Influence of GLP-1 on Myocardial Glucose Metabolism in Healthy Men during Normo- or Hypoglycemia

Background and Aims

Glucagon-like peptide-1 (GLP-1) may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency by increasing myocardial glucose uptake (MGU). We assessed the effects of GLP-1 on MGU in healthy subjects during normo- and hypoglycemia.

Materials and Methods

We included eighteen healthy men in two randomized, double-blinded, placebo-controlled cross-over studies. MGU was assessed with GLP-1 or saline infusion during pituitary-pancreatic normo- (plasma glucose (PG): 4.5 mM, n = 10) and hypoglycemic clamps (PG: 3.0 mM, n = 8) by positron emission tomography with ¹⁸fluoro-deoxy-glucose (¹⁸F-FDG) as tracer.

Results

In the normoglycemia study mean (± SD) age was 25±3 years, and BMI was 22.6±0.6 kg/m² and in the hypoglycemia study the mean age was 23±2 years with a mean body mass index of 23±2 kg/m². GLP-1 did not change MGU during normoglycemia (mean (+/− SD) 0.15+/−0.04 and 0.16+/−0.03 µmol/g/min, P = 0.46) or during hypoglycemia (0.16+/−0.03 and 0.13+/−0.04 µmol/g/min, P = 0.14). However, the effect of GLP-1 on MGU was negatively correlated to baseline MGU both during normo- and hypoglycemia, (P = 0.006, r² = 0.64 and P = 0.018, r² = 0.64, respectively) and changes in MGU correlated positively with the level of insulin resistance (HOMA 2IR) during hypoglycemia, P = 0.04, r² = 0.54. GLP-1 mediated an increase in circulating glucagon levels at PG levels below 3.5 mM and increased glucose infusion rates during the hypoglycemia study. No differences in other circulating hormones or metabolites were found.

Conclusions

While GLP-1 does not affect overall MGU, GLP-1 induces changes in MGU dependent on baseline MGU such that GLP-1 increases MGU in subjects with low baseline MGU and decreases MGU in subjects with high baseline MGU. GLP-1 preserves MGU during hypoglycemia in insulin resistant subjects.ClinicalTrials.gov registration numbers: {"type":"clinical-trial","attrs":{"text":"NCT00418288","term_id":"NCT00418288"}}NCT00418288: (hypoglycemia) and {"type":"clinical-trial","attrs":{"text":"NCT00256256","term_id":"NCT00256256"}}NCT00256256: (normoglycemia).     

Endothelial Dysfunction and Specific Inflammation in Obesity Hypoventilation Syndrome

Background

Obesity hypoventilation syndrome (OHS) is associated with increased cardiovascular morbidity. What moderate chronic hypoventilation adds to obesity on systemic inflammation and endothelial dysfunction remains unknown.

Question

To compare inflammatory status and endothelial function in OHS versus eucapnic obese patients.

Methodology

14 OHS and 39 eucapnic obese patients matched for BMI and age were compared. Diurnal blood gazes, overnight polysomnography and endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), were assessed. Inflammatory (Leptin, RANTES, MCP-1, IL-6, IL-8, TNFα, Resistin) and anti-inflammatory (adiponectin, IL-1Ra) cytokines were measured by multiplex beads immunoassays.

Principal Findings

OHS exhibited a higher PaCO₂, a lower forced vital capacity (FVC) and tended to have a lower PaO₂ than eucapnic obese patients. _HS-CRP, RANTES levels and glycated haemoglobin (HbA1c) were significantly increased in OHS (respectively 11.1±10.9 vs. 5.7±5.5 mg.l⁻¹ for _HS-CRP, 55.9±55.3 vs 23.3±15.8 ng/ml for RANTES and 7.3±4.3 vs 6.1±1.7 for HbA1c). Serum adiponectin was reduced in OHS (7606±2977 vs 13660±7854 ng/ml). Endothelial function was significantly more impaired in OHS (RH-PAT index: 0.22±0.06 vs 0.51±0.11).

Conclusions

Compared to eucapnic obesity, OHS is associated with a specific increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin and impaired endothelial function. These three conditions are known to be strongly associated with an increased cardiovascular risk.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00603096","term_id":"NCT00603096"}}NCT00603096     

Metabolic Implications when Employing Heavy Pre- and Post-Exercise Rapid-Acting Insulin Reductions to Prevent Hypoglycaemia in Type 1 Diabetes Patients: A Randomised Clinical Trial

Aim

To examine the metabolic, gluco-regulatory-hormonal and inflammatory cytokine responses to large reductions in rapid-acting insulin dose administered prandially before and after intensive running exercise in male type 1 diabetes patients.

Methods

This was a single centre, randomised, controlled open label study. Following preliminary testing, 8 male patients (24±2 years, HbA1c 7.7±0.4%/61±4 mmol.l⁻¹) treated with insulin''s glargine and aspart, or lispro attended the laboratory on two mornings at ∼08:00 h and consumed a standardised breakfast carbohydrate bolus (1 g carbohydrate.kg⁻¹BM; 380±10 kcal) and self-administered a 75% reduced rapid-acting insulin dose 60 minutes before 45 minutes of intensive treadmill running at 73.1±0.9% VO_2peak. At 60 minutes post-exercise, patients ingested a meal (1 g carbohydrate.kg⁻¹BM; 660±21 kcal) and administered either a Full or 50% reduced rapid-acting insulin dose. Blood glucose and lactate, serum insulin, cortisol, non-esterified-fatty-acids, β-Hydroxybutyrate, and plasma glucagon, adrenaline, noradrenaline, IL-6, and TNF-α concentrations were measured for 180 minutes post-meal.

Results

All participants were analysed. All glycaemic, metabolic, hormonal, and cytokine responses were similar between conditions up to 60 minutes following exercise. Following the post-exercise meal, serum insulin concentrations were lower under 50% (p<0.05) resulting in 75% of patients experiencing hyperglycaemia (blood glucose ≥8.0 mmol.l⁻¹; 50% n = 6, Full n = 3). β-Hydroxybutyrate concentrations decreased similarly, such that at 180 minutes post-meal concentrations were lower than rest under Full and 50%. IL-6 and TNF-α concentrations remained similar to fasting levels under 50% but declined under Full. Under 50% IL-6 concentrations were inversely related with serum insulin concentrations (r = −0.484, p = 0.017).

Conclusions

Heavily reducing rapid-acting insulin dose with a carbohydrate bolus before, and a meal after intensive running exercise may cause hyperglycaemia, but does not augment ketonaemia, raise inflammatory cytokines TNF-α and IL-6 above fasting levels, or cause other adverse metabolic or hormonal disturbances.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01531855","term_id":"NCT01531855"}}NCT01531855     

Effect of Antioxidant Supplementation on Exercise-Induced Cardiac Troponin Release in Cyclists: A Randomized Trial

Background

Cardiac troponin is the biochemical gold standard to diagnose acute myocardial infarction. Interestingly however, elevated cardiac troponin concentrations are also frequently observed during and after endurance-type exercise. Oxidative stress associated with prolonged exercise has been proposed to contribute to cardiac troponin release. Therefore, the aim of this study was to assess the effect of 4 week astaxanthin supplementation (a potent cartenoid antioxidant) on antioxidant capacity and exercise-induced cardiac troponin release in cyclists.

Methods

Thirty-two well-trained male cyclists (age 25±5, weight 73±7 kg, maximum O₂ uptake 60±5 mL·kg⁻¹·min⁻¹, W_max 5.4±0.5 W·kg⁻¹; mean ± SD) were repeatedly subjected to a laboratory based standardized exercise protocol before and after 4 weeks of astaxanthin (20 mg/day), or placebo supplementation in a double-blind randomized manner. Blood samples were obtained at baseline, at 60 min of cycling and immediately post-exercise (≈ 120 min).

Results

The pre-supplementation cycling trial induced a significant rise of median cardiac troponin T concentrations from 3.2 (IQR 3.0–4.2) to 4.7 ng/L (IQR 3.7–6.7), immediately post-exercise (p<0.001). Four weeks of astaxanthin supplementation significantly increased mean basal plasma astaxanthin concentrations from non-detectable values to 175±86 µg·kg⁻¹. However, daily astaxanthin supplementation had no effect on exercise-induced cardiac troponin T release (p = 0.24), as measured by the incremental area under the curve. Furthermore, the elevation in basal plasma astaxanthin concentrations was not reflected in changes in antioxidant capacity markers (trolox equivalent antioxidant capacity, uric acid, and malondialdehyde). Markers of inflammation (high-sensitivity C-reactive protein) and exercise-induced skeletal muscle damage (creatine kinase) were equally unaffected by astaxanthin supplementation.

Conclusion

Despite substantial increases in plasma astaxanthin concentrations, astaxanthin supplementation did not improve antioxidant capacity in well-trained cyclists. Accordingly, exercise-induced cardiac troponin T concentrations were not affected by astaxanthin supplementation.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01241877","term_id":"NCT01241877"}}NCT01241877     

The Effect of Aerobic Exercise on Intrahepatocellular and Intramyocellular Lipids in Healthy Subjects

Background

Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass).

Aim

To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy.

Methods

Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO_2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO_2max) using ¹H-MR-spectroscopy.

Results

Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO_2max, 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (−22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity.

Conclusions

IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions.

Trial Registration

ClinicalTrial.gov {"type":"clinical-trial","attrs":{"text":"NCT00491582","term_id":"NCT00491582"}}NCT00491582     

The Potential of a High Protein-Low Carbohydrate Diet to Preserve Intrahepatic Triglyceride Content in Healthy Humans

Background

Protein supplementation has been shown to reduce the increases in intrahepatic triglyceride (IHTG) content induced by acute hypercaloric high-fat and high-fructose diets in humans.

Objective

To assess the effect of a 12-wk iso-energetic high protein-low carbohydrate (HPLC) diet compared with an iso-energetic high carbohydrate-low protein (HCLP) diet on IHTG content in healthy non-obese subjects, at a constant body weight.

Design

Seven men and nine women [mean ± SD age: 24±5 y; BMI: 22.9±2.1 kg/m²] were randomly allocated to a HPLC [30/35/35% of energy (En%) from protein/carbohydrate/fat] or a HCLP (5/60/35 En%) diet by stratification on sex, age and BMI. Dietary guidelines were prescribed based on individual daily energy requirements. IHTG content was measured by ¹H-magnetic resonance spectroscopy before and after the dietary intervention.

Results

IHTG content changed in different directions with the HPLC (CH₂H₂O: 0.23±0.17 to 0.20±0.10; IHTG%: 0.25±0.20% to 0.22±0.11%) compared with the HCLP diet (CH₂H₂O: 0.34±0.20 vs. 0.38±0.21; IHTG%: 0.38±0.22% vs. 0.43±0.24%), which resulted in a lower IHTG content in the HPLC compared with the HCLP diet group after 12 weeks, which almost reached statistical significance (P = 0.055).

Conclusions

A HPLC vs. a HCLP diet has the potential to preserve vs. enlarge IHTG content in healthy non-obese subjects at a constant body weight.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01551238","term_id":"NCT01551238"}}NCT01551238     

Peak Oxygen Uptake after Cardiac Rehabilitation: A Randomized Controlled Trial of a 12-Month Maintenance Program versus Usual Care

Background

Exercise capacity is a strong predictor of survival in patients with coronary artery disease (CAD). Exercise capacity improves after cardiac rehabilitation exercise training, but previous studies have demonstrated a decline in peak oxygen uptake after ending a formal rehabilitation program. There is a lack of knowledge on how long-term exercise adherence can be achieved in CAD patients. We therefore assessed if a 12-month maintenance program following cardiac rehabilitation would lead to increased adherence to exercise and increased exercise capacity compared to usual care.

Materials and Methods

Two-centre, open, parallel randomized controlled trial with 12 months follow-up comparing usual care to a maintenance program. The maintenance program consisted of one monthly supervised high intensity interval training session, a written exercise program and exercise diary, and a maximum exercise test every third month during follow-up. Forty-nine patients (15 women) on optimal medical treatment were included following discharge from cardiac rehabilitation. The primary endpoint was change in peak oxygen uptake at follow-up; secondary endpoints were physical activity level, quality of life and blood markers of cardiovascular risk.

Results

There was no change in peak oxygen uptake from baseline to follow-up in either group (intervention group 27.9 (±4.7) to 28.8 (±5.6) mL·kg (-1) min (−1), control group 32.0 (±6.2) to 32.8 (±5.8) mL·kg (−1) min (−1), with no between-group difference, p = 0.22). Quality of life and blood biomarkers remained essentially unchanged, and both self-reported and measured physical activity levels were similar between groups after 12 months.

Conclusions

A maintenance exercise program for 12 months did not improve adherence to exercise or peak oxygen uptake in CAD patients after discharge from cardiac rehabilitation compared to usual care. This suggests that infrequent supervised high intensity interval training sessions are inadequate to improve peak oxygen uptake in this patient group.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01246570","term_id":"NCT01246570"}}NCT01246570     

Effect of Arginase Inhibition on Ischemia-Reperfusion Injury in Patients with Coronary Artery Disease with and without Diabetes Mellitus

Background

Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes (Clinical trial registration number: {"type":"clinical-trial","attrs":{"text":"NCT02009527","term_id":"NCT02009527"}}NCT02009527).

Methods

Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (N^ω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline.

Results

The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). N^ω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions.

Conclusions

Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.     

A T Cell-Inducing Influenza Vaccine for the Elderly: Safety and Immunogenicity of MVA-NP+M1 in Adults Aged over 50 Years

Background

Current influenza vaccines have reduced immunogenicity and are of uncertain efficacy in older adults. We assessed the safety and immunogenicity of MVA-NP+M1, a viral-vectored influenza vaccine designed to boost memory T cell responses, in a group of older adults.

Methods

Thirty volunteers (aged 50–85) received a single intramuscular injection of MVA-NP+M1 at a dose of 1·5×10⁸ plaque forming units (pfu). Safety and immunogenicity were assessed over a period of one year. The frequency of T cells specific for nucleoprotein (NP) and matrix protein 1 (M1) was determined by interferon-gamma (IFN-γ) ELISpot, and their phenotypic and functional properties were characterized by polychromatic flow cytometry. In a subset of M1-specific CD8⁺ T cells, T cell receptor (TCR) gene expression was evaluated using an unbiased molecular approach.

Results

Vaccination with MVA-NP+M1 was well tolerated. ELISpot responses were boosted significantly above baseline following vaccination. Increases were detected in both CD4⁺ and CD8⁺ T cell subsets. Clonality studies indicated that MVA-NP+M1 expanded pre-existing memory CD8⁺ T cells, which displayed a predominant CD27⁺CD45RO⁺CD57⁻CCR7⁻ phenotype both before and after vaccination.

Conclusions

MVA-NP+M1 is safe and immunogenic in older adults. Unlike seasonal influenza vaccination, the immune responses generated by MVA-NP+M1 are similar between younger and older individuals. A T cell-inducing vaccine such as MVA-NP+M1 may therefore provide a way to circumvent the immunosenescence that impairs routine influenza vaccination.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00942071","term_id":"NCT00942071"}}NCT00942071     

Multidisciplinary Predialysis Education Reduced the Inpatient and Total Medical Costs of the First 6 Months of Dialysis in Incident Hemodialysis Patients

Background

The multidisciplinary pre-dialysis education (MPE) retards renal progression, reduce incidence of dialysis and mortality of CKD patients. However, the financial benefit of this intervention on patients starting hemodialysis has not yet been evaluated in prospective and randomized trial.

Methods

We studied the medical expenditure and utilization incurred in the first 6 months of dialysis initiation in 425 incident hemodialysis patients who were randomized into MPE and non-MPE groups before reaching end-stage renal disease. The content of the MPE was standardized in accordance with the National Kidney Foundation Dialysis Outcomes Quality Initiative guidelines.

Results

The mean age of study patients was 63.8±13.2 years, and 221 (49.7%) of them were men. The mean serum creatinine level and estimated glomerular filtration rate was 6.1±4.0 mg/dL and 7.6±2.9 mL⋅min⁻¹⋅1.73 m⁻², respectively, at dialysis initiation. MPE patients tended to have lower total medical cost in the first 6 months after hemodialysis initiation (9147.6±0.1 USD/patient vs. 11190.6±0.1 USD/patient, p = 0.003), fewer in numbers [0 (1) vs. 1 (2), p<0.001] and length of hospitalization [0 (15) vs. 8 (27) days, p<0.001], and also lower inpatient cost [0 (2617.4) vs. 1559,4 (5019.6) USD/patient, p<0.001] than non-MPE patients, principally owing to reduced cardiovascular hospitalization and vascular access–related surgeries. The decreased inpatient and total medical cost associated with MPE were independent of patients'' demographic characteristics, concomitant disease, baseline biochemistry and use of double-lumen catheter at initiation of hemodialysis.

Conclusions

Participation of multidisciplinary education in pre-dialysis period was independently associated with reduction in the inpatient and total medical expenditures of the first 6 months post-dialysis owing to decreased inpatient service utilization secondary to cardiovascular causes and vascular access–related surgeries.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00644046","term_id":"NCT00644046"}}NCT00644046     

The Effect of Neoadjuvant Chemoradiotherapy on Whole-Body Physical Fitness and Skeletal Muscle Mitochondrial Oxidative Phosphorylation In Vivo in Locally Advanced Rectal Cancer Patients – An Observational Pilot Study

Background

In the United Kingdom, patients with locally advanced rectal cancer routinely receive neoadjuvant chemoradiotherapy. However, the effects of this on physical fitness are unclear. This pilot study is aimed to investigate the effect of neoadjuvant chemoradiotherapy on objectively measured in vivo muscle mitochondrial function and whole-body physical fitness.

Methods

We prospectively studied 12 patients with rectal cancer who completed standardized neoadjuvant chemoradiotherapy, recruited from a large tertiary cancer centre, between October 2012 and July 2013. All patients underwent a cardiopulmonary exercise test and a phosphorus magnetic resonance spectroscopy quadriceps muscle exercise-recovery study before and after neoadjuvant chemoradiotherapy. Data were analysed and reported blind to patient identity and clinical course. Primary variables of interest were the two physical fitness measures; oxygen uptake at estimated anaerobic threshold and oxygen uptake at Peak exercise (ml.kg⁻¹.min⁻¹), and the post-exercise phosphocreatine recovery rate constant (min⁻¹), a measure of muscle mitochondrial capacity in vivo.

Results

Median age was 67 years (IQR 64–75). Differences (95%CI) in all three primary variables were significantly negative post-NACRT: Oxygen uptake at estimated anaerobic threshold −2.4 ml.kg⁻¹.min⁻¹ (−3.8, −0.9), p = 0.004; Oxygen uptake at Peak −4.0 ml.kg⁻¹.min⁻¹ (−6.8, −1.1), p = 0.011; and post-exercise phosphocreatine recovery rate constant −0.34 min⁻¹ (−0.51, −0.17), p<0.001.

Conclusion

The significant decrease in both whole-body physical fitness and in vivo muscle mitochondrial function raises the possibility that muscle mitochondrial mechanisms, no doubt multifactorial, may be important in deterioration of physical fitness following neoadjuvant chemoradiotherapy. This may have implications for targeted interventions to improve physical fitness pre-surgery.

Trial Registration

Clinicaltrials.gov registration {"type":"clinical-trial","attrs":{"text":"NCT01859442","term_id":"NCT01859442"}}NCT01859442     

Metabolic and Behavioral Compensations in Response to Caloric Restriction: Implications for the Maintenance of Weight Loss

Background

Metabolic and behavioral adaptations to caloric restriction (CR) in free-living conditions have not yet been objectively measured.

Methodology and Principal Findings

Forty-eight (36.8±1.0 y), overweight (BMI 27.8±0.7 kg/m²) participants were randomized to four groups for 6-months; Control: energy intake at 100% of energy requirements; CR: 25% calorie restriction; CR+EX: 12.5% CR plus 12.5% increase in energy expenditure by structured exercise; LCD: low calorie diet (890 kcal/d) until 15% weight reduction followed by weight maintenance. Body composition (DXA) and total daily energy expenditure (TDEE) over 14-days by doubly labeled water (DLW) and activity related energy activity (AREE) were measured after 3 (M3) and 6 (M6) months of intervention. Weight changes at M6 were −1.0±1.1% (Control), −10.4±0.9% (CR), −10.0±0.8% (CR+EX) and −13.9±0.8% (LCD). At M3, absolute TDEE was significantly reduced in CR (−454±76 kcal/d) and LCD (−633±66 kcal/d) but not in CR+EX or controls. At M6 the reduction in TDEE remained lower than baseline in CR (−316±118 kcal/d) and LCD (−389±124 kcal/d) but reached significance only when CR and LCD were combined (−351±83 kcal/d). In response to caloric restriction (CR/LCD combined), TDEE adjusted for body composition, was significantly lower by −431±51 and −240±83 kcal/d at M3 and M6, respectively, indicating a metabolic adaptation. Likewise, physical activity (TDEE adjusted for sleeping metabolic rate) was significantly reduced from baseline at both time points. For control and CR+EX, adjusted TDEE (body composition or sleeping metabolic rate) was not changed at either M3 or M6.

Conclusions

For the first time we show that in free-living conditions, CR results in a metabolic adaptation and a behavioral adaptation with decreased physical activity levels. These data also suggest potential mechanisms by which CR causes large inter-individual variability in the rates of weight loss and how exercise may influence weight loss and weight loss maintenance.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00099151","term_id":"NCT00099151"}}NCT00099151     

Effects of Sodium Bicarbonate on High-Intensity Endurance Performance in Cyclists: A Double-Blind,Randomized Cross-Over Trial

Background

While the ergogenic effect of sodium bicarbonate (BICA) on short-term, sprint-type performance has been repeatedly demonstrated, little is known about its effectiveness during prolonged high-intensity exercise in well-trained athletes. Therefore, this study aims to examine the influence of BICA on performance during exhaustive, high-intensity endurance cycling.

Methods

This was a single-center, double-blind, randomized, placebo-controlled cross-over study. Twenty-one well-trained cyclists (mean ± SD: age 24±8 y, BMI 21.3±1.7, VO_2peak 67.3±9.8 ml·kg⁻¹·min⁻¹) were randomly allocated to sequences of following interventions: oral ingestion of 0.3 g·kg⁻¹ BICA or 4 g of sodium chloride (placebo), respectively. One h after ingestion subjects exercised for 30 min at 95% of the individual anaerobic threshold (IAT) followed by 110% IAT until exhaustion. Prior to these constant load tests stepwise incremental exercise tests were conducted under both conditions to determine IAT and VO_2peak. Analysis of blood gas parameters, blood lactate (BLa) and gas exchange measurements were conducted before, during and after the tests. The main outcome measure was the time to exhaustion in the constant load test.

Results

Cycling time to exhaustion was improved (p<0.05) under BICA (49.5±11.5 min) compared with placebo (45.0±9.5 min). No differences in maximal or sub-maximal measures of performance were observed during stepwise incremental tests. BICA ingestion resulted in an increased pH, bicarbonate concentration and BLa before, throughout and after both exercise testing modes.

Conclusion

The results suggest that ingestion of BICA may improve prolonged, high-intensity cycling performance.

Trial Registration

German Clinical Trials Register (DRKS) DRKS00006198.     

The Relationship between Inflammatory Biomarkers and Telomere Length in an Occupational Prospective Cohort Study

Background

Chronic inflammation from recurring trauma is an underlying pathophysiological basis of numerous diseases. Furthermore, it may result in cell death, scarring, fibrosis, and loss of tissue function. In states of inflammation, subsequent increases in oxidative stress and cellular division may lead to the accelerated erosion of telomeres, crucial genomic structures which protect chromosomes from decay. However, the association between plasma inflammatory marker concentrations and telomere length has been inconsistent in previous studies.

Objective

The purpose of this study was to determine the longitudinal association between telomere length and plasma inflammatory biomarker concentrations including: CRP, SAA, sICAM-1, sVCAM-1, VEGF, TNF-α, IL-1β, IL-2, IL-6, IL-8, and IL-10.

Methods

The longitudinal study population consisted of 87 subjects. The follow-up period was approximately 2 years. Plasma inflammatory biomarker concentrations were assessed using highly sensitive electrochemiluminescent assays. Leukocyte relative telomere length was assessed using Real-Time qPCR. Linear mixed effects regression models were used to analyze the association between repeated-measurements of relative telomere length as the outcome and each inflammatory biomarker concentration as continuous exposures separately. The analyses controlled for major potential confounders and white blood cell differentials.

Results

At any follow-up time, each incremental ng/mL increase in plasma CRP concentration was associated with a decrease in telomere length of −2.6×10⁻² (95%CI: −4.3×10⁻², −8.2×10⁻³, p = 0.004) units. Similarly, the estimate for the negative linear association between SAA and telomere length was −2.6×10⁻² (95%CI:−4.5×10⁻², −6.1×10⁻³, p = 0.011). No statistically significant associations were observed between telomere length and plasma concentrations of pro-inflammatory interleukins, TNF-α, and VEGF.

Conclusions

Findings from this study suggest that increased systemic inflammation, consistent with vascular injury, is associated with decreased leukocyte telomere length.     

Impact of Metformin on Endothelial Ischemia-Reperfusion Injury in Humans In Vivo: A Prospective Randomized Open,Blinded-Endpoint Study

Introduction

Large prospective studies in patients with type 2 diabetes mellitus have demonstrated that metformin treatment improves cardiovascular prognosis, independent of glycemic control. Administration of metformin potently limits infarct size in murine models of myocardial infarction. This study examined, for the first time in humans, whether metformin limits ischemia-reperfusion (IR) injury in vivo using a well-validated forearm model of endothelial IR-injury.

Methods

Twenty-eight healthy volunteers (age 41±6 years, 10 male/16 female) were randomized between pretreatment with metformin (500 mg three times a day for 3 days) or no treatment in a Prospective Randomized Open Blinded Endpoint study. Brachial artery flow mediated dilation (FMD) was measured before and after 20 minutes of forearm ischemia and 20 minutes of reperfusion. FMD analysis was performed offline by investigators blinded for the treatment arm.

Results

Baseline FMD did not differ between metformin pretreatment and no pretreatment (6.9±3.6% and 6.1±3.5%, respectively, p = 0.27, n = 26). FMD was significantly lower after forearm IR in both treatment arms (4.4±3.3% and 4.3±2.8%, respectively, P<0.001 in both conditions). A linear mixed model analysis revealed that metformin treatment did not prevent the decrease in FMD by IR.

Conclusion

A 3 day treatment with metformin in healthy, middle-aged subjects does not protect against endothelial IR-injury, measured with brachial artery FMD after forearm ischemia. Further studies are needed to clarify what mechanism underlies the cardiovascular benefit of metformin treatment.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01610401","term_id":"NCT01610401"}}NCT01610401     

Progesterone Therapy,Endothelial Function and Cardiovascular Risk Factors: A 3-Month Randomized,Placebo-Controlled Trial in Healthy Early Postmenopausal Women

Background

Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation.

Methods and Results

We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003–2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1–11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55±4 years, body mass index 25±3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487±189%, n = 18) compared with placebo (408±278%, n = 16) (95% CI diff [−74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (−0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo.

Conclusions

Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change).

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00152438","term_id":"NCT00152438"}}NCT00152438     

Pioglitazone Improves Fat Distribution,the Adipokine Profile and Hepatic Insulin Sensitivity in Non-Diabetic End-Stage Renal Disease Subjects on Maintenance Dialysis: A Randomized Cross-Over Pilot Study

Background

Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity.

Trial Design

This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects.

Methods

At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored.

Results

Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10⁻³ to 0.76×10⁻³. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP.

Conclusions/Limitations

Pioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation.

Trial Registration

ClinicalTrial.gov {"type":"clinical-trial","attrs":{"text":"NCT01253928","term_id":"NCT01253928"}}NCT01253928     

A Phase Ia Study to Assess the Safety and Immunogenicity of New Malaria Vaccine Candidates ChAd63 CS Administered Alone and with MVA CS

Background

Plasmodium falciparum (P. falciparum) malaria remains a significant cause of mortality and morbidity throughout the world. Development of an effective vaccine would be a key intervention to reduce the considerable social and economic impact of malaria.

Methodology

We conducted a Phase Ia, non-randomized, clinical trial in 24 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding the circumsporozoite protein (CS) of P. falciparum.

Results

ChAd63-MVA CS administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to CS. With a priming ChAd63 CS dose of 5×10⁹ vp responses peaked at a mean of 1947 SFC/million PBMC (median 1524) measured by ELIspot 7 days after the MVA boost and showed a mixed CD4+/CD8+ phenotype. With a higher priming dose of ChAd63 CS dose 5×10¹⁰ vp T cell responses did not increase (mean 1659 SFC/million PBMC, median 1049). Serum IgG responses to CS were modest and peaked at day 14 post ChAd63 CS (median antibody concentration for all groups at day 14 of 1.3 µg/ml (range 0–11.9), but persisted throughout late follow-up (day 140 median antibody concentration groups 1B & 2B 0.9 µg/ml (range 0–4.7).

Conclusions

ChAd63-MVA is a safe and highly immunogenic delivery platform for the CS antigen in humans which warrants efficacy testing.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01450280","term_id":"NCT01450280"}}NCT01450280     

Comparison of Corneal Epithelial and Stromal Thickness Distributions between Eyes with Keratoconus and Healthy Eyes with Corneal Astigmatism ≥2.0 D

Purpose

To identify corneal epithelial- and stromal-thickness distribution patterns in keratoconus using spectral-domain optical coherence tomography (SD-OCT).

Patients and Methods

We analyzed SD-OCT findings in 20 confirmed cases of keratoconus (group 1) and in 20 healthy subjects with corneal astigmatism ≥2 D (group 2). Epithelial and stromal thicknesses were measured at 11 strategic locations along the steepest and flattest meridians, previously located by corneal topography. Vertical mirrored symmetry superimposition was used in the statistical analysis.

Results

The mean maximum keratometry measurements in groups 1 and 2 were 47.9±2.9 D (range, 41.8–52.8) and 45.6±1.1 D (range, 42.3–47.5), respectively, with mean corneal cylinders of 3.3±2.2 D (range, 0.5–9.5) and 3.6±1.2 D (range, 2.0–6.4), respectively. The mean epithelial thickness along the steepest meridian in group 1 was the lowest (37.4±4.4 µm) at 1.2 mm inferotemporally and the highest (59.3±4.4 µm) at 1.4 mm supranasally from the corneal vertex. There was only a small deviation in thickness along the steepest meridian in group 2, as well as along the flattest meridians in both groups. The stromal thickness distribution in the two groups was similar to the epithelial, while the stromal thickness was generally lower in group 1 than in group 2.

Conclusions

SD-OCT provides details about the distribution of corneal epithelial and stromal thicknesses. The epithelium and stroma in keratoconic eyes were thinner inferotemporally and thicker supranasally compared with control eyes. The distribution pattern was more distinct in epithelium than in stroma. This finding may help improve the early diagnosis of keratoconus.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02023619","term_id":"NCT02023619"}}NCT02023619     

Effect of Tree Nuts on Glycemic Control in Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Dietary Trials

Background

Tree nut consumption has been associated with reduced diabetes risk, however, results from randomized trials on glycemic control have been inconsistent.

Objective

To provide better evidence for diabetes guidelines development, we conducted a systematic review and meta-analysis of randomized controlled trials to assess the effects of tree nuts on markers of glycemic control in individuals with diabetes.

Data Sources

MEDLINE, EMBASE, CINAHL, and Cochrane databases through 6 April 2014.

Study Selection

Randomized controlled trials ≥3 weeks conducted in individuals with diabetes that compare the effect of diets emphasizing tree nuts to isocaloric diets without tree nuts on HbA1c, fasting glucose, fasting insulin, and HOMA-IR.

Data Extraction and Synthesis

Two independent reviewer’s extracted relevant data and assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% CI’s. Heterogeneity was assessed (Cochran Q-statistic) and quantified (I²).

Results

Twelve trials (n = 450) were included. Diets emphasizing tree nuts at a median dose of 56 g/d significantly lowered HbA1c (MD = −0.07% [95% CI:−0.10, −0.03%]; P = 0.0003) and fasting glucose (MD = −0.15 mmol/L [95% CI: −0.27, −0.02 mmol/L]; P = 0.03) compared with control diets. No significant treatment effects were observed for fasting insulin and HOMA-IR, however the direction of effect favoured tree nuts.

Limitations

Majority of trials were of short duration and poor quality.

Conclusions

Pooled analyses show that tree nuts improve glycemic control in individuals with type 2 diabetes, supporting their inclusion in a healthy diet. Owing to the uncertainties in our analyses there is a need for longer, higher quality trials with a focus on using nuts to displace high-glycemic index carbohydrates.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01630980","term_id":"NCT01630980"}}NCT01630980