Date: 09-1998
Publisher: American Physiological Society
Date: 11-2022
DOI: 10.1152/AJPENDO.00109.2022
Abstract: Adipose tissue blood flow plays a key role in postprandial nutrient storage. People at-risk of type 2 diabetes have impaired postmeal adipose tissue blood flow. Impaired adipose tissue blood flow is associated with altered fat oxidation. Risk of type 2 diabetes may be elevated by poor adipose tissue blood flow.
Publisher: American Diabetes Association
Date: 02-2004
DOI: 10.2337/DIABETES.53.2.447
Abstract: We have reported that insulin exerts two vascular actions in muscle it both increases blood flow and recruits capillaries. In parallel hyperinsulinemic-euglycemic cl studies, we compared the insulin dose response of muscle microvascular recruitment and femoral blood flow as well as hindleg glucose uptake in fed, hooded Wistar and fasted Sprague-Dawley rats. Using insulin doses between 0 and 30 mU−1 · min−1 · kg−1, we measured microvascular recruitment at 2 h by 1-methylxanthine (1-MX) metabolism or contrast-enhanced ultrasound (CEU), and muscle glucose uptake was measured by either arteriovenous differences or using 2-deoxyglucose. We also examined the time course for reversal of microvascular recruitment following cessation of a 3 mU · min−1 · kg−1 insulin infusion. In both groups, whether measured by 1-MX metabolism or CEU, microvascular recruitment was fully activated by physiologic hyperinsulinemia and occurred at lower insulin concentrations than those that stimulated glucose uptake or hindleg total blood flow. The latter processes were insulin dose dependent throughout the entire dose range studied. Upon stopping the insulin infusion, increases in microvascular volume persisted for 15–30 min after insulin concentrations returned to basal levels. We conclude that the precapillary arterioles that regulate microvascular recruitment are more insulin sensitive than resistance arterioles that regulate total flow.
Publisher: American Diabetes Association
Date: 17-01-2013
DOI: 10.2337/DB12-1193
Publisher: Springer Science and Business Media LLC
Date: 08-10-2015
DOI: 10.1038/JHH.2015.101
Abstract: Brachial-to-radial-systolic blood pressure lification (Bra-Rad-SBPAmp) can affect central SBP estimated by radial tonometry. Patients with type 2 diabetes mellitus (T2DM) have vascular irregularities that may alter Bra-Rad-SBPAmp. By comparing T2DM with non-diabetic controls, we aimed to determine the (1) magnitude of Bra-Rad-SBPAmp (2) haemodynamic factors related to Bra-Rad-SBPAmp and (3) effect of Bra-Rad-SBPAmp on estimated central SBP. Twenty T2DM (64±8 years) and 20 non-diabetic controls (60±8 years 50% male both) underwent simultaneous cuff deflation and two-dimensional ultrasound imaging of the brachial and radial arteries. The first Korotkoff sound (denoting SBP) was identified from the first inflection point of Doppler flow during cuff deflation. Bra-Rad-SBPAmp was calculated by radial minus brachial SBP. Upper limb and systemic haemodynamics were recorded by tonometry and ultrasound. Radial SBP was higher than brachial SBP for T2DM (136±19 vs 127±17 mm Hg P<0.001) and non-diabetic controls (135±12 vs 121±11 mm Hg P<0.001), but Bra-Rad-SBPAmp was significantly lower in T2DM (9±8 vs 14±7 mm Hg P=0.042). The product of brachial mean flow velocity × brachial diameter was inversely and independently correlated with Bra-Rad-SBPAmp in T2DM (β=-0.033 95% confidence interval -0.063 to -0.004, P=0.030). When radial waveforms were calibrated using radial, compared with brachial SBP, central SBP was significantly higher in both groups (T2DM, 116±13 vs 125±15 mm Hg and controls, 112±10 vs 124±11 mm Hg P<0.001 both) and there was a significant increase in the number of participants classified with 'central hypertension' (SBP⩾130 mm Hg P=0.004). Compared with non-diabetic controls, Bra-Rad-SBPAmp is significantly lower in T2DM. Regardless of disease status, radial SBP is higher than brachial SBP and this results in underestimation of central SBP using brachial-BP-calibrated radial tonometry.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2022
DOI: 10.1007/S00125-021-05572-7
Abstract: Microvascular blood flow (MBF) increases in skeletal muscle postprandially to aid in glucose delivery and uptake in muscle. This vascular action is impaired in in iduals who are obese or have type 2 diabetes. Whether MBF is impaired in normoglycaemic people at risk of type 2 diabetes is unknown. We aimed to determine whether apparently healthy people at risk of type 2 diabetes display impaired skeletal muscle microvascular responses to a mixed-nutrient meal. In this cross-sectional study, participants with no family history of type 2 diabetes (FH-) for two generations (n = 18), participants with a positive family history of type 2 diabetes (FH+ i.e. a parent with type 2 diabetes n = 16) and those with type 2 diabetes (n = 12) underwent a mixed meal challenge (MMC). Metabolic responses (blood glucose, plasma insulin and indirect calorimetry) were measured before and during the MMC. Skeletal muscle large artery haemodynamics (2D and Doppler ultrasound, and Mobil-O-graph) and microvascular responses (contrast-enhanced ultrasound) were measured at baseline and 1 h post MMC. Despite normal blood glucose concentrations, FH+ in iduals displayed impaired metabolic flexibility (reduced ability to switch from fat to carbohydrate oxidation vs FH- p < 0.05) during the MMC. The MMC increased forearm muscle microvascular blood volume in both the FH- (1.3-fold, p < 0.01) and FH+ (1.3-fold, p < 0.05) groups but not in participants with type 2 diabetes. However, the MMC increased MBF (1.9-fold, p < 0.01), brachial artery diameter (1.1-fold, p < 0.01) and brachial artery blood flow (1.7-fold, p < 0.001) and reduced vascular resistance (0.7-fold, p < 0.001) only in FH- participants, with these changes being absent in FH+ and type 2 diabetes. Participants with type 2 diabetes displayed significantly higher vascular stiffness (p < 0.001) compared with those in the FH- and FH+ groups however, vascular stiffness did not change during the MMC in any participant group. Normoglycaemic FH+ participants display impaired postprandial skeletal muscle macro- and microvascular responses, suggesting that poor vascular responses to a meal may contribute to their increased risk of type 2 diabetes. We conclude that vascular insulin resistance may be an early precursor to type 2 diabetes in humans, which can be revealed using an MMC.
Publisher: Wiley
Date: 02-2022
DOI: 10.1113/JP282428
Abstract: Insulin infusion increases skeletal muscle microvascular blood flow (MBF) in healthy people but is impaired during insulin resistance. However, we have shown that eliciting insulin secretion via oral glucose loading in healthy people impairs muscle MBF, whilst others have demonstrated intravenous glucose infusion stimulates MBF. We aimed to show that the route of glucose administration (oral versus intravenous) influences muscle MBF, and explore potential gut‐derived hormones that may explain these ergent responses. Ten healthy in iduals underwent a 120 min oral glucose tolerance test (OGTT 75 g glucose) and on a subsequent occasion an intravenous glucose tolerance test (IVGTT, bypassing the gut) matched for similar blood glucose excursions. Femoral artery and thigh muscle microvascular (contrast‐enhanced ultrasound) haemodynamics were measured at baseline and during the OGTT/IVGTT. Plasma insulin, C‐peptide, glucagon, non‐esterified fatty acids and a range of gut‐derived hormones and incretins (gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1(GLP‐1)) were measured at baseline and throughout the OGTT/IVGTT. The IVGTT increased whereas the OGTT impaired MBF (1.3‐fold versus 0.5‐fold from baseline, respectively, P = 0.0006). The impairment in MBF during the OGTT occurred despite producing 2.8‐fold higher plasma insulin concentrations ( P = 0.0001). The change in MBF from baseline (ΔMBF) negatively correlated with ΔGIP concentrations ( r = −0.665, P 0.0001). The natural log ratio of incretins GLP‐1:GIP was positively associated with ΔMBF ( r = 0.658, P 0.0001), suggesting they have opposing actions on the microvasculature. Postprandial hyperglycaemia per se does not acutely determine opposing microvascular responses between OGTT and IVGTT. Incretins may play a role in modulating skeletal muscle MBF in humans. Insulin or mixed nutrient meals stimulate skeletal muscle microvascular blood flow (MBF) to aid in the delivery of nutrients however, this vascular effect is lost during insulin resistance. Food/drinks containing large glucose loads impair MBF in healthy people however, this impairment is not observed when glucose is infused intravenously (bypassing the gut). We investigated skeletal muscle MBF responses to a 75 g oral glucose tolerance test and intravenous glucose infusion and aimed to identify potential gut hormones responsible for glucose‐mediated changes in MBF. Despite similar blood glucose concentrations, orally ingested glucose impaired, whereas intravenously infused glucose augmented, skeletal muscle MBF. The incretin gastric inhibitory polypeptide was negatively associated with MBF, suggestive of an incretin‐mediated MBF response to oral glucose ingestion. This work provides new insight into why diets high in glucose may be detrimental to vascular health and provides new avenues for novel treatment strategies targeting microvascular dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2022
DOI: 10.1038/S41387-022-00209-Z
Abstract: There is increasing evidence that skeletal muscle microvascular (capillary) blood flow plays an important role in glucose metabolism by increasing the delivery of glucose and insulin to the myocytes. This process is impaired in insulin-resistant in iduals. Studies suggest that in diet-induced insulin-resistant rodents, insulin-mediated skeletal muscle microvascular blood flow is impaired post-short-term high fat feeding, and this occurs before the development of myocyte or whole-body insulin resistance. These data suggest that impaired skeletal muscle microvascular blood flow is an early vascular step before the onset of insulin resistance. However, evidence of this is still lacking in humans. In this review, we summarise what is known about short-term high-calorie and/or high-fat feeding in humans. We also explore selected animal studies to identify potential mechanisms. We discuss future directions aimed at better understanding the ‘early’ vascular mechanisms that lead to insulin resistance as this will provide the opportunity for much earlier screening and timing of intervention to assist in preventing type 2 diabetes.
Publisher: Wiley
Date: 20-01-2020
Abstract: Skeletal muscle contributes to ~40% of total body mass and has numerous important mechanical and metabolic roles in the body. Skeletal muscle is a major site for glucose disposal following a meal. Consequently, skeletal muscle plays an important role in postprandial blood glucose homeostasis. Over the past number of decades, research has demonstrated that insulin has an important role in vasodilating the vasculature in skeletal muscle in response to an insulin infusion (hyperinsulinaemic-euglycaemic cl ) or following the ingestion of a meal. This vascular action of insulin is pivotal for glucose disposal in skeletal muscle, as insulin-stimulated vasodilation increases the delivery of both glucose and insulin to the myocyte. Notably, in insulin-resistant states such as obesity and type 2 diabetes, this vascular response of insulin in skeletal muscle is significantly impaired. Whereas the majority of work in this field has focussed on the action of insulin alone on skeletal muscle microvascular blood flow and myocyte glucose metabolism, there is less understanding of how the consumption of a meal may affect skeletal muscle blood flow. This is in part due to complex variations in glucose and insulin dynamics that occurs postprandially-with changes in humoral concentrations of glucose, insulin, amino acids, gut and pancreatic peptides-compared to the hyperinsulinaemic-euglycaemic cl . This review will address the emerging body of evidence to suggest that postprandial blood flow responses in skeletal muscle may be a function of the nutritional composition of a meal.
Publisher: American Physiological Society
Date: 12-2007
DOI: 10.1152/AJPENDO.00498.2007
Abstract: Acute physiological hyperinsulinemia increases skeletal muscle capillary blood volume (CBV), presumably to augment glucose and insulin delivery. We hypothesized that insulin-mediated changes in CBV are impaired in type 2 diabetes mellitus (DM) and are improved by angiotensin-converting enzyme inhibition (ACE-I). Zucker obese diabetic rats (ZDF, n = 18) and control rats ( n = 9) were studied at 20 wk of age. One-half of the ZDF rats were treated with quinapril (ZDF-Q) for 15 wk prior to study. CBV and capillary flow in hindlimb skeletal muscle were measured by contrast-enhanced ultrasound (CEU) at baseline and at 30 and 120 min after initiation of a euglycemic hyperinsulinemic cl (3 mU·min −1 ·kg −1 ). At baseline, ZDF and ZDF-Q rats were hyperglycemic and hyperinsulinemic vs. controls. Glucose utilization in ZDF rats was 60–70% lower ( P 0.05) than in controls after 30 and 120 min of hyperinsulinemia. In ZDF-Q rats, glucose utilization was impaired at 30 min but similar to controls at 120 min. Basal CBV was lower in ZDF and ZDF-Q rats compared with controls (13 ± 4, 7 ± 3, and 9 ± 2 U, respectively). With hyperinsulinemia, CBV increased by about twofold in control animals at 30 and 120 min, did not change in ZDF animals, and increased in ZDF-Q animals only at 120 min to a level similar to controls. Anatomic capillary density on immunohistology was not different between groups. We conclude that insulin-mediated capillary recruitment in skeletal muscle, which participates in glucose utilization, is impaired in animals with DM and can be partially reversed by chronic ACE-I therapy.
Publisher: Wiley
Date: 12-2014
Publisher: Wiley
Date: 23-03-2022
DOI: 10.1111/SMS.14155
Abstract: There is a universal need to increase the number of adults meeting physical activity (PA) recommendations to help improve health. In recent years, electrically assisted bicycles (e-bikes) have emerged as a promising method for supporting people to initiate and maintain physical activity levels. To the best of our knowledge, there have been no meta-analyses conducted to quantify the difference in physiological responses between e-cycling with electrical assistance, e-cycling without assistance, conventional cycling, and walking. A systematic review and meta-analysis was conducted following PRISMA guidelines. We identified short-term e-bike studies, which utilized a crossover design comparing physiological outcomes when e-cycling with electrical assistance, e-cycling without electrical assistance, conventional cycling, or walking. Energy expenditure (EE), heart rate (HR), oxygen consumption (VO Fourteen studies met our inclusion criteria (N = 239). E-cycling with electrical assistance resulted in a lower energy expenditure (EE) [SMD = -0.46 (-0.98, 0.06), p = 0.08], heart rate (HR) [MD = -11.41 (-17.15, -5.68), p < 0.000, beats per minute], oxygen uptake (VO E-cycling was associated with increased physiological responses that can confer health benefits.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.ULTRASMEDBIO.2017.05.012
Abstract: Most methods of assessing flowmotion (rhythmic oscillation of blood flow through tissue) are limited to small sections of tissue and are invasive in tissues other than skin. To overcome these limitations, we adapted the contrast-enhanced ultrasound (CEUS) technique to assess microvascular flowmotion throughout a large region of tissue, in a non-invasive manner and in real time. Skeletal muscle flowmotion was assessed in anaesthetised Sprague Dawley rats, using CEUS and laser Doppler flowmetry (LDF) for comparison. Wavelet transformation of CEUS and LDF data was used to quantify flowmotion. The α-adrenoceptor antagonist phentolamine was infused to predictably blunt the neurogenic component of flowmotion. Both techniques identified similar flowmotion patterns, validating the use of CEUS to assess flowmotion. This study demonstrates for the first time that the novel technique of CEUS can be adapted for determination of skeletal muscle flowmotion in large regions of skeletal muscle.
Publisher: Springer Science and Business Media LLC
Date: 07-2003
DOI: 10.1007/S11892-003-0018-9
Abstract: Insulin has important vascular actions that regulate blood flow, in addition to its classical actions to coordinate glucose homeostasis. Insulin-stimulated production of nitric oxide in vascular endothelium results in capillary recruitment and vasodilation that erts and increases blood flow to skeletal muscle and consequently increases glucose disposal. Thus, vascular actions of insulin may be essential for coupling hemodynamic and metabolic homeostasis. A complete biochemical signaling pathway linking the insulin receptor to activation of endothelial nitric oxide synthase in vascular endothelium has recently been elucidated. Moreover, the time course and dose response for capillary recruitment in response to physiologic concentrations of insulin parallels that of insulin-mediated glucose uptake in vivo. Taken together, these observations suggest a molecular mechanism that may help to explain how insulin resistance contributes to cardiovascular components of the metabolic syndrome and vascular complications of diabetes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2018
DOI: 10.1161/CIRCIMAGING.117.007074
Abstract: In obesity and type 2 diabetes mellitus (T2D), adipose tissue expansion (because of larger adipocytes) results in reduced microvascular density which is thought to lead to adipocyte hypoxia, inflammation, and reduced nutrient delivery to the adipocyte. Adipose tissue microvascular responses in humans with T2D have not been extensively characterized. Furthermore, it has not been determined whether impaired microvascular responses in human adipose tissue are most closely associated with adiposity, inflammation, or altered metabolism. Overnight-fasted healthy controls (n=24, 9 females/15 males) and people with T2D (n=21, 8 females/13 males) underwent a body composition scan (dual-energy X-ray absorptiometry), an oral glucose challenge (50 g glucose) and blood analysis of clinical chemistries and inflammatory markers. Abdominal subcutaneous adipose tissue microvascular responses were measured by contrast-enhanced ultrasound at baseline and 1-hour post-oral glucose challenge. Adipose tissue microvascular blood volume was significantly elevated in healthy subjects 1-hour post-oral glucose challenge however, this effect was absent in T2D. Adipose tissue microvascular blood flow was lower in people with T2D at baseline and was significantly blunted post-oral glucose challenge compared with controls. Adipose tissue microvascular blood flow was negatively associated with truncal fat (%), glucoregulatory function, fasting triglyceride and nonesterified fatty acid levels, and positively associated with insulin sensitivity. Truncal fat (%), systolic blood pressure, and insulin sensitivity were the only correlates with microvascular blood volume. Systemic inflammation was not associated with adipose tissue microvascular responses. Impaired microvascular function in adipose tissue during T2D is not conditionally linked to systemic inflammation but is associated with other characteristics of the metabolic syndrome (obesity, insulin resistance, hyperglycemia, and dyslipidemia).
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.JCMG.2014.12.033
Abstract: This study sought to investigate the association of exercise intolerance in type 2 diabetes (T2DM) with skeletal muscle capillary blood flow (CBF) reserve. Exercise intolerance in T2DM strongly predicts adverse prognosis, but associations with muscle blood flow independent of cardiac dysfunction are undefined. In 134 T2DM patients without cardiovascular disease, left ventricular function and contrast-enhanced ultrasound of the quadriceps (for CBF i.e., product of capillary blood volume and velocity) were assessed at rest and immediately following treadmill exercise for peak oxygen uptake (Vo2peak). Left ventricular systolic and diastolic functional reserve indexes were derived from changes in systolic and early diastolic color tissue Doppler velocities. Cardiac index reserve and its constituents (stroke volume and chronotropic indexes) and left ventricular filling pressure (ratio of early diastolic mitral inflow and annular velocities) were also measured. Vo2peak correlated with muscle CBF reserve (β = 0.16, p = 0.005) independent of cardiac index reserve and clinical covariates. This was explained by higher muscle capillary blood velocity reserve (β = 0.18, p = 0.002), rather than blood volume reserve (p > 0.10) in patients with higher Vo2peak. A concurrent association of Vo2peak with cardiac index reserve (β = 0.20, p 0.10), although the systolic functional reserve index was also identified as an independent correlate (β = 0.16, p = 0.028). No associations of Vo2peak with diastolic functional reserve were identified (p > 0.10). Vo2peak is associated with muscle CBF reserve in T2DM, independent of parallel associations with cardiac functional reserve. This is consistent with a multifactorial basis for exercise intolerance in T2DM.
Publisher: Elsevier BV
Date: 2001
Publisher: American Physiological Society
Date: 02-2003
DOI: 10.1152/AJPENDO.00408.2002
Abstract: The vascular system controls the delivery of nutrients and hormones to muscle, and a number of hormones may act to regulate muscle metabolism and contractile performance by modulating blood flow to and within muscle. This review examines evidence that insulin has major hemodynamic effects to influence muscle metabolism. Whole body, isolated hindlimb perfusion studies and experiments with cell cultures suggest that the hemodynamic effects of insulin emanate from the vasculature itself and involve nitric oxide-dependent vasodilation at large and small vessels with the purpose of increasing access for insulin and nutrients to the interstitium and muscle cells. Recently developed techniques for detecting changes in microvascular flow, specifically capillary recruitment in muscle, indicate this to be a key site for early insulin action at physiological levels in rats and humans. In the absence of increases in bulk flow to muscle, insulin may act to switch flow from nonnutritive to the nutritive route. In addition, there is accumulating evidence to suggest that insulin resistance of muscle in vivo in terms of impaired glucose uptake could be partly due to impaired insulin-mediated capillary recruitment. Exercise training improves insulin-mediated capillary recruitment and glucose uptake by muscle.
Publisher: American Physiological Society
Date: 06-2006
DOI: 10.1152/AJPENDO.00497.2005
Abstract: Intense exercise and insulin each increases total limb blood flow and recruits muscle capillaries, presumably to facilitate nutrient exchange. Whether mixed meals or light exercise likewise recruits capillaries is unknown. We fed 18 (9 M, 9 F) healthy volunteers a 480-kcal liquid mixed meal. Plasma glucose, insulin, brachial artery flow, and forearm muscle microvascular blood volume were measured before and after the meal. Brachial artery flow and microvascular volume were also examined with light (25% max), moderate (50%), and heavy (80%) forearm contraction every 20 s in 5 (4 M, 1 F) healthy adults. After the meal, glucose and insulin rose modestly (to ∼7 mM and ∼270 pM) and peaked by 30 min, whereas brachial artery blood flow ( P 0.05) and the microvascular volume ( P 0.01) each increased significantly by 60 min, and microvascular flow velocity did not change. For exercise, both 50 and 80%, but not 25% maximal handgrip, increased average forearm and brachial artery blood flow ( P 0.01). Flow increased immediately after each contraction and declined toward basal over 15 s. Exercise at 25% max increased microvascular volume threefold ( P 0.01) without affecting microvascular flow velocity or total forearm blood flow. Forearm exercise at 80% maximal grip increased both microvascular volume and microvascular flow velocity ( P 0.05 each). We conclude that light exercise and simple meals each markedly increases muscle microvascular volume, thereby expanding the endothelial surface for nutrient exchange, and that capillary recruitment is an important physiological response to facilitate nutrient/hormone delivery in healthy humans.
Publisher: Wiley
Date: 04-2000
DOI: 10.1046/J.1365-201X.2000.00704.X
Abstract: There is growing evidence to support the notion of two vascular routes within, or closely associated with skeletal muscle. One route is in intimate contact with muscle cells (hence is known as 'nutritive') and the other functions as a vascular shunt (and has had the interesting misnomer of 'non-nutritive'). Recent findings suggest that the 'non-nutritive' route may, in part, be those vessels in closely associated (interlacing?) connective tissue that nourishes attached fat cells, and may form the basis of 'marbling' of muscle in obesity. In addition, embolism studies using various size microspheres indicate that the 'non-nutritive' vessels are likely to be capillaries fed by terminal arterioles that branch from the same transverse arterioles as those supplying terminal arterioles of the muscle capillaries (i.e. two vascular systems operating in parallel). The proportion of flow distributed between the two routes is tightly regulated and controls muscle metabolism and contraction by regulating hormone and substrate delivery as well as product removal. Because a high proportion of nutritive flow may elevate the set point for basal metabolism, a low proportion of nutritive flow in muscle at rest confers an evolutionary advantage, particularly when food is scarce. In addition, the proportion of flow that is carried by the non-nutritive routes at rest affords a flow reserve that can be switched to the nutritive route to lify nutrient supply during exercise. Alternatively the non-nutritive route may allow flow to escape when active muscle contraction compresses its nutritive capillaries. Thus rhythmic oscillation of blood flow between the non-nutritive and nutritive networks may aid the muscle pump.
Publisher: Wiley
Date: 23-07-2010
DOI: 10.1111/J.1463-1326.2010.01235.X
Abstract: The aetiology of the development of type 2 diabetes remains unresolved. In the present study, we assessed whether an impairment of insulin-mediated microvascular perfusion occurs early in the onset of insulin resistance. Hooded Wistar rats were fed either a normal diet (ND) or a high-fat diet (HFD) for 4 weeks. Anaesthetized animals were subjected to an isoglycaemic hyperinsulinaemic cl (3 or 10 mU/min/kg x 2 h), and measurements were made of glucose infusion rate (GIR), hindleg glucose uptake, muscle glucose uptake by 2-deoxy-d-glucose (R'g), glucose appearance (Ra), glucose disappearance (Rd), femoral blood flow (FBF) and hindleg 1-methylxanthine disappearance (1-MXD, an index of microvascular perfusion). Compared with ND-fed animal, HFD feeding led to a mild increase in fasting plasma glucose and plasma insulin, without an increase in total body weight. During the cl s, HFD rats showed an impairment of insulin-mediated action on GIR, hindleg glucose uptake, R'g, Ra, Rd and FBF, with a greater loss of insulin responsiveness at 3 mU/min/kg than at 10 mU/min/kg. The HFD also impaired insulin-mediated microvascular perfusion as assessed by 1-MXD. Interestingly, 1-MXD was the only measurement that remained unresponsive to the higher dose of 10 mU/min/kg insulin. We conclude that the early stage of insulin resistance is characterized by an impairment of the insulin-mediated microvascular responses in skeletal muscle. This is likely to cause greater whole body insulin resistance by limiting the delivery of hormones and nutrients to muscle.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: MDPI AG
Date: 13-06-2018
DOI: 10.3390/NU10060758
Publisher: American Physiological Society
Date: 11-2018
DOI: 10.1152/AJPHEART.00232.2018
Abstract: Peripheral arterial disease (PAD) is characterized by stenosis and occlusion of the lower limb arteries. Although leg blood flow is limited in PAD, it remains unclear whether skeletal muscle microvascular perfusion is affected. We compared whole leg blood flow and calf muscle microvascular perfusion after cuff occlusion and submaximal leg exercise between patients with PAD ( n = 12, 69 ± 9 yr) and healthy age-matched control participants ( n = 12, 68 ± 7 yr). Microvascular blood flow (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after the following: 1) 5 min of thigh-cuff occlusion, and 2) a 5-min bout of intermittent isometric plantar-flexion exercise (400 N) using real-time contrast-enhanced ultrasound. Whole leg blood flow was measured after thigh-cuff occlusion and during submaximal plantar-flexion exercise using strain-gauge plethysmography. Postocclusion whole leg blood flow and calf muscle microvascular perfusion were lower in patients with PAD than control participants, and these parameters were strongly correlated ( r = 0.84, P 0.01). During submaximal exercise, total whole leg blood flow and vascular conductance were not different between groups. There were also no group differences in postexercise calf muscle microvascular perfusion, although microvascular blood volume was higher in patients with PAD than control participants (12.41 ± 6.98 vs. 6.34 ± 4.98 arbitrary units, P = 0.03). This study demonstrates that the impaired muscle perfusion of patients with PAD during postocclusion hyperemia is strongly correlated with disease severity and is likely mainly determined by the limited conduit artery flow. In response to submaximal leg exercise, microvascular flow volume was elevated in patients with PAD, which may reflect a compensatory mechanism to maintain muscle perfusion and oxygen delivery during recovery from exercise. NEW & NOTEWORTHY This study suggests that peripheral arterial disease (PAD) has different effects on the microvascular perfusion responses to cuff occlusion and submaximal leg exercise. Patients with PAD have impaired microvascular perfusion after cuff occlusion, similar to that previously reported after maximal exercise. In response to submaximal exercise, however, the microvascular flow volume response was elevated in patients with PAD compared with control. This finding may reflect a compensatory mechanism to maintain perfusion and oxygen delivery during recovery from exercise.
Publisher: Wiley
Date: 12-01-2015
Publisher: American Diabetes Association
Date: 07-07-2017
DOI: 10.2337/DC16-2750
Abstract: Insulin increases glucose disposal in part by enhancing microvascular blood flow (MBF) and substrate delivery to myocytes. Insulin’s microvascular action is impaired with insulin resistance and type 2 diabetes. Resistance training (RT) improves glycemic control and insulin sensitivity, but whether this improvement is linked to augmented skeletal muscle microvascular responses in type 2 diabetes is unknown. Seventeen (11 male and 6 female 52 ± 2 years old) sedentary patients with type 2 diabetes underwent 6 weeks of whole-body RT. Before and after RT, participants who fasted overnight had clinical chemistries measured (lipids, glucose, HbA1c, insulin, and advanced glycation end products) and underwent an oral glucose challenge (OGC) (50 g × 2 h). Forearm muscle MBF was assessed by contrast-enhanced ultrasound, skin MBF by laser Doppler flowmetry, and brachial artery flow by Doppler ultrasound at baseline and 60 min post-OGC. A whole-body DEXA scan before and after RT assessed body composition. After RT, muscle MBF response to the OGC increased, while skin microvascular responses were unchanged. These microvascular adaptations were accompanied by improved glycemic control (fasting blood glucose, HbA1c, and glucose area under the curve [AUC] during OGC) and increased lean body mass and reductions in fasting plasma triglyceride, total cholesterol, advanced glycation end products, and total body fat. Changes in muscle MBF response after RT significantly correlated with reductions in fasting blood glucose, HbA1c, and OGC AUC with adjustment for age, sex, % body fat, and % lean mass. RT improves OGC-stimulated muscle MBF and glycemic control concomitantly, suggesting that MBF plays a role in improved glycemic control from RT.
Publisher: Frontiers Media SA
Date: 22-06-2021
DOI: 10.3389/FENDO.2021.692677
Abstract: Body composition (fat, skeletal muscle and bone mass) is an important determinant of overall health and risk of endocrine disorders such as type 2 diabetes and osteoporosis. Although diet and physical activity are strongly implicated, body composition is also heritable. We conducted a discovery genome-wide association study on 31 phenotypes from the three-compartment body composition model (fat, lean and bone mass) in a set of 4 386 in iduals (n = 2 109 males, n = 2 294 females) from the UK Biobank pilot imaging enhancement program that underwent a dual energy X-ray absorptiometry (DXA) scan for assessment of body composition and genetic screening. From 6 137 607 imputed single nucleotide polymorphisms (SNPs) we identified 17 body composition loci (P& .0 x 10-8). GWAS from the combined dataset identified four statistically significant SNPs (rs7592270, rs145972737, rs13212044, rs77772562). In sex-stratified GWAS, 10 male specific SNPs across all traits were identified and five female specific SNPs. Of the 17 SNPs, six were in or close to a gene where there was a plausible functional connection. Three SNPs (rs7592270, rs77772562 and rs7552312) were correlated with obesity phenotypes, one SNP (rs2236705) with lean phenotypes and two with bone mass phenotypes (rs112098641 and rs113380185). These results highlight candidate genes and biological pathways related to body composition, including glucose metabolism and estrogen regulation, that are of interest to replicate in future studies.
Publisher: American Physiological Society
Date: 07-2003
DOI: 10.1152/AJPENDO.00021.2003
Abstract: We examined the effects of inhibiting nitric oxide synthase with N ω -nitro-l-arginine-methyl ester (l-NAME) on total hindlimb blood flow, muscle microvascular recruitment, and hindlimb glucose uptake during euglycemic hyperinsulinemia in vivo in the rat. We used two independent methods to measure microvascular perfusion. In one group of animals, microvascular recruitment was measured using the metabolism of exogenously infused 1-methylxanthine (1-MX), and in a second group contrast-enhanced ultrasound (CEU) was used. Limb glucose uptake was measured by arterial-venous concentration differences after 2 h of insulin infusion. Saline alone did not alter femoral artery flow, glucose uptake, or 1-MX metabolism. Insulin (10 mU·min -1 ·kg -1 ) significantly increased hindlimb total blood flow (0.69 ± 0.02 to 1.22 ± 0.11 ml/min, P 0.05), glucose uptake (0.27 ± 0.05 to 0.95 ± 0.08 μmol/min, P 0.05), 1-MX uptake (5.0 ± 0.5 to 8.5 ± 1.0 nmol/min, P 0.05), and skeletal muscle microvascular volume measured by CEU (10.0 ± 1.6 to 15.0 ± 1.2 video intensity units, P 0.05). Addition of l-NAME to insulin completely blocked the effect of insulin on both total limb flow and microvascular recruitment (measured using either 1-MX or CEU) and blunted glucose uptake by 40% ( P 0.05). We conclude that insulin specifically recruits flow to the microvasculture in skeletal muscle via a nitric oxide-dependent pathway and that this may be important to insulin's overall action to regulate glucose disposal.
Publisher: Wiley
Date: 12-2014
Publisher: Wiley
Date: 24-02-2015
Publisher: Springer Science and Business Media LLC
Date: 26-10-2017
DOI: 10.1038/S41598-017-14114-4
Abstract: Type 2 diabetes is a chronic metabolic disorder that is becoming a leading cause of morbidity and mortality. The prolonged time-course of human type 2 diabetes makes modelling of the disease difficult and additional animal models and methodologies are needed. The goal of this study was to develop and characterise a new method that allows controlled, targeted and sustained induction of discrete stages of type 2 diabetes in rodents. Using adult, male rats, we employed a three-week high fat-diet regimen and confirmed development of obesity-associated glucose intolerance, a key feature of human type 2 diabetes. Next, we utilised osmotic mini-pumps to infuse streptozotocin (STZ doses ranging 80–200 mg/kg) over the course of 14-days to decrease insulin-producing capacity thus promoting hyperglycemia. Using this new approach, we demonstrate a dose-dependent effect of STZ on circulating glucose and insulin levels as well as glucose tolerance, while retaining a state of obesity. Importantly, we found that insulin secretion in response to a glucose load was present, but reduced in a dose-dependent manner by increasing STZ. In conclusion, we demonstrate a novel method that enables induction of discrete stages of type 2 diabetes in rodents that closely mirrors the different stages of type 2 diabetes in humans.
Publisher: American Physiological Society
Date: 09-2022
DOI: 10.1152/AJPENDO.00025.2022
Abstract: We provide novel evidence that OGN and LCN2 decrease 120 min after ingesting a high-glucose mixed-nutrient meal in healthy adults. Acute aerobic exercise increases circulating LCN2 for up to 3-h postexercise, whereas circulating OGN remains similar to baseline. Despite differing postexercise responses, postprandial LCN2 and OGN are elevated when the high-glucose meal is ingested 3-h and 24-h postexercise. Findings support that OGN and LCN2 are dynamically linked to energy homeostasis in humans.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.JNUTBIO.2016.10.005
Abstract: Epidemiological studies show a dose-dependent relationship between green tea consumption and reduced risk for type 2 diabetes and cardiovascular disease. Bioactive compounds in green tea including the polyphenol epigallocatechin 3-gallate (EGCG) have insulin-mimetic actions on glucose metabolism and vascular function in isolated cell culture studies. The aim of this study is to explore acute vascular and metabolic actions of EGCG in skeletal muscle of Sprague-Dawley rats. Direct vascular and metabolic actions of EGCG were investigated using surgically isolated constant-flow perfused rat hindlimbs. EGCG infused at 0.1, 1, 10 and 100 μM in 15 min step-wise increments caused dose-dependent vasodilation in 5-hydroxytryptamine pre-constricted hindlimbs. This response was not impaired by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin or the AMP-kinase inhibitor Compound C. The nitric oxide synthase (NOS) inhibitor N
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2015
Publisher: Wiley
Date: 2004
DOI: 10.1002/DMRR.414
Abstract: Whether a discrete vascular action of insulin in skeletal muscle integrally participates in insulin-mediated glucose disposal has been extensively examined but remains a contentious issue. Here, we review some of the data both supporting and questioning the role of insulin-mediated increases in limb blood flow in glucose metabolism. We advance the hypothesis that controversy has arisen, at least in part, from a failure to recognize that insulin exerts at least three separate actions on the peripheral vasculature, each with its own characteristic dose and time responsiveness. We summarize how, viewed in this manner, certain points of contention can be resolved. We also advance the hypothesis that an action on the precapillary arteriole may play the dominant role in mediating perfusion-dependent effects of insulin on glucose metabolism in muscle.
Publisher: Frontiers Media SA
Date: 13-08-2019
Start Date: 2018
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2018
Funder: Royal Hobart Hospital Research Foundation
View Funded ActivityStart Date: 2017
End Date: 2017
Funder: University of Texas Rio Grande Valley
View Funded ActivityStart Date: 2021
End Date: 2024
Funder: Diabetes Australia
View Funded ActivityStart Date: 2020
End Date: 2021
Funder: National Heart Foundation of Australia
View Funded ActivityStart Date: 2012
End Date: 2012
Funder: The Select Foundation
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: National Health & Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2013
Funder: Fruit Growers Tasmania Inc
View Funded ActivityStart Date: 2008
End Date: 12-2010
Amount: $390,000.00
Funder: Australian Research Council
View Funded Activity