Michelle A. Keske

Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal.

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

Age-related anabolic resistance after endurance-type exercise in healthy humans

Age‐related skeletal muscle loss is thought to stem from suboptimal nutrition and resistance to anabolic stimuli. Impaired microcirculatory (nutritive) blood flow may contribute to anabolic resistance by reducing delivery of amino acids to skeletal muscle. In this study, we employed contrast‐enhanced ultrasound, microdialysis sampling of skeletal muscle interstitium, and stable isotope methodology, to assess hemodynamic and metabolic responses of older individuals to endurance type (walking) exercise during controlled amino acid provision. We hypothesized that older individuals would exhibit reduced microcirculatory blood flow, interstitial amino acid concentrations, and amino acid transport when compared with younger controls. We report for the first time that aging induces anabolic resistance following endurance exercise, manifested as reduced (by ∼40%) efficiency of muscle protein synthesis. Despite lower (by ∼40–45%) microcirculatory flow in the older than in the younger participants, circulating and interstitial amino acid concentrations and phenylalanine transport into skeletal muscle were all equal or higher in older individuals than in the young, comprehensively refuting our hypothesis that amino acid availability limits postexercise anabolism in older individuals. Our data point to alternative mediators of age‐related anabolic resistance and importantly suggest correction of these impairments may reduce requirements for, and increase the efficacy of, dietary protein in older individuals. Durham, W. J., Casperson, S. L., Dillon, E. L., Keske, M. A., Paddon‐Jones, D., Sanford, A. P., Hickner, R. C., Grady, J. J., Sheffield‐Moore, M. Age‐related anabolic resistance after endurance‐type exercise in healthy humans. FASEB J. 24, 4117–4127 (2010). www.fasebj.org

Vascular and Metabolic Actions of the Green Tea Polyphenol Epigallocatechin Gallate

Epidemiological studies demonstrate robust correlations between green tea consumption and reduced risk of type 2 diabetes and its cardiovascular complications. However, underlying molecular, cellular, and physiological mechanisms remain incompletely understood. Health promoting actions of green tea are often attributed to epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea. Insulin resistance and endothelial dysfunction play key roles in the pathogenesis of type 2 diabetes and its cardiovascular complications. Metabolic insulin resistance results from impaired insulin-mediated glucose disposal in skeletal muscle and adipose tissue, and blunted insulin-mediated suppression of hepatic glucose output that is often associated with endothelial/vascular dysfunction. This endothelial dysfunction is itself caused, in part, by impaired insulin signaling in vascular endothelium resulting in reduced insulin-stimulated production of NO in arteries, and arterioles that regulate nutritive capillaries. In this review, we discuss the considerable body of literature supporting insulin-mimetic actions of EGCG that oppose endothelial dysfunction and ameliorate metabolic insulin resistance in skeletal muscle and liver. We conclude that EGCG is a promising therapeutic to combat cardiovascular complications associated with the metabolic diseases characterized by reciprocal relationships between insulin resistance and endothelial dysfunction that include obesity, metabolic syndrome and type 2 diabetes. There is a strong rationale for well-powered randomized placebo controlled intervention trials to be carried out in insulin resistant and diabetic populations.

Loss of insulin-mediated microvascular perfusion in skeletal muscle is associated with the development of insulin resistance

Aim: 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.

Muscle insulin resistance resulting from impaired microvascular insulin sensitivity in Sprague Dawley rats

AIMS 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. METHODS AND RESULTS 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 clamp (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 clamps 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. CONCLUSIONS 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.

Increased muscle blood supply and transendothelial nutrient and insulin transport induced by food intake and exercise: effect of obesity and ageing

This review concludes that a sedentary lifestyle, obesity and ageing impair the vasodilator response of the muscle microvasculature to insulin, exercise and VEGF‐A and reduce microvascular density. Both impairments contribute to the development of insulin resistance, obesity and chronic age‐related diseases. A physically active lifestyle keeps both the vasodilator response and microvascular density high. Intravital microscopy has shown that microvascular units (MVUs) are the smallest functional elements to adjust blood flow in response to physiological signals and metabolic demands on muscle fibres. The luminal diameter of a common terminal arteriole (TA) controls blood flow through up to 20 capillaries belonging to a single MVU. Increases in plasma insulin and exercise/muscle contraction lead to recruitment of additional MVUs. Insulin also increases arteriolar vasomotion. Both mechanisms increase the endothelial surface area and therefore transendothelial transport of glucose, fatty acids (FAs) and insulin by specific transporters, present in high concentrations in the capillary endothelium. Future studies should quantify transporter concentration differences between healthy and at risk populations as they may limit nutrient supply and oxidation in muscle and impair glucose and lipid homeostasis. An important recent discovery is that VEGF‐B produced by skeletal muscle controls the expression of FA transporter proteins in the capillary endothelium and thus links endothelial FA uptake to the oxidative capacity of skeletal muscle, potentially preventing lipotoxic FA accumulation, the dominant cause of insulin resistance in muscle fibres.

Muscle microvascular blood flow responses in insulin resistance and ageing

Insulin resistance plays a key role in the development of type 2 diabetes. Skeletal muscle is the major storage site for glucose following a meal and as such has a key role in maintenance of blood glucose concentrations. Insulin resistance is characterised by impaired insulin‐mediated glucose disposal in skeletal muscle. Multiple mechanisms can contribute to development of muscle insulin resistance and our research has demonstrated an important role for loss of microvascular function within skeletal muscle. We have shown that insulin can enhance blood flow to the microvasculature in muscle thus improving the access of glucose and insulin to the myocytes to augment glucose disposal. Obesity, insulin resistance and ageing are all associated with impaired microvascular responses to insulin in skeletal muscle. Impairments in insulin‐mediated microvascular perfusion in muscle can directly cause insulin resistance, and this event can occur early in the aetiology of this condition. Understanding the mechanisms involved in the loss of microvascular function in muscle has the potential to identify novel treatment strategies to prevent or delay progression of insulin resistance and type 2 diabetes.

Local NOS inhibition impairs vascular and metabolic actions of insulin in rat hindleg muscle in vivo

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 clamp (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 insulins metabolic actions.

Brachial-to-radial SBP amplification: implications of age and estimated central blood pressure from radial tonometry.

Objectives: The reference standard for noninvasive estimation of central blood pressure (BP) is radial tonometry calibrated using brachial SBP and DBP. Brachial-to-radial-SBP amplification (B-R-SBPAmp) may introduce error into central BP estimation, but the magnitude of such amplification is uncertain. This study aimed to determine the magnitude and effect of ageing on B-R-SBPAmp; the effect of B-R-SBPAmp on radial tonometry estimated central SBP; and correlates of B-R-SBPAmp. Methods: Forty young (28 ± 5 years) and 20 older (60 ± 8 years) healthy participants underwent brachial and radial artery ultrasound to identify SBP from the first Doppler flow inflection during BP cuff deflation (first Korotkoff sound). Impedance cardiography, ultrasound, tonometry and anthropometric data were collected to explore B-R-SBPAmp correlates. Results: Radial SBP was significantly higher than brachial SBP in younger (118 ± 12 versus 110 ± 10 mmHg; P < 0.001) and older (135 ± 12 versus 121 ± 11 mmHg; P < 0.001) participants. The magnitude of B-R-SBPAmp (radial minus brachial SBP) was higher in older than younger participants (14 ± 7 versus 8 ± 7 mmHg; P = 0.002), independent of sex and heart rate. Estimated central SBP was higher in both age groups when radial waveforms were recalibrated using radial (versus brachial) SBP (P < 0.001). The central SBP change relative to B-R-SBPAmp was associated with augmentation index (r = 0.739, P < 0.001), independent of age, sex and heart rate. Age, male sex and high-density lipoprotein each positively related to B-R-SBPAmp in multiple regression analysis (P < 0.05). Conclusion: Major B-R-SBPAmp occurs in healthy people and is higher with increasing age. Furthermore, B-R-SBPAmp contributes to underestimation of radial tonometry derived central SBP.

Microvascular Contributions to Insulin Resistance

The notion that type 2 diabetes and insulin resistance are associated with many macro- and microvascular defects (1,2) is unquestionable, but whether vascular defects precede and contribute to insulin resistance is less certain and has been a controversial topic. The most compelling evidence for a vascular involvement in insulin resistance has been in skeletal muscle (3), but recent research has also implicated its involvement in adipose tissue (4), which may then lead to whole body insulin resistance via inflammation (5). The suggestion that the vasculature may be a potent contributor to insulin resistance in muscle came from early, indirect clinical studies in which insulin resistance was inversely associated with skeletal muscle capillary density in Pima Indians (6) and from studies of total blood flow during euglycemic-hyperinsulinemic clamps in normal and insulin-resistant subjects (7). Many subsequent studies by various research groups have reported corroborating data that vascular defects (especially in the microvasculature) can contribute to insulin resistance in muscle (rev. in 3 and reference list therein). The underlying consequence of the vascular defect is impaired delivery of insulin and/or glucose to the skeletal myocyte, which leads to insulin resistance. Because the muscle myocyte (and other tissues) also exhibit defects in insulin signaling and responsiveness in established states of obesity, hypertension, and diabetes (all of which are associated with insulin resistance), the significance of a vascular contribution is often questioned or undervalued. In the current issue of Diabetes , Bonner et al. (8) report data on the effects …