Adrenergic regulation of carbohydrate metabolism during exercise

1. This series of studies was undertaken to examine the adrenergic regulation of carbohydrate metabolism during exercise. Recreationally active males were tested during moderate to intense exercise on a stationary cycle ergometer. Venous and arterial plasma obtained from indwelling catheters was analysed for hormonal and metabolite responses, and hepatic glucose production and glucose uptake were measured using the tracer-dilution method with stable isotopes. Muscle samples were obtained by the needle biopsy technique to examine muscle glycogen utilisation and the flux of related muscle metabolites using enzymatic, fluorometric and radioisotopic techniques. 2. During moderate exercise adrenaline infusion induced a marked hyperglycemia and this was due to reduced glucose uptake rather than enhanced hepatic glucose production. The reduction in glucose uptake was most likely mediated by a decrease in glucose phosphorylation, as indicated by the accumulation of glucose 6-phosphate with adrenaline infusion. 3. The hyperglycemic response to intense exercise was prevented by the administration of α- and β-adrenergic antagonists. Adrenergic blockade was without effect on hepatic glucose production whereas glucose uptake was enhanced when compared with control subjects. These data support the notion that adrenergic mechanisms are more important in restraining glucose uptake than enhancing hepatic glucose production during intense exercise. Other glucoregulatory factors are responsible for the increase in glucose production during intense exercise. 4. Elevated plasma adrenaline levels during moderate exercise in untrained men increases skeletal muscle glycogen breakdown and PDH activation which result

Reduced glycogen availability is associated with increased AMPKα2 activity, nuclear AMPKα2 protein abundance, and GLUT4 mRNA expression in contracting human skeletal muscle

Glycogen availability can influence glucose transporter 4 (GLUT4) expression in skeletal muscle through unknown mechanisms. The multisubstrate enzyme AMP-activated protein kinase (AMPK) has also been shown to play an important role in the regulation of GLUT4 expression in skeletal muscle. During contraction, AMPK [alpha]2 translocates to the nucleus and the activity of this AMPK isoform is enhanced when skeletal muscle glycogen is low. In this study, we investigated if decreased pre-exercise muscle glycogen levels and increased AMPK [alpha]2 activity reduced the association of AMPK with glycogen and increased AMPK [alpha]2 translocation to the nucleus and GLUT4 mRNA expression following exercise. Seven males performed 60 min of exercise at ~70% [VO.sub.2] peak on 2 occasions: either with normal (control) or low (LG) carbohydrate pre-exercise muscle glycogen content. Muscle samples were obtained by needle biopsy before and after exercise. Low muscle glycogen was associated with elevated AMPK [alpha]2 activity and acetyl-CoA carboxylase [beta] phosphorylation, increased translocation of AMPK [alpha]2 to the nucleus, and increased GLUT4 mRNA. Transfection of primary human myotubes with a constitutively active AMPK adenovirus also stimulated GLUT4 mRNA, providing direct evidence of a role of AMPK in regulating GLUT4 expression. We suggest that increased activation of AMPK [alpha]2 under conditions of low muscle glycogen enhances AMPK [alpha]2 nuclear translocation and increases GLUT4 mRNA expression in response to exercise in human skeletal muscle. <br /

Systemic inflammatory profile and response to anti-tumor necrosis factor therapy in chronic obstructive pulmonary disease

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers. Despite correlative evidence for a role for tumor necrosis factor-alpha in the pathogenesis of COPD, the anti-tumor necrosis factor-alpha, infliximab did not show clinical efficacy in a double-blind, placebo-controlled, phase II clinical trial. This study sought to evaluate the systemic inflammatory profile associated with COPD and to assess the impact of tumor necrosis factor neutralization on systemic inflammation.</p> <p>Methods</p> <p>Serum samples (n = 234) from the phase II trial were collected at baseline and after 24 weeks of placebo or infliximab. Additionally, baseline serum samples were obtained from an independent COPD cohort (n = 160) and 2 healthy control cohorts (n = 50; n = 109). Serum concentrations of a broad panel of inflammation-associated analytes were measured using a 92-analyte multiplex assay.</p> <p>Results</p> <p>Twenty-five proteins were significantly elevated and 2 were decreased in COPD, including highly elevated CD40 ligand, brain-derived neurotrophic factor, epidermal growth factor, acute-phase proteins, and neutrophil-associated proteins. This profile was largely independent of smoking status, age, and clinical phenotype. The majority of these associations of serum analytes with COPD are novel findings. Increased serum creatine kinase-muscle/brain and myoglobin correlated modestly with decreased forced expiratory volume at 1 second, suggesting cardiac involvement. Infliximab did not affect this systemic inflammatory profile.</p> <p>Conclusions</p> <p>A robust systemic inflammatory profile was associated with COPD. This profile was generally independent of disease severity. Because anti-tumor necrosis factor-alpha did not influence systemic inflammation, how to control the underlying pathology beyond symptom suppression remains unclear.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov, <it>No</it>.: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00056264">NCT00056264</a>.</p

The King–Devick test for sideline concussion screening in collegiate football

AbstractPurposeSports-related concussion has received increasing attention as a result of neurologic sequelae seen among athletes, highlighting the need for a validated, rapid screening tool. The King–Devick (K–D) test requires vision, eye movements, language function and attention in order to perform and has been proposed as a promising tool for assessment of concussion. We investigated the K–D test as a sideline screening tool in a collegiate cohort to determine the effect of concussion.MethodsAthletes (n=127, mean age 19.6±1.2 years) from the Wheaton College football and men's and women's basketball teams underwent baseline K–D testing at pre-season physicals for the 2012–2013 season. K–D testing was administered immediately on the sidelines for football players with suspected head injury during regular games and changes compared to baseline were determined. Post-season testing was also performed to compare non-concussed athletes’ test performance.ResultsConcussed athletes (n=11) displayed sideline K–D scores that were significantly higher (worse) than baseline (36.5±5.6s vs. 31.3±4.5s, p<0.005, Wilcoxon signed-rank test). Post-season testing demonstrated improvement of scores and was consistent with known learning effects (35.1±5.2s vs. 34.4±5.0s, p<0.05, Wilcoxon signed-rank test). Test-retest reliability was analyzed between baseline and post-season administrations of the K–D test resulting in high levels of test-retest reliability (intraclass correlation coefficient (ICC)=0.95 [95% Confidence Interval 0.85–1.05]).ConclusionsThe data show worsening of K–D test scores following concussion further supporting utility of the K–D test as an objective, reliable and effective sideline visual screening tool to help identify athletes with concussion

TCPTP-deficiency in muscle does not alter insulin signalling and glucose homeostasis.

Aims/Hypothesis: Insulin activates the insulin receptor (IR) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The IR can serve as a substrate for the protein tyrosine phosphatases (PTP) 1B and TCPTP, which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the IR in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates IR signalling and gluconeogenesis in the liver. In this study we have assessed for the first time the role of TCPTP in the regulation of IR signalling in muscle. Methods: We generated muscle-specific TCPTP-deficient (MCK-Cre;Ptpn2lox/lox) mice and assessed the impact on glucose homeostasis and muscle IR signalling in chow versus high fat fed mice. Results: Blood glucose and insulin levels, insulin and glucose tolerances and insulininduced muscle IR activation and downstream PI3K/Akt signalling remained unaltered in chow fe

Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance

OBJECTIVE—Skeletal muscle insulin resistance is associated with lipid accumulation, but whether insulin resistance is due to reduced or enhanced flux of long-chain fatty acids into the mitochondria is both controversial and unclear. We hypothesized that skeletal muscle–specific overexpression of the muscle isoform of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acyl CoA into mitochondria, would enhance rates of fatty acid oxidation and improve insulin action in muscle in high-fat diet insulin-resistant rats

Access to general practice and visits to accident and emergency departments in England: cross-sectional analysis of a national patient survey.

BACKGROUND: The annual number of unplanned attendances at accident and emergency (A&E) departments in England increased by 11% (2.2 million attendances) between 2008-2009 and 2012-2013. A national review of urgent and emergency care has emphasised the role of access to primary care services in preventing A&E attendances. AIM: To estimate the number of A&E attendances in England in 2012-2013 that were preceded by the attending patient being unable to obtain an appointment or a convenient appointment at their general practice. DESIGN AND SETTING: Cross-sectional analysis of a national survey of adults registered with a GP in England. METHOD: The number of general practice consultations in England in 2012-2013 was estimated by extrapolating the linear trend of published data for 2000-2001 to 2008-2009. This parameter was multiplied by the ratio of attempts to obtain a general practice appointment that resulted in an A&E attendance to attempts that resulted in a general practice consultation estimated using the GP Patient Survey 2012-2013. A sensitivity analysis varied the number of consultations by ±12% and the ratio by ±25%. RESULTS: An estimated 5.77 million (99.9% confidence interval = 5.49 to 6.05 million) A&E attendances were preceded by the attending patient being unable to obtain a general practice appointment or a convenient appointment, comprising 26.5% of unplanned A&E attendances in England in 2012-2013. The sensitivity analysis produced values between 17.5% and 37.2% of unplanned A&E attendances. CONCLUSION: A large number of A&E attendances are likely to be preceded by unsuccessful attempts to obtain convenient general practice appointments in England each year

Liberal market economies, business, and political finance: Britain under New Labour

The extent and nature of business financing of parties is an important feature of political finance. Britain’s transparent and permissive regulatory system provides an excellent opportunity to study business financing of parties. Business donations have been very important to the Conservative party over the last decade, and of only marginal importance to Labour. Unlike other Conservative contributors, business donors are more likely to contribute when the party is popular. In contrast to the previous period of Conservative government, the biggest British businesses tended to abstain from political finance under New Labour. However, their bias towards the Conservatives is affected by the party’s popularity and the closeness of an election. Britain shares the political importance of business financing of parties and its mixture of ideological and pragmatic motivations with other liberal market economies. However, in Britain the bias towards the right is much stronger and the role of big business more marginal