ORCID Profile
0000-0002-5988-0423
Current Organisation
University of Tasmania
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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: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.MVR.2007.11.002
Abstract: Contrast-enhanced ultrasound (CEU) has been used to measure muscle microvascular perfusion in vivo in response to exercise and insulin. In the present study we address whether CEU measurement of capillary volume is influenced by bulk flow and if measured capillary filling rate allows discrimination of different flow pattern changes within muscle. Three in vitro models were used: (i) bulk flow rate was varied within a single length of capillary tubing (ii) at constant bulk flow, capillary volume was increased 3-fold by joining lengths of capillary in series, and compared to a single length and (iii) at constant bulk flow, capillary volume was increased by sharing flow between a number of lengths of identical capillaries in parallel. The contrast medium for CEU was gas-filled albumin microbubbles. Pulsing interval (time) versus acoustic-intensity curves were constructed and from these, capillary volume and capillary filling rate were calculated. CEU estimates of capillary volume were not affected by changes in bulk flow. Furthermore, as CEU estimates of capillary volume increased, measures of capillary filling rate decreased, regardless of whether capillaries were connected in series or parallel. Therefore, CEU can detect a change in filling rate of the microvascular volume under measurement, but it can not be used to discriminate between different flow patterns within muscle that might account for capillary recruitment in vivo.
Publisher: American Physiological Society
Date: 08-2011
DOI: 10.1152/AJPENDO.00691.2010
Abstract: There is considerable support for the concept that insulin-mediated increases in microvascular blood flow to muscle impact significantly on muscle glucose uptake. Since the microvascular blood flow increases with insulin have been shown to be nitric oxide-dependent inhibition of cGMP-degrading phosphodiesterases (cGMP PDEs) is predicted to enhance insulin-mediated increases in microvascular perfusion and muscle glucose uptake. Therefore, we studied the effects of the pan-cGMP PDE inhibitor zaprinast on the metabolic and vascular actions of insulin in muscle. Hyperinsulinemic euglycemic cl s (3 mU·min −1 ·kg −1 ) were performed in anesthetized rats and changes in microvascular blood flow assessed from rates of 1-methylxanthine metabolism across the muscle bed by capillary xanthine oxidase in response to insulin and zaprinast. We also characterized cGMP PDE isoform expression in muscle by real-time PCR and immunostaining of frozen muscle sections. Zaprinast enhanced insulin-mediated microvascular perfusion by 29% and muscle glucose uptake by 89%, while whole body glucose infusion rate during insulin infusion was increased by 33% at 2 h. PDE2, -9, and -10 were the major isoforms expressed at the mRNA level in muscle, while PDE1B, -9A, -10A, and -11A proteins were expressed in blood vessels. Acute administration of the cGMP PDE inhibitor zaprinast enhances muscle microvascular blood flow and glucose uptake response to insulin. The expression of a number of cGMP PDE isoforms in skeletal muscle suggests that targeting specific cGMP PDE isoforms may provide a promising avenue for development of a novel class of therapeutics for enhancing muscle insulin sensitivity.
Publisher: Springer Science and Business Media LLC
Date: 10-2009
DOI: 10.1007/S10886-009-9702-9
Abstract: Papyriferic acid (PA) is a triterpene that is secreted by glands on twigs of the juvenile ontogenetic phase of resin producing tree birches (e.g., Betula neoalaskana, B. pendula) and that deters browsing by mammals such as the snowshoe hare (Lepus americanus). We investigated the pharmacology of PA as a first step in understanding its antifeedant effect. After oral administration to rats, PA and several metabolites were found in feces but not urine, indicating that little was absorbed systemically. Metabolism involved various combinations of hydrolysis of its acetyl and malonyl ester groups, and hydroxylation of the terpene moiety. The presence of a malonyl group suggested a possible interaction with succinate dehydrogenase (SDH), a mitochondrial enzyme known to be competitively inhibited by malonic acid. The effect of PA on the oxidation of succinate by SDH was examined in mitochondrial preparations from livers of ox, rabbit, and rat. In all three species, PA was a potent inhibitor of SDH. Kinetic analysis indicated that, unlike malonate, PA acted by an uncompetitive mechanism, meaning that it binds to the enzyme-substrate complex. The hydrolysis product of PA, betulafolienetriol oxide, was inactive on SDH. Overall, the evidence suggests that PA acts as the intact molecule and interacts at a site other than the succinate binding site, possibly binding to the ubiquinone sites on complex II. Papyriferic acid was potent (K(iEIS) ranged from 25 to 45 microM in the three species) and selective, as malate dehydrogenase was unaffected. Although rigorous proof will require further experiments, we have a plausible mechanism for the antifeedant effect of PA: inhibition of SDH in gastrointestinal cells decreases mitochondrial energy production resulting in a noxious stimulus, 5-HT release, and sensations of nausea and discomfort. There is evidence that the co-evolution of birches and hares over a large and geographically- erse area in Northern Europe and America has produced marked differences in the formation of PA by birches, and the tolerance of hares to dietary PA. The present findings on the metabolic fate and biochemical effects of PA provide a rational basis for investigating the mechanisms underlying differences among populations of hares in their tolerance of a PA-rich diet.
Publisher: Wiley
Date: 14-11-2007
Publisher: Georg Thieme Verlag KG
Date: 11-2005
Abstract: A recent report indicates that the Na+-D-glucose cotransporter SGLT1 is present in capillaries of skeletal muscle and is required for insulin-mediated glucose uptake in myocytes. This result is based on the complete inhibition of insulin-mediated muscle glucose uptake by phlorizin, an inhibitor of SGLT1. Using the pump-perfused rat hind limb, we measured glucose uptake, lactate efflux, and radioactive 2-deoxyglucose uptake into in idual muscles with saline (control), phlorizin, insulin, and insulin plus phlorizin, as well as with saline and insulin using normal and low Na+ perfusion buffer. Insulin-mediated glucose uptake was not inhibited after correction for phlorizin interference in the glucose assay. Lactate efflux and 2-deoxyglucose uptake by in idual muscles were unaffected by phlorizin. Low Na+ buffer did not affect insulin-mediated glucose uptake, lactate efflux, or 2-deoxyglucose uptake. We conclude that endothelial SGLT1 exerts no barrier for glucose delivery to myocytes.
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: 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: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2005
DOI: 10.1161/01.HYP.0000173069.53699.D9
Abstract: Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II–mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20% 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (≈45% reduction in dP/dt max and dP/dt min at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca 2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.
Publisher: Wiley
Date: 25-01-2007
DOI: 10.1111/J.1440-1681.2007.04575.X
Abstract: 1. The present study examined the potential for reduced exercise capacity observed in hypertensive patients as a result of elevated levels of endothelin (ET)-1. We have previously reported that ET-1 exerts low-dose stimulatory or high-dose inhibitory effects on the metabolism of the rat isolated perfused hindlimb from its vasoconstrictor activity. 2. Herein, we determined whether there are similar effects on tension development by the rat isolated constant-flow hindlimb during ET-1-mediated vasoconstriction. 3. The dose-dependent vasoconstrictor effects of ET-1 on metabolism in contracting muscle were the same as those observed previously in resting muscle. Highest concentrations of ET-1 gave rise to a transient stimulation followed by a marked inhibition of tension development, consistent with a decrease in aerobic capacity of the muscle. The vasoconstriction due to the higher doses of ET-1 was not dilated by electrical stimulation. 4. In conclusion, the biphasic nature of the actions of ET-1 suggests that although lower concentrations of ET-1 do not affect exercise capacity, higher concentrations that may occur in hypertension are inhibitory to metabolism and aerobic capacity of muscle. The inhibitory effects of ET-1 appear to result from enhanced functional shunting.
Publisher: BMJ
Date: 09-2008
Abstract: To examine whether the inverse association between birth weight and blood pressure varies by skin pigmentation and/or related genotypes. 671 children from a predominantly caucasian birth cohort were followed-up to adolescence (mean (SD) age 14.4 (0.64)). Data on birth weight, socioeconomic status, maternal antenatal smoking, adolescent blood pressure and polymorphisms of candidate genes were obtained and analysed by multiple linear regression. An increase in birth weight of 1 kg was associated with an non-significant difference in adolescent systolic blood pressure of -0.53 mm Hg (95% CI -1.72 to 0.66) per kg after adjustment for child age and cohort entry criteria. The inverse association between birth weight and systolic blood pressure was stronger for those with darker skin (> or =2% melanin) (difference in effect, p = 0.02), those with more copies of the C allele of corticotropin-releasing hormone (CRH) +T1273C (p = 0.06), and those with more copies of the short (< or =236 bp) form of the 11beta-HSD2{CA}n(repeat) microsatellite (p = 0.03). These findings add to the evidence that cortisol-related pathways may account for at least part of the observed birth weight-blood pressure associations.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2005
DOI: 10.1007/S00125-005-1887-Z
Abstract: Glucose toxicity and glucosamine-induced insulin resistance have been attributed to products of glucosamine metabolism. In addition, endothelial cell nitric oxide synthase is inhibited by glucosamine. Since insulin has endothelial nitric-oxide-dependent vasodilatory effects in muscle, we hypothesise that glucosamine-induced insulin resistance in muscle in vivo is associated with impaired vascular responses including capillary recruitment. Glucosamine (6.48 mg kg(-1) min(-1) for 3 h) was infused with or without insulin (10 mU kg(-1) min(-1)) into anaesthetised rats under euglycaemic conditions. Glucosamine infusion alone increased blood glucosamine (1.9+/-0.1 mmol/l) and glucose (5.4+/-0.2 to 7.7+/-0.3 mmol/l) (p<0.05) but not insulin. Glucosamine induced both hepatic and muscle insulin resistance as evident from measures of glucose appearance and disposal as well as hind-leg glucose uptake, which was inhibited by approx. 50% (p<0.05). Insulin-mediated increases in femoral arterial blood flow and capillary recruitment were completely blocked by glucosamine. Glucosamine mediates a major impairment of insulin action in muscle vasculature associated with the insulin resistance of muscle. Further studies will be required to assess whether the impaired capillary recruitment contributes to insulin resistance.
Publisher: Wiley
Date: 12-2003
Publisher: Portland Press Ltd.
Date: 13-03-2007
DOI: 10.1042/CS20060311
Abstract: Insulin increases capillary recruitment in vivo and impairment of this may contribute to muscle insulin resistance by limiting either insulin or glucose delivery. In the present study, the effect of progressively decreased rat muscle perfusion on insulin action using graded occlusion with MS (microspheres 15 μm in diameter) was examined. EC (energy charge), PCr/Cr (phosphocreatine/creatine ratio), AMPK (AMP-activated protein kinase) phosphorylation on Thr172 (P-AMPKα/total AMPK), oxygen uptake, nutritive capacity, 2-deoxyglucose uptake, Akt phosphorylation on Ser473 (P-Akt/total Akt) and muscle 2-deoxyglucose uptake were determined. Arterial injection of MS (0, 9, 15 and 30×106 MS/15 g of hindlimb muscle, as a bolus) into the pump-perfused (0.5 ml·min−1·g−1 of wet weight) rat hindlimb led to increased pressure (−0.5±0.8, 15.9±2.1, 28.7±4.6 and 60.3±9.4 mmHg respectively) with minimal changes in oxygen uptake. Nutritive capacity was decreased from 10.6±1.0 to 3.8±0.9 μmol·g−1 of muscle·h−1 (P& .05) with 30×106 MS. EC was unchanged, but PCr/Cr was decreased dose-dependently to 61% of basal with 30×106 MS. Insulin-mediated increases in P-Akt/total Akt decreased from 2.15±0.35 to 1.41±0.23 (P& .05) and muscle 2-deoxyglucose uptake decreased from 130±19 to 80±12 μg·min−1·g−1 of dry weight (P& .05) with 15×106 MS basal P-AMPKα in the absence of insulin was increased, but basal P-Akt/total Akt and muscle 2-deoxyglucose uptake were unaffected. In conclusion, partial occlusion of the hindlimb muscle has no effect on basal glucose uptake and marginally impacts on oxygen uptake, but markedly impairs insulin delivery to muscle and, thus, insulin-mediated Akt phosphorylation and glucose uptake.
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: Springer Science and Business Media LLC
Date: 02-2006
DOI: 10.1007/S00125-005-0110-6
Abstract: Methacholine (MC) is a nitric oxide vasodilator, but unlike other vasodilators, it potentiates insulin-mediated glucose uptake by muscle. The present study aimed to resolve whether this action was the result of a vascular effect of MC leading to increased muscle perfusion or a direct effect of MC on the myocytes. We hypothesise that vascular-mediated insulin-stimulated glucose uptake responses to MC occur at lower doses than direct myocyte MC-mediated increases in glucose uptake. The vascular and metabolic effects of this vasodilator were examined in rats in vivo using a novel local infusion technique, and in the pump-perfused rat hindlimb under conditions of constant flow. Local infusion of low-dose MC (0.3 micromol/l) into the epigastric artery of one leg (test) in vivo markedly increased femoral blood flow and decreased vascular resistance, without effects in the contra-lateral leg. Capillary recruitment, but not glucose uptake, was increased in the test leg. All increases caused by MC were confined to the test leg and blocked by local infusion into the test leg of N-nitro-L-arginine methyl ester (L-NAME), but not by infusion of N-nitro-D-arginine methyl ester (D-NAME). In the constant-flow pump-perfused rat hindlimb, infusion of 0.6 micromol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 micromol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 micromol/l MC (p or =30 micromol/l) MC has a direct metabolic effect leading to increased glucose uptake. Both the vascular and metabolic effects are sensitive to L-NAME. The low-dose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects.
Publisher: American Physiological Society
Date: 07-2011
DOI: 10.1152/AJPHEART.00864.2010
Abstract: Recent studies have shown that adiponectin is able to increase nitric oxide (NO) production by the endothelium and relax preconstricted isolated aortic rings, suggesting that adiponectin may act as a vasodilator. Endothelin-1 (ET-1) is a potent vasoconstrictor, elevated levels of which are associated with obesity, type 2 diabetes, hypertension, and cardiovascular disease. We hypothesized that adiponectin has NO-dependent vascular actions opposing the vasoconstrictor actions of ET-1. We studied the vascular and metabolic effects of a physiological concentration of adiponectin (6.5 μg/ml) on hooded Wistar rats in the constant-flow pump-perfused rat hindlimb. Adiponectin alone had no observable vascular activity however, adiponectin pretreatment and coinfusion inhibited the increase in perfusion pressure and associated metabolic stimulation caused by low-dose (1 nM) ET-1. Adiponectin was not able to oppose vasoconstriction when infusion was commenced after ET-1. This is in contrast to the NO donor sodium nitroprusside, which significantly reduced the pressure due to established ET-1 vasoconstriction, suggesting dissociation of the actions of adiponectin and NO. In addition, adiponectin had no effect on vasoconstriction caused by either high-dose (20 nM) ET-1 or low-dose (50 nM) norepinephrine. Our findings suggest that adiponectin has specific, apparently NO-independent, vascular activity to oppose the vasoconstrictor effects of ET-1. The hemodynamic actions of adiponectin may be an important aspect of its insulin-sensitizing ability by regulating access of insulin and glucose to myocytes. Imbalance in the relationship between adiponectin and ET-1 in obesity may contribute to the development of insulin resistance and cardiovascular disease.
Publisher: Wiley
Date: 06-2009
Publisher: Bentham Science Publishers Ltd.
Date: 02-2006
DOI: 10.2174/157339906775473653
Abstract: Insulin mediates its own access and that of glucose to muscle by capillary recruitment and an increase in bulk blood flow. In addition, insulin resistance of muscle may result in part from an impaired hemodynamic action of insulin. The present review examines some of the factors that influence the effects of insulin both at the level of hemodynamics and metabolism in muscle. Factors include fatty acids, the inflammatory cytokine TNFalpha, vasodilators that relax the blood vessels and increase bulk flow, and elevated blood pressure that may be mediated by endothelin, a potent locally released vasoconstrictor, or other vasoconstrictor influences.
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: 09-2003
DOI: 10.1152/AJPENDO.00119.2003
Abstract: TNF-α is elevated in many states of insulin resistance, and acutely administered TNF-α in vivo inhibits insulin-mediated hemodynamic effects and glucose uptake in muscle. In this study, we assess whether the inhibitory effects of TNF-α are affected by insulin dose or muscle contraction. Whole body glucose infusion rate (GIR), femoral blood flow (FBF), hindleg vascular resistance, hindleg glucose uptake (HGU), 2-deoxyglucose uptake into muscles of the lower leg (R′g) and hindleg metabolism of infused 1-methylxanthine (1-MX), a measure of capillary recruitment, were determined. Three groups were studied with and without infusion of TNF-α: euglycemic insulin-cl ed, one-leg field-stimulated (2 Hz, 0.1 ms at 30 V), and saline-infused control anesthetized rats. Insulin infusions were 3, 10, or 30 mU · kg - 1 · min - 1 for 2 h. 1-MX metabolism was maximally increased by all three doses of insulin. GIR, HGU, and R′g were maximal at 10 mU and FBF was maximal at 30 mU of insulin. Contraction increased FBF, HGU, and 1-MX. TNF-α (0.5 μg · kg - 1 · h - 1 ) totally blocked the 3 and 10 mU insulin-mediated increases in FBF and 1-MX, and partly blocked GIR, HGU, and R′g. None of the increases due to twitch contraction was affected by TNF-α, and only the increase in FBF due to 30 mU of insulin was partly affected. We conclude that muscle capillary recruitment and glucose uptake due to high levels of insulin or muscle contraction under twitch stimuli at 2 Hz are resistant to TNF-α. These findings may have implications for ameliorating muscle insulin resistance resulting from increased plasma TNF-α and for the differing mechanisms by which contraction and insulin recruit capillary flow in muscle.
Publisher: Springer Science and Business Media LLC
Date: 12-2004
DOI: 10.1007/S00125-004-1580-7
Abstract: Insulin has nitric-oxide-dependent vasodilatory effects in muscle, including capillary recruitment, that enhance access for itself and glucose. However, nitric-oxide-dependent vasodilators other than methacholine do not enhance insulin action. Our hypothesis is that methacholine, unlike bradykinin, enhances insulin-mediated glucose uptake in muscle by augmenting capillary recruitment. Local infusion of either methacholine or bradykinin into one leg of the anaesthetised rat was made during physiological insulin (3 mU.kg(-1).min(-1)) infusion under euglycaemic conditions and without affecting systemic blood pressure. Whole-body glucose infusion was determined, as was femoral blood flow, 2-deoxyglucose uptake into calf muscles and the metabolism of infused 1-methylxanthine, a measure of capillary recruitment for each leg. Methacholine alone (0.3 micromol.l(-1)) increased femoral arterial blood flow, increased capillary recruitment but had no effect on 2-deoxyglucose uptake of the test leg relative to the contra-lateral control leg. Insulin alone (systemically) required a glucose infusion rate of 8.7 mg.kg(-1).min(-1) to maintain euglycaemia, increased 2-deoxyglucose uptake and capillary recruitment, but was without effect on femoral blood flow in either leg. Local methacholine with systemic insulin infusion increased femoral blood flow, 2-deoxyglucose uptake and capillary recruitment in the test leg only. Bradykinin (0.07 micromol.l(-1)), alone or with insulin, administered in a manner that increased femoral blood flow similarly to methacholine, did not affect 2-deoxyglucose uptake or capillary recruitment. Methacholine but not bradykinin enhances insulin-mediated muscle glucose uptake in vivo. We conclude that methacholine acts at specific sites in the vasculature of muscle to stimulate capillary recruitment and thereby enhance insulin access.
Publisher: Wiley
Date: 09-2008
DOI: 10.1038/OBY.2008.302
Abstract: We aimed to (i) determine the relative importance of childhood gain in upper body adiposity for insulin resistance (IR) and triglyceridemia (TG) (ii) examine whether the associations between adiposity and metabolic indices were more evident in those with the ACE DD genotype. We examined a birth cohort study of 292 children with measures in the neonatal period (day 4) including subscapular and triceps skinfolds repeat skinfold measures at age 8, cardiorespiratory (CR) fitness, IR by the homeostasis model assessment (HOMA) equation (HOMA-IR) and serum triglyceride (TG) concentrations and measures of ACE I/D gene variants. A multiple linear regression analysis incorporating a life course approach was undertaken. Childhood gain in upper body adiposity was positively associated with HOMA-IR and TG independently of neonatal skinfolds (P < or = 0.02). The magnitude of these associations was higher among those of the ACE DD genotype. For ex le, subscapular skinfold gain was not strongly associated with HOMA-IR or TG among those with II or ID genotype (b = 0.03, P = 0.05 b = 0.02, P = 0.18 respectively) but was positively associated among those with the DD genotype (b = 0.11, P = 0.001 b = 0.08, P = 0.003) difference in effect P = 0.05 P = 0.01 respectively. Upper body fat accumulation during childhood was positively associated with HOMA-IR and TG independently of neonatal skinfolds. Further, the stronger associations for those with the ACE DD genotype is consistent with randomised controlled trial findings that ACE inhibition is associated with a reduced risk of developing type 2 diabetes. Further work is required to confirm and extend these findings.
Publisher: Wiley
Date: 12-01-2015
Publisher: Portland Press Ltd.
Date: 27-11-2006
DOI: 10.1042/BSE0420133
Abstract: The evidence that muscle metabolism is determined by available capillary surface area is examined. From newly developed methods it is clear that exercise and insulin mediate capillary recruitment as part of their actions in vivo. In all insulin-resistant states examined thus far, insulin-mediated capillary recruitment is impaired with little or no change to the exercise response. Control mechanisms for capillary recruitment for exercise and insulin are considered, and the failure of the microvasculature to respond to insulin is examined for possible mechanisms that might account for impaired vascular responses to insulin in insulin resistance.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.MVR.2005.06.001
Abstract: Vasoconstrictors can either increase or decrease metabolism of the constant flow pump-perfused rat hindlimb. In addition, there is indirect evidence from vascular casts, surface fluorometry, dye entrapment studies, and fluorescent microsphere mapping of flow that this may be due to redistribution of flow between putatively nutritive and non-nutritive routes within muscle. In the present study, we used two methods in an attempt to identify perfused nutritive and non-nutritive vessels in muscle sections: (i) a combination of perfusion fixation with glutaraldehyde and post-perfusion Griffonia simplicifolia lectin and (ii) perfusion with rhodamine-dextran70 (lysine fixable) and post-fixation with formaldehyde. Perfusions involved vehicle only (control, a mix of nutritive and non-nutritive flow), 15 nM angiotensin II (AII) to increase, or 1 microM serotonin (5-HT) to decrease nutritive flow. Microscopic examination of muscle sections following AII showed an increase in perfused capillaries with fewer areas of under-perfusion, relative to control. In contrast, 5-HT caused a marked decrease in perfused capillaries relative to control and evidence that flow was carried by connective tissue vessels that on average were of greater diameter and were more sparsely distributed than capillaries. It is concluded that vasoconstrictors that alter hindlimb metabolism do so by intra-muscle redistribution between capillaries (nutritive) and non-nutritive (connective tissue) vessels within each muscle.
Publisher: American Physiological Society
Date: 10-2004
DOI: 10.1152/AJPENDO.00077.2004
Abstract: Exercise and insulin increase muscle glucose uptake by different mechanisms and also increase capillary recruitment, which is proposed to facilitate access for hormones and nutrients. The genetically obese Zucker rat shows impaired insulin- but not contraction-mediated glucose uptake in muscle. Recently, we have shown the genetically obese Zucker rats to have impaired insulin-mediated capillary recruitment and proposed that this contributes to the insulin resistance of muscle in vivo. Because this might imply a general loss of recruitable capillaries, we now assess responses to contraction in muscles of 18 ± 3-wk-old lean and obese Zucker rats in vivo. Field stimulation (2 Hz, 0.1 ms) was conducted for 1 h on one leg of anesthetized instrumented rats, and measurements were made of femoral blood flow (FBF), heart rate (HR), blood pressure (BP), hindleg metabolism of 1-methylxanthine (a measure of capillary recruitment), hindleg glucose uptake (HGU), and lower leg muscle glucose uptake by 2-deoxyglucose (R′g). Lean animals (311 ± 9 g) developed tension at 219 ± 27 g/g muscle with no change in BP but with significant increases in HR, FBF, HGU, 1-MX metabolism, and R′g ( P 0.05), compared with nonstimulated control leans. Obese animals (469 ± 7 g) developed tension at 265 ± 31 g/g muscle with no change in HR or BP but with significant increases in FBF, HGU, 1-MX metabolism, and R′g ( P 0.05) compared with nonstimulated control obese rats. Muscle contraction of lean animals led to a greater increase in lower leg R′g, similar responses in HGU and 1-MX, and a smaller increase in FBF than in obese animals. A tight correlation between FBF and capillary recruitment was noted for all data ( P 0.001). It is concluded that contraction-mediated muscle capillary recruitment and glucose uptake are essentially normal in the obese Zucker rat and that control of FBF and capillary recruitment in exercise is closely linked.
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: Wiley
Date: 08-2005
Publisher: Wiley
Date: 07-06-2007
DOI: 10.1080/10739680701282796
Abstract: ABSTRACT Objective: Insulin has vascular actions within the skeletal muscle microcirculation (capillary recruitment) that enhance its own access and that of glucose to the muscle cells. Obesity and insulin resistance are associated with dysregulated vascular function within muscle and a loss of insulin‐mediated capillary recruitment. Furthermore, agents that impair insulin's vascular actions to recruit capillaries lead to acute insulin resistance in terms of muscle glucose uptake. Together these data suggest a strong connection between the loss of insulin‐mediated capillary recruitment and the development of insulin resistance. This review examines the mechanisms involved in insulin‐mediated capillary recruitment and the vascular defects associated with obesity and insulin resistance that may impair the capillary recruiting process. Understanding the mechanisms of insulin‐mediated capillary recruitment and its impairment may lead to new treatment avenues to prevent the progression of obesity to diabetes.
Publisher: Springer Science and Business Media LLC
Date: 22-07-2015
Publisher: Springer Science and Business Media LLC
Date: 30-07-2005
DOI: 10.1007/S00125-005-1887-Z
Abstract: Glucose toxicity and glucosamine-induced insulin resistance have been attributed to products of glucosamine metabolism. In addition, endothelial cell nitric oxide synthase is inhibited by glucosamine. Since insulin has endothelial nitric-oxide-dependent vasodilatory effects in muscle, we hypothesise that glucosamine-induced insulin resistance in muscle in vivo is associated with impaired vascular responses including capillary recruitment. Glucosamine (6.48 mg kg(-1) min(-1) for 3 h) was infused with or without insulin (10 mU kg(-1) min(-1)) into anaesthetised rats under euglycaemic conditions. Glucosamine infusion alone increased blood glucosamine (1.9+/-0.1 mmol/l) and glucose (5.4+/-0.2 to 7.7+/-0.3 mmol/l) (p<0.05) but not insulin. Glucosamine induced both hepatic and muscle insulin resistance as evident from measures of glucose appearance and disposal as well as hind-leg glucose uptake, which was inhibited by approx. 50% (p<0.05). Insulin-mediated increases in femoral arterial blood flow and capillary recruitment were completely blocked by glucosamine. Glucosamine mediates a major impairment of insulin action in muscle vasculature associated with the insulin resistance of muscle. Further studies will be required to assess whether the impaired capillary recruitment contributes to insulin resistance.
No related grants have been discovered for Stephen Richards.