Gerrit van Hall

IT University of Copenhagen, København, Capital Region, Denmark

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Publications (65)298.45 Total impact

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    ABSTRACT: Patients with blocked muscle glycogen breakdown (McArdle disease) have severely reduced exercise capacity compared to healthy individuals and suggested not to produce lactate during exercise. The objectives were to: 1) quantifying systemic and muscle lactate kinetics and oxidation rates and muscle energy utilization during exercise in patients with McArdle disease; 2) elucidate the role of lactate formation in muscle energy production. Single trial Setting: Hospital Participants: Four patients with McArdle disease and seven healthy subjects. Patients and healthy controls were studied at rest, followed by 40 min of cycle-ergometer exercise at 60% of the patients maximal oxygen uptake (∼35 W). Systemic and leg skeletal muscle lactate, alanine, fatty acids and glucose kinetics. McArdle patients had a marked decrease in plasma lactate concentration at the onset of exercise that remained suppressed during exercise. A substantial leg net lactate uptake and subsequent oxidation occurred over the entire exercise period in contrast to a net lactate release or no exchange in the healthy controls. Despite a net lactate uptake by the active leg, a simultaneous unidirectional lactate release was observed in McArdle patients at rates, which were similar to the healthy controls. Lactate is an important energy source for contracting skeletal muscle in patients with myophosphorylase deficiency. Although McArdle patients had net leg lactate consumption, a simultaneous release of lactate was observed at rates similar to that found in healthy individuals exercising at the same very low workload, suggesting that lactate formation is mandatory for muscle energy generation during exercise.
    The Journal of Clinical Endocrinology and Metabolism 06/2015; DOI:10.1210/jc.2015-1339 · 6.31 Impact Factor
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    ABSTRACT: Combining endurance and strength training in the same session has been reported to reduce the anabolic response to the latter form of exercise. The underlying mechanism, based primarily on results from rodent muscle, is proposed to involve AMPK-dependent inhibition of mTORC1 signaling. This hypothesis was tested in eight trained male subjects who in a randomized order performed either resistance exercise only (R) or interval cycling followed by resistance exercise (ER). Biopsies taken from the vastus lateralis before and after endurance exercise and repeatedly after resistance exercise were assessed for glycogen content, kinase activity, protein phosphorylation and gene expression. Mixed muscle fractional synthetic rate was measured at rest and during 3h of recovery using the stable isotope technique. In ER, AMPK activity was elevated immediately after both endurance and resistance exercise (~90%, P<0.05) but was unchanged in R. Thr389 phosphorylation of S6K1 was increased several-fold immediately after exercise (P<0.05) in both trials and increased further throughout recovery. After 90 and 180 min recovery, S6K1 activity was elevated (~55% and ~110%, respectively, P<0.05) and eEF2 phosphorylation was reduced (~55%, P<0.05) with no difference between trials. In contrast, markers for protein catabolism were differently influenced by the two modes of exercise; ER induced a significant increase in gene and protein expression of MuRF1 (P<0.05), which was not observed following R exercise only. In conclusion, cycling-induced elevation in AMPK activity does not inhibit mTORC1 signaling after subsequent resistance exercise, but may instead interfere with the hypertrophic response by influencing key components in protein breakdown. Copyright © 2015, American Journal of Physiology - Endocrinology and Metabolism.
    AJP Endocrinology and Metabolism 01/2015; 308(6):ajpendo.00486.2014. DOI:10.1152/ajpendo.00486.2014 · 4.09 Impact Factor
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    ABSTRACT: Context: Ketone bodies are substrates during fasting and when on a ketogenic diet not the least for the brain and implicated in the management of epileptic seizures and dementia. Moreover, D-β-hydroxybutyrate (HOB) is suggested to reduce blood glucose and fatty acids levels. Objectives: Quantitating systemic, cerebral and skeletal muscle HOB utilization and its effect on energy metabolism. Design: Single trial. Setting: Hospital. Participant: Healthy post-absorptive males (n=6). Interventions: Subjects were studied under basal condition and three consecutive 1 h periods with a 3-, 6- and 12-fold increased HOB concentration via HOB infusion. Main outcome measures: Systemic, cerebral and skeletal muscle HOB kinetics, oxidation, glucose turnover and lipolysis via arterial, jugular and femoral venous differences in combination with stable isotopically labelled HOB, glucose and glycerol infusion. Results: 1. An increase in HOB from the basal 160 to 450 μmol/L elicited 14±2% reduction (P=0.03) in glucose appearance and 37±4% decrease (P=0.03) in lipolytic rate while insulin and glucagon were unchanged; 2. Endogenous HOB appearance was reduced in a dose-dependent manner with complete inhibition at the highest HOB concentration (1.7 mmol/L); 3. Cerebral HOB uptake and subsequent oxidation was linearly related to the arterial HOB concentration; 4. Resting skeletal muscle HOB uptake showed saturation kinetics. Conclusion: A small increase in the HOB concentration decreases glucose production and lipolysis in post-absorptive healthy males. Moreover, cerebral HOB uptake and oxidation rates are linearly related to the arterial HOB concentration of importance for modifying brain energy utilization, potentially of relevance for patients with epileptic seizures and dementia.
    Journal of Clinical Endocrinology &amp Metabolism 11/2014; 100(2):jc20142608. DOI:10.1210/jc.2014-2608 · 6.31 Impact Factor
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    ABSTRACT: In healthy individuals post-exercise protein supplementation increases muscle protein anabolism. In patients with muscular dystrophies, aerobic exercise improves muscle function, but the effect of exercise on muscle protein balance is unknown. Therefore, we investigated 1) muscle protein balance before, during, and after exercise and 2) the effect of post-exercise protein-carbohydrate supplementation on muscle protein balance in patients with muscular dystrophies. In 17 patients (7 women and 10 men, age 33 ± 11 years (18-52), BMI: 22 ± 3 kg/m2 (16-26)) and 8 healthy matched controls (3 women and 5 men, age 33 ± 13 years (19-54), BMI: 23 ± 3 kg/m2 (19-27)), muscle protein synthesis, breakdown, and fractional synthesis rates (FSR) were measured across the leg using tracer dilution methodology on two occasions; with and without oral post-exercise protein-carbohydrate supplementation. In patients, muscle protein breakdown increased in the recovery period (11 ± 1 µmol phenylalanine/min) versus rest (8 ± 1 µmol phenylalanine/min, P = 0.02) enhancing net muscle protein loss. In contrast, post-exercise protein-carbohyddrate supplementation reduced protein breakdown, abolished net muscle protein loss and increased the muscle FSR in patients (0.04 to 0.06 % per hour, P = 0.03). In conclusion, post-exercise protein-carbohydrate supplementation reduces skeletal mixed muscle protein breakdown, enhances FSR, resulting in a reduced net muscle loss in patients with muscular dystrophies. The findings suggest that post-exercise protein-carbohydrate supplementation could be an important add-on to exercise training therapy in muscular dystrophies, and long-term studies of post-exercise protein-carbohydrate supplementation are warranted in these conditions. Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    AJP Regulatory Integrative and Comparative Physiology 11/2014; 308(2):ajpregu.00321.2014. DOI:10.1152/ajpregu.00321.2014 · 3.53 Impact Factor
  • Andreas Bornø, Lene Foged, Gerrit van Hall
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    ABSTRACT: The present study describes a new liquid chromatography tandem mass spectrometry method for high-throughput quantification of glucose and glycerol in human plasma using stable isotopically labeled internal standards and is suitable for simultaneous measurements of glucose and glycerol enrichments in connection to in vivo metabolic studies investigating glucose turnover and lipolytic rate. Moreover, in order to keep up with this new fast analysis, simple derivatization procedures have been developed.Prior to analysis, glucose and glycerol were derivatized using benzoyl chloride in order to form benzoylated derivatives via new simplified fast procedures. For glucose, two internal standards were evaluated, [U-13C6]glucose and [U-13C6, D7]glucose, and for glycerol, [U-13C3, D8]glycerol was used. The method was validated by means of calibration curves, quality control samples, and plasma samples spiked with [6,6-D2]glucose, [U-13C6]glucose, and [1,1,2,3,3-D5]glycerol in order to test accuracy, precision, and recovery of the method. Moreover, post preparative and freeze-thaw sample stability were tested.The correlation of calibration curves for the glucose concentration were r2 = 0.9998 for [U-13C6]glucose and r2 = 0.9996 for [U-13C6, D7]glucose, and r2 = 0.9995 for the glycerol concentration. Interday accuracy for glucose using [U-13C6]glucose and glycerol determined in spiked plasma were respectively 103.5% and 106.0%, and the coefficients of variation were 2.0% and 9.7%, respectively. After derivatization, plasma samples were stable for at least 14 days.In conclusion, we have developed and validated a novel, accurate, and sensitive high-throughput liquid chromatography tandem mass spectrometry method for simultaneous determination of glucose and glycerol concentrations and enrichment of infused tracers most commonly used in human metabolic kinetic studies. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Mass Spectrometry 10/2014; 49(10). DOI:10.1002/jms.3407 · 2.71 Impact Factor
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    ABSTRACT: We investigated glucose tolerance and postprandial glucose fluxes immediately after a single bout of aerobic exercise in subjects representing the entire glucose tolerance continuum. Twenty-four men with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or type 2 diabetes (T2D; age: 56 ± 1 years; body mass index: 27.8 ± 0.7 kg/m2, P > 0.05) underwent a 180-min oral glucose tolerance test (OGTT) combined with constant intravenous infusion of [6,6-2H2]glucose and ingestion of [U-13C]glucose, following 1 h of exercise (50% of peak aerobic power) or rest. In both trials, plasma glucose concentrations and kinetics, insulin, C-peptide, and glucagon were measured. Rates (mg kg−1 min−1) of glucose appearance from endogenous (RaEndo) and exogenous (oral glucose; RaOGTT) sources, and glucose disappearance (Rd) were determined. We found that exercise increased RaEndo, RaOGTT, and Rd (all P < 0.0001) in all groups with a tendency for a greater (~20%) peak RaOGTT value in NGT subjects when compared to IGT and T2D subjects. Accordingly, following exercise, the plasma glucose concentration during the OGTT was increased in NGT subjects (P < 0.05), while unchanged in subjects with IGT and T2D. In conclusion, while a single bout of moderate-intensity exercise increased the postprandial glucose response in NGT subjects, glucose tolerance following exercise was preserved in the two hyperglycemic groups. Thus, postprandial plasma glucose responses immediately following exercise are dependent on the underlying degree of glycemic control.
    08/2014; 2(8). DOI:10.14814/phy2.12114
  • Andreas Bornø, Carl J. Hulston, Gerrit van Hall
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    ABSTRACT: In the present study, different MS methods for the determination of human muscle protein fractional synthesis rate (FSR) using [ring-13C6]phenylalanine as a tracer were evaluated. Because the turnover rate of human skeletal muscle is slow, only minute quantities of the stable isotopically labeled amino acid will be incorporated within the few hours of a typical laboratory experiment. GC combustion isotope ratio MS (GC-C-IRMS) has thus far been considered the ‘gold’ standard for the precise measurements of these low enrichment levels. However, advances in liquid chromatography-tandem MS (LC-MS/MS) and GC-tandem MS (GC-MS/MS) have made these techniques an option for human muscle FSR measurements. Human muscle biopsies were freeze dried, cleaned, and hydrolyzed, and the amino acids derivatized using either N-acetyl-n-propyl, phenylisothiocyanate, or N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA) for GC-C-IRMS, LC-MS/MS, and GC-MS/MS analysis, respectively. A second derivative, heptafluorobutyric acid (HFBA), was also used for GC-MS/MS analysis as an alternative for MTBSTFA. The machine reproducibility or the coefficients of variation for delta tracer-tracee-ratio measurements (delta tracer-tracee-ratio values around 0.0002) were 2.6%, 4.1%, and 10.9% for GC-C-IRMS, LC-MS/MS, and GC-MS/MS (MTBSTFA), respectively. FSR determined with LC-MS/MS compared well with GC-C-IRMS and so did the GC-MS/MS when using the HFBA derivative (linear fit Y = 1.08 ± 0.10, X + 0.0049 ± 0.0061, r = 0.89 ± 0.01, P < 0.0001). In conclusion, (1) IRMS still offers the most precise measurement of human muscle FSR, (2) LC-MS/MS comes quite close and is a good alternative when tissue quantities are too small for GC-C-IRMS, and (3) If GC-MS/MS is to be used, then the HFBA derivative should be used instead of MTBSTFA, which gave unacceptably high variability. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Mass Spectrometry 08/2014; 49(8). DOI:10.1002/jms.3387 · 2.71 Impact Factor
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    ABSTRACT: Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic and glucagon-like peptide 1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM).Ten male subjects with T1DM (C-peptide negative, age: 26±1 years (mean±SEM); BMI: 24±0.5 kg/m(2); HbA1c 7.3±0.2%) were studied in a randomized, double-blinded, cross-over study, with 2-hour iv administration of saline, GIP or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a 'recovery phase'.During the recovery phase GIP infusions elicited larger glucagon responses (164±50 (GIP) vs. 23±25 (GLP-1) vs. 17±46 (saline) min×pmol/l, P<0.03) and endogenous glucose production was higher with GIP and lower with GLP-1 as compared to saline (P<0.02). On the GIP days significantly less exogenous glucose was needed to keep plasma glucose above 2 mmol/l (155±36 (GIP) vs. 232±40 (GLP-1) vs. 212±56 (saline) mg×kg(-1), P<0.05). Levels of insulin, cortisol, growth hormone, and noradrenaline, as well as hypoglycemic symptoms and cognitive function, were similar on all days.Our results suggest that during hypoglycemia in patients with T1DM exogenous GIP increases glucagon responses during the 'recovery phase' after hypoglycemia and reduces the need for glucose administration.
    Diabetes 07/2014; 64(1). DOI:10.2337/db14-0440 · 8.47 Impact Factor
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    ABSTRACT: It is an ongoing discussion the extent to which oxygen delivery and oxygen extraction contribute to an elevated muscle oxygen uptake during dynamic exercise. It has been proposed that local muscle factors including the capillary bed and mitochondrial oxidative capacity play a large role in prolonged low intensity training of a small muscle group when the cardiac output capacity is not directly limiting. The purpose of this study was to investigate the relative roles of circulatory and muscle metabolic mechanisms by which prolonged low-intensity exercise training alters regional muscle VO2 . In 9 healthy volunteers (7 male, 2 female), hemodynamic and metabolic responses to incremental arm cycling were measured by the Fick method and biopsy of the deltoid and triceps muscles before and after 42 days of skiing for 6 hr(.) day(-1) at 60% max heart rate. Peak pulmonary VO2 during arm crank was unchanged after training (2.38±0.19 vs. 2.18±0.2 L(.) min(-1) pre-training) yet arm VO2 (1.04±0.08 vs. 0.83±0.1 L(.) min(1) , P<0.05) and power output (137±9 vs. 114±10 Watts) were increased along with a higher arm blood flow (7.9±0.5 vs. 6.8±0.6 L(.) min(-1) , P<0.05) and expanded muscle capillary volume (76±7 vs. 62±4 ml, P<0.05). Muscle O2 diffusion capacity (16.2±1 vs. 12.5 ±0.9 ml(.) min(-1.) mHg(-1) , P<0.05) and O2 extraction (68±1 vs. 62±1%, P<0.05) were enhanced at a similar mean capillary transit time (569±43 vs. 564±31 ms) and P50 (35.8±0.7 vs. 35±0.8), whereas mitochondrial O2 flux capacity was unchanged (147±6 ml(.) kg(.) min(-1) vs. 146±8 ml(.) kg(.) min(-1) ). The mechanisms underlying the increase in peak arm VO2 with prolonged low intensity training in previously untrained subjects are an elevated convective O2 delivery specifically to the muscles of the arm combined with a larger capillary-muscle surface area that enhance diffusional O2 conductance, with no apparent role of mitochondrial respiratory capacity. This article is protected by copyright. All rights reserved.
    Acta Physiologica 02/2014; DOI:10.1111/apha.12258 · 4.25 Impact Factor
  • Andreas Bornø, Gerrit van Hall
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    ABSTRACT: An important area within clinical functional metabolomics is in vivo amino acid metabolism and protein turnover measurements for which accurate amino acid concentrations and stable isotopically labeled amino acid enrichments are mandatory not the least when tissue metabolomics is determined. The present study describes a new sensitive liquid chromatography tandem mass-spectrometry method quantifying 20 amino acids and their tracer(s) ([ring-(13)C6]/D5Phenylalanine) in human plasma and skeletal muscle specimens. Before analysis amino acids were extracted and purified via deprotonization/ion exchange, derivatized using a phenylisothiocyanate reagent and each amino acid was quantitated with its own stable isotopically labeled internal standard (uniformly labeled-(13)C/(15)N). The method was validated according to general recommendations for chromatographic analytical methods. The calibration curve correlations for amino acids were on average; r(2)=0.998. Interday accuracy for amino acids determined in spiked plasma was on average 97.3% and the coefficient of variation (CV) was 2.6%. The ([ring-(13)C6]/D5Phenylalanine) enrichment CV's for machine reproducibility in muscle tissue fluid and plasma were 4.4 and 0.8%, and the interday variability was 3.4% and the recovery was 90.5%, respectively. In conclusion, we have developed and validated a method for quantitative amino acid profiling that meets the requirements for systemic and tissue human in vivo amino acid and protein turnover kinetics measurements. Moreover, citrulline, ornithine, π-methyl-histidine, τ-methyl-l-histidine, hydroxy-proline and carnitine were analysed but when similar precision and accuray are required an additional stable istopically labeled internal standard for these meatablites should be be added.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 01/2014; 951-952C:69-77. DOI:10.1016/j.jchromb.2014.01.019 · 2.69 Impact Factor
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    ABSTRACT: Type 2 diabetes is characterized by increased insulin resistance and impaired insulin secretion. Type 2 diabetes is also associated with low-grade inflammation and increased levels of proinflammatory cytokines such as TNF- α . TNF- α has been shown to impair peripheral insulin signaling in vitro and in vivo. However, it is unclear whether TNF- α may also affect endogenous glucose production (EGP) during fasting and glucose-stimulated insulin secretion (GSIS) in vivo. We hypothesized that low-dose TNF- α would increase EGP and attenuate GSIS. Recombinant human TNF- α or placebo was infused in healthy, nondiabetic young men (n = 10) during a 4-hour basal period followed by an intravenous glucose tolerance test (IVGTT). TNF- α lowered insulin levels by 12% during the basal period (P < 0.05). In response to the IVGTT, insulin levels increased markedly in both trials, but there was no difference between trials. Compared to placebo, TNF- α did not affect EGP during the basal period. Our results indicate that TNF- α acutely lowers basal plasma insulin levels but does not impair GSIS. The mechanisms behind this are unknown but we suggest that it may be due to TNF- α increasing clearance of insulin from plasma without impairing beta-cell function or hepatic insulin sensitivity.
    Mediators of Inflammation 01/2014; 2014:295478. DOI:10.1155/2014/295478 · 2.42 Impact Factor
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    ABSTRACT: Roux-en-Y gastric bypass surgery (RYGB) improves glucose tolerance in patients with type 2 diabetes, but also changes the glucose profile in response to a meal in glucose-tolerant individuals. We hypothesised that the driving force for the changed postprandial glucose profiles after RYGB is rapid entry of glucose into the systemic circulation due to modified gastrointestinal anatomy, causing hypersecretion of insulin and other hormones influencing glucose disappearance and endogenous glucose production. We determined glucose absorption and metabolism and the rate of lipolysis before and 3 months after RYGB in obese glucose-tolerant individuals using the double-tracer technique during a mixed meal. After RYGB, the postprandial plasma glucose profile changed, with a higher peak glucose concentration followed by a faster return to lower than basal levels. These changes were brought about by changes in glucose kinetics: (1) a more rapid appearance of ingested glucose in the systemic circulation, and a concomitant increase in insulin and glucagon-like peptide-1 secretion; (2) postprandial glucose disappearance was maintained at a high rate for a longer time after RYGB. Endogenous glucose production was similar before and after surgery. Postoperative glucagon secretion increased and showed a biphasic response after RYGB. Adipose tissue basal rate of lipolysis was higher after RYGB. A rapid rate of absorption of ingested glucose into the systemic circulation, followed by increased insulin secretion and glucose disappearance appears to drive the changes in the glucose profile observed after RYGB, while endogenous glucose production remains unchanged. NCT01559792. The study was part of the UNIK program: Food, Fitness & Pharma for Health and Disease (see ). Funding was received from the Novo Nordisk foundation and the Strategic Research Counsel for the Capital Area and Danish Research Agency. The primary investigator received a PhD scholarship from the University of Copenhagen, which was one-third funded by Novo Nordisk.
    Diabetologia 07/2013; 56(10). DOI:10.1007/s00125-013-3003-0 · 6.88 Impact Factor
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    ABSTRACT: Patients with mitochondrial DNA mutations often have elevated plasma lactate at rest and during exercise, but it is unknown whether the high lactate levels are caused by a high production, an impaired oxidation or a combination. We studied lactate kinetics in 10 patients with mtDNA mutations and 10 matched healthy control subjects at rest and during cycle exercise with a combination of femoral arterio-venous differences of lactate, and lactate tracer dilution methodology. During exercise, lactate concentration and production rates were several-fold higher in patients, but despite mitochondrial dysfunction, lactate was oxidized in muscle to the same extent as in healthy control subjects. This surprisingly high ability to burn lactate in working muscle with defective mitochondria, probably relates to the variability of oxidative capacity among muscle fibers. The data suggests that lactate is not solely an indicator of impaired oxidative capacity, but an important fuel for oxidative metabolism, even in muscle with severely impaired mitochondrial function.
    Neuromuscular Disorders 07/2013; 23(8). DOI:10.1016/j.nmd.2013.05.007 · 3.13 Impact Factor
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    ABSTRACT: Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigates if endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and 10 healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy x-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistics: Two-way ANOVA. Endurance training increased VO2max (ml(O2)/min/kg) by 11% and 13% in patients and controls, respectively (p<0.0001). The patients and controls demonstrated an increase in peripheral insulin sensitivity of 14% and 11%, respectively (p<0.05), with no effect on hepatic insulin sensitivity (p=0.32). Muscle protein content of GLUT4 and total Akt was also increased in response to the training (p<0.05 and p<0.01, respectively). Body weight (p<0.0001) and whole-body fat mass (p<0.01) were reduced, while lean body mass (p=0.99) was unchanged. Additionally, reductions were noted in abdominal (p<0.01), subcutaneous (p<0.05) and visceral fat mass (p<0.01). Plasma markers of systemic inflammation were unchanged in response to the training. No group×time interactions were found, except for thigh intermuscular adipose tissue (IMAT) (p=0.01), reflecting a significant reduction in IMAT in controls (p<0.05) not observed in patients (p=0.64). In response to endurance training, ADT-treated prostate cancer patients improved insulin sensitivity and body composition to a similar degree as eugonadal men.
    Endocrine Related Cancer 06/2013; 20(5). DOI:10.1530/ERC-12-0393 · 4.91 Impact Factor
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    ABSTRACT: PURPOSE: Resistance exercise and amino acid availability are positive regulators of muscle protein net balance (NB). However, anabolic responses to resistance exercise and protein supplementation deserve further elucidation. The purpose was to compare intakes of whey, caseinate (both: 0.30 g/kg lean body mass), or a non-caloric control after heavy resistance exercise on protein turnover and mRNA expressions of forkhead homeobox type O (FOXO) isoforms, muscle RING finger 1 (MuRF1), and Atrogin1 in young healthy males. METHODS: Protein turnover was determined by stable isotope-labeled leucine and femoral arteriovenous blood samples at rest and during 6-h recovery. Muscle biopsies were collected at -60 min (rest) and at 60, 210, and 360 min in the recovery period. RESULTS: During recovery, leucine NB was significantly higher in the protein groups compared to control (P < 0.001). Differences in leucine NB, rate of disappearance, and oxidation were observed in the early recovery period between whey and caseinate. FOXO1A and MuRF1 were upregulated at 60 and 210 min, and, in contrast, FOXO3 and Atrogin1 were downregulated at 210 and 360 min. For leucine rate of appearance and all FOXO and atrogene mRNA expressions, no differences were observed between groups. CONCLUSIONS: Whey and caseinate were equally superior to control in the 6-h recovery period and displayed temporal differences with whey having a fast and superior effect in the early part of the recovery period. Effects on mRNA expressions indicate different regulatory mechanisms on the ubiquitin ligases MuRF1 and Atrogin1 in recovery from heavy resistance exercise.
    European Journal of Nutrition 05/2013; DOI:10.1007/s00394-013-0530-x · 3.84 Impact Factor
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    ABSTRACT: Leptin is considered an adipokine, however, cultured myocytes have also been found to release leptin. Therefore, as proof-of-concept we investigated if human skeletal muscle synthesized leptin by measuring leptin in skeletal muscle biopsies. Following this, we quantified human skeletal muscle and adipose tissue leptin release in vivo. We recruited 16 healthy male human participants. Catheters were inserted into the femoral artery and vein draining skeletal muscle, as well as an epigastric vein draining the abdominal subcutaneous adipose tissue. By combining the veno-arterial differences in plasma leptin with measurements of blood flow, leptin release from both tissues was quantified. To induce changes in leptin, the participants were infused with either saline or adrenaline in normo-physiological concentrations. The presence of leptin in skeletal muscle was confirmed by western blotting. Leptin was released from leg skeletal muscle (50.6±12ngmin(-1)) and the pattern of release was different from subcutaneous adipose tissue. Moreover, during adrenaline infusion the leptin release from leg skeletal muscle was strongly suppressed (20.5±7.9ngmin(-1), p<0.017), whereas the release from fat was unaltered. During saline infusion the adipose tissue release averaged 0.8±0.3ngmin(-1) 100g tissue(-1) whereas skeletal muscle release was 0.5±0.1ngmin(-1) 100g tissue(-1). In young healthy humans, skeletal muscle contribution to whole body leptin production could be substantial given the greater mass of muscle compared to fat. An understanding of the role that leptin plays in skeletal muscle metabolism may prove important in light of several late-phase trials with recombinant leptin as an anti-obesity drug.
    Cytokine 09/2012; 60(3). DOI:10.1016/j.cyto.2012.08.021 · 2.87 Impact Factor
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    ABSTRACT: A lifestyle characterized by inactivity and a high-calorie diet is a known risk factor for impaired insulin sensitivity and development of Type 2 diabetes mellitus. To investigate possible links, nine young healthy men (24 ± 3 yr; body mass index of 21.6 ± 2.5 kg/m(2)) completed 14 days of step reduction (10,000 to 1,500 steps/day) and overfeeding (+50% kcal). Body composition (dual X-ray absorptiometry, MRI), aerobic fitness (maximal O(2) consumption), systemic inflammation and insulin sensitivity [oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp] were assessed before (day 0), during (days 3 and 7), and immediately after the intervention (day 14), with follow-up tests (day 30). Body weight had increased at days 7 and 14 (P < 0.05). The amount of visceral fat had increased at day 14 compared with day 0 (P < 0.05). The insulin response to the OGTT had increased at days 7 and 14 (P < 0.05). Insulin sensitivity, estimated using the Matsuda index, had decreased at days 3 and 7 (P < 0.01). At day 14, glucose infusion rates had decreased by ∼44% during the euglycemic clamps (P < 0.05). Also, plasma levels of leptin and adiponectin had increased (P < 0.05), whereas no changes were seen in inflammatory markers. At day 30, body weight and whole body adiposity were still elevated compared with day 0 (P < 0.05), whereas the insulin sensitivity as well as the insulin response to the OGTT did not differ from baseline. The glucose response to the OGTT was only affected at day 30, with a decrease compared with day 0. Our data show that insulin sensitivity was impaired after 3 days of inactivity and overfeeding. Impairments in insulin sensitivity occurred before changes in body composition, supporting the notion that the initial steps in impairment of insulin sensitivity may be linked directly to the effects of inactivity and a high calorie intake.
    Journal of Applied Physiology 05/2012; 113(1):7-15. DOI:10.1152/japplphysiol.00189.2011 · 3.43 Impact Factor
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    ABSTRACT: To elucidate the molecular mechanisms behind physical inactivity-induced insulin resistance in skeletal muscle, 12 young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies obtained before and after. In six of the subjects, muscle biopsies were taken from both legs before and after a 3-h hyperinsulinemic euglycemic clamp performed 3 h after a 45-min, one-legged exercise. Blood samples were obtained from one femoral artery and both femoral veins before and during the clamp. Glucose infusion rate and leg glucose extraction during the clamp were lower after than before bed rest. This bed rest-induced insulin resistance occurred together with reduced muscle GLUT4, hexokinase II, protein kinase B/Akt1, and Akt2 protein level, and a tendency for reduced 3-hydroxyacyl-CoA dehydrogenase activity. The ability of insulin to phosphorylate Akt and activate glycogen synthase (GS) was reduced with normal GS site 3 but abnormal GS site 2+2a phosphorylation after bed rest. Exercise enhanced insulin-stimulated leg glucose extraction both before and after bed rest, which was accompanied by higher GS activity in the prior-exercised leg than the rested leg. The present findings demonstrate that physical inactivity-induced insulin resistance in muscle is associated with lower content/activity of key proteins in glucose transport/phosphorylation and storage.
    Diabetes 03/2012; 61(5):1090-9. DOI:10.2337/db11-0884 · 8.47 Impact Factor
  • Gerrit van Hall
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    ABSTRACT: This review highlights the role of cytokines, in particular tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in relation to the nature of human in-vivo muscle wasting in disease. Infusion of human TNF-α and IL-6 in healthy individuals, acutely raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle protein synthesis and breakdown, that is, reduced turnover with a minor increase in net muscle degradation. Very similar observations have been made in models of acute inflammation, induced by high-dose endotoxin injection. However, these changes were suggested not to be attributed to a direct effect of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability. Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However, these cytokines can initiate important changes in secondary mediators and/or clinical complications that need correction therapies causing muscle wasting. Moreover, the general view from animal work is that in muscle wasting the rate of muscle protein synthesis is decreased and the rate of breakdown is increased. However, this does not seem applicable for inflammatory diseases or human models of sepsis, in which the enhanced imbalance between these two processes is observed within an enhanced, normal or reduced muscle protein turnover.
    11/2011; 15(1):85-91. DOI:10.1097/MCO.0b013e32834e6ea2
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    ABSTRACT: Obese and lean humans treated with leptin have not experienced convincing weight-loss results compared with the dramatic weight losses observed in obese rodents. We sought to investigate the effect of acutely elevating leptin to concentrations observed in obese individuals on muscle and adipose tissue metabolism and muscle signaling in healthy lean males. Healthy, lean, postabsorptive males were infused with either recombinant human leptin (rhleptin; n = 8) or saline (control; n = 8) for 4 h, which elicited leptin concentrations of ~ 20 and ~ 1 ng/mL, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism in vivo were assessed before, during, and 2 h after cessation of the infusion. Skeletal muscle biopsy specimens were obtained to quantify changes in signal transducers and activators of transcription-5'AMP-activated protein kinase (STAT-AMPK) signaling. During the infusion of rhleptin, no differences in either systemic, skeletal muscle, or adipose tissue glucose or fat metabolism were observed. These observations were made despite increased activation of STAT (~ 17-fold) and AMPK (1.43-fold) after 1 h of rhleptin infusion. After the rhleptin infusion, an increase in systemic palmitate and fat oxidation was observed (P < 0.0003), which likely was caused by a concomitant increase in skeletal muscle palmitate oxidation (P < 0.02). This was observed despite lowered leptin concentrations and basal skeletal muscle STAT-AMPK signaling. Elevating circulating leptin concentrations to concentrations comparable with those of obese individuals increases human in vivo skeletal muscle signaling through the AMPK pathway and causes an increase in skeletal muscle fatty acid oxidation. Abdominal adipose tissue was unaffected by the acute physiologic increase in leptin concentrations.
    American Journal of Clinical Nutrition 11/2011; 94(6):1533-44. DOI:10.3945/ajcn.111.012260 · 6.92 Impact Factor

Publication Stats

2k Citations
298.45 Total Impact Points


  • 2000–2015
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 2011
    • Wernersville State Hospital
      Wernersville, Pennsylvania, United States
  • 2009–2010
    • Steno Diabetes Center
      Gjentofte, Capital Region, Denmark
  • 2007
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2003
    • Rigshospitalet
      København, Capital Region, Denmark
  • 2002
    • Copenhagen University Hospital
      København, Capital Region, Denmark