Gerrit van Hall

IT University of Copenhagen, København, Capital Region, Denmark

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Publications (73)336.93 Total impact

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    ABSTRACT: Glucagon is believed to be a pancreas-specific hormone and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from alpha cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy controls to a 75g-oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich enzyme-linked immunosorbent assay and mass-spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.
    Full-text · Article · Dec 2015 · Diabetes
  • Gerrit van Hall
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    ABSTRACT: Energy substrates that are important to the working muscle at moderate intensities are the non-esterified fatty acids (NEFAs) taken up from the circulation and NEFAs originating from lipolysis of the intramuscular triacylglycerol (IMTAG). Moreover, NEFA from lipolysis via lipoprotein lipase (LPL) in the muscle of the very-low-density lipoproteins and in the (semi) post-prandial state chylomicrons may also contribute. In this review, the NEFA fluxes and oxidation by skeletal muscle during prolonged moderate-intensity exercise are described in terms of the integration of physiological systems. Steps involved in the regulation of the active muscle NEFA uptake include (1) increased energy demand; (2) delivery of NEFA to the muscle; (3) transport of NEFA into the muscle by NEFA transporters; and (4) activation of the NEFAs and either oxidation or re-esterification into IMTAG. The increased metabolic demand of the exercising muscle is the main driving force for all physiological regulatory processes. It elicits functional hyperemia, increasing the recruitment of capillaries and muscle blood flow resulting in increased NEFA delivery and accessibility to NEFA transporters and LPL. It also releases epinephrine that augments adipose tissue NEFA release and thereby NEFA delivery to the active muscle. Moreover, NEFA transporters translocate to the plasma membrane, further increasing the NEFA uptake. The majority of the NEFAs taken up by the active muscle is oxidized and a minor portion is re-esterified to IMTAG. Net IMTAG lipolysis occurs; however, the IMTAG contribution to total fat oxidation is rather limited compared to plasma-derived NEFA oxidation, suggesting a complex role and regulation of IMTAG utilization.
    No preview · Article · Nov 2015
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    ABSTRACT: Background & aims: We evaluated the glucagon-suppressive effect of glucagon-like peptide-1 (GLP-1) and its potential effects on endogenous glucose production and whole body lipolysis in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD). Methods: On two separate days 10 non-diabetic patients with liver biopsy-verified NAFLD (NAFLD activity score 2.5±1.0) and 10 matched controls underwent a 2-hour intravenous infusions of GLP-1 (0.8 pmol × kg(-1) × min(-1)) and placebo. Since GLP-1-mediated glucagon suppression has been shown to be glucose-dependent, plasma glucose was clamped at fasting level during the first hour, and then raised and clamped at 'postprandial level' (fasting plasma glucose level plus 3 mmol/L) for the remaining hour. We evaluated relative plasma levels of glucagon, endogenous glucose production and whole body lipolysis rates with stable isotopes and respiratory quotient using indirect calorimety. Results: Compared to controls, patients with NAFLD were insulin resistant (homeostasis model assessment (HOMAIR): 3.8±2.2 vs. 1.6±1.5, p=0.003) and had fasting hyperglucagonaemia (7.5±5.3 vs. 5.8±1.5 mmol/L, p=0.045). Similar relative glucagon suppression was seen in both groups during GLP-1 infusion at fasting (-97±75 vs. -93±41 pmol/L × min(-1)p=0.566) and 'postprandial' plasma glucose levels (-108±101 vs. -97±53 pmol/L × min(-1), p=0.196). Increased insulinotropic effects of GLP-1 was observed in NAFLD patients. No effect of GLP-1 on endogenous glucose production was observed in any of the groups. Conclusions: Patients with NAFLD exhibited fasting hyperglucagonaemia, but intact GLP-1-mediated glucagon suppression independently of plasma glucose concentrations. Preserved glucagonostatic effect and increased insulinotropic effects of GLP-1 in NAFLD may be important to maintain normoglycaemia in these patients.
    No preview · Article · Nov 2015 · Journal of Hepatology
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    ABSTRACT: Aims: The impact of diet-induced weight loss and weight loss due to RYGB in patients with (T2DM, N = 16) and without (OB, N = 27) type 2 diabetes was studied. Methods: At inclusion (A), after diet-induced weight loss (B), 4 months post-surgery (C) and 18 months post-surgery (D) body composition, hepatic glucose production (HGP), insulin-mediated glucose uptake (GIR), respiratory exchange ratio, hepatic insulin sensitivity and clearance were determined. GLUT4, intramuscular triglycerides (IMTG) and glycogen content were measured in skeletal muscle. Results: Weight loss was 35-40 kg, and approximately one-third of the total improvement in GIR in T2DM was observed after the diet-induced weight loss of only ~6 kg (B). Insulin clearance, visceral fat and fasting plasma insulin also improved significantly after the diet (P < 0.05). Throughout the study, HGP, GLUT4 and glycogen content did not change significantly, but IMTG decreased significantly consistent with significant increases in GIR. Metabolic flexibility and hepatic insulin sensitivity improved after RYGB. Conclusions: Metabolic improvements of RYGB are present already after the diet-induced weight loss prior to surgery. GLUT4 content in skeletal muscle cannot and IMTG content can only partly explain increases in GIR after RYGB.
    No preview · Article · Oct 2015 · Acta Diabetologica
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    ABSTRACT: To study adipose tissue mitochondrial respiration and lipolysis following a massive weight loss. High resolution respirometry of adipose tissue biopsies and tracer determined whole body lipolysis. Sixteen obese patients with type 2 diabetes (T2DM) and 27 without (OB) were studied following a massive weight loss by diet and Roux-en-Y gastric bypass (RYGB). The mitochondrial respiratory rates were similar in OB and T2DM, and the mass-specific oxygen flux increased significantly 4 and 18 months post-surgery (P < 0.05). With normalization to mitochondrial content, no differences in oxidative capacity after RYGB were seen. The ratio between the oxidative phosphorylation system capacity (P) and the capacity of the electron transfer system (E) increased 18 months after RYGB in both groups (P < 0.05). Lipolysis per fat mass was similar in the two groups and was increased (P < 0.05) and lipid oxidation during hyperinsulinemia decreased 4 months post-surgery. In T2DM, visceral fat mass was always higher relative to the body fat mass (%) compared to OB. Adipose tissue mitochondrial respiratory capacity increases with RYGB. Adipocytes adapt to massive weight loss by increasing the phosphorylation system ratio (P/E), suggesting an increased ability to oxidize substrates after RYGB. Lipolysis increases in the short term post-surgery, and insulin sensitivity for suppression of lipolysis increases with RYGB. © 2015 The Obesity Society.
    No preview · Article · Sep 2015 · Obesity
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    ABSTRACT: Temperature-sensitive mechanisms may contribute to blood flow regulation, but the influence of temperature on perfusion to exercising and non-exercising human limbs is not established. Blood temperature (TB ), blood flow and oxygen uptake (VO2 ) in the legs and arms were measured in 16 healthy humans during 90 min of leg and arm exercise and during exhaustive incremental leg or arm exercise. During prolonged exercise, leg blood flow (LBF) was 4-fold higher than arm blood flow (ABF) in association with higher TB and limb VO2 . Leg and arm vascular conductance during exercise compared to rest was related closely to TB (R(2) = 0.91; P < 0.05), plasma adenosine triphosphate (ATP) (R(2) = 0.94; P < 0.05) and limb VO2 (R(2) = 0.99; P < 0.05). During incremental leg exercise, LBF increased in association with elevations in TB and limb VO2 whereas ABF, arm TB and VO2 remained largely unchanged. During incremental arm exercise, both ABF and LBF increased in relation to similar increases in VO2 . In 12 trained males, increases in femoral TB and LBF during incremental leg exercise were mirrored by similar pulmonary artery TB and cardiac output dynamics, suggesting that processes in active limbs dominate central temperature and perfusion responses. The present data reveal a close coupling among perfusion, TB and aerobic metabolism in exercising and non-exercising extremities and a tight association between limb vasodilatation and increases in plasma ATP. These findings suggest that temperature and VO2 contribute to the regulation of limb perfusion through control of intravascular ATP. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2015 · Experimental physiology
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    ABSTRACT: Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in admixture of gastro-pancreatic enzymes, which could have a major impact on protein digestion and amino acid absorption. We investigated the effect of RYGB on amino acid appearance in the systemic circulation from orally ingested protein and from endogenous release. Nine obese glucose-tolerant subjects, with a mean body mass index (in kg/m(2)) of 39.2 (95% CI: 35.2, 43.3) and mean glycated hemoglobin of 5.3% (95% CI: 4.9%, 5.6%), were studied before and 3 mo after RYGB. Leucine and phenylalanine kinetics were determined under basal conditions and during 4 postprandial hours by intravenous infusions of [3,3,3-(2)H3]-leucine and [ring-(2)D5]-phenylalanine combined with ingestion of [1-(13)C]-leucine intrinsically labeled caseinate as the sole protein source of the meal. Changes in body composition were assessed by dual-energy X-ray absorptiometry. After RYGB, basal plasma leucine concentration did not change, but marked changes were seen postprandially with 1.7-fold increased peak concentrations (before: mean: 217 μmol/L; 95% CI: 191, 243 μmol/L; 3 mo: mean: 377 μmol/L; 95% CI: 252, 502 μmol/L; P = 0.012) and 2-fold increased incremental AUC (before: mean: 4.1 mmol · min/L; 95% CI: 2.7, 5.5 mmol · min/L; 3 mo: mean: 9.5 mmol · min/L; 95% CI: 4.9, 14.2 mmol · min/L; P = 0.032). However, the postprandial hyperleucinemia was transient, and concentrations were below basal concentrations in the fourth postprandial hour. These concentration differences were mainly caused by changes in leucine appearance rate from orally ingested caseinate: peak rate increased nearly 3-fold [before: mean: 0.5 μmol/(kg fat-free mass · min); 95% CI: 0.4, 0.5 μmol/(kg fat-free mass · min); 3 mo: mean 1.4 μmol/(kg fat-free mass · min); 95% CI: 0.8, 1.9 μmol/(kg fat-free mass · min); P = 0.002], and time to peak was much shorter (before: mean: 173 min; 95% CI: 137, 209 min; 3 mo: mean: 65 min; 95% CI: 46, 84 min; P < 0.001). Only minor changes were seen in endogenous leucine release after RYGB. RYGB accelerates caseinate digestion and amino acid absorption, resulting in faster and higher but more transient postprandial elevation of plasma amino acids. Changes are likely mediated by accelerated intestinal nutrient entry and clearly demonstrate that protein digestion is not impaired after RYGB. This trial was registered at clinicaltrials.gov as NCT01559792. © 2015 American Society for Nutrition.
    No preview · Article · Aug 2015 · American Journal of Clinical Nutrition
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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.
    No preview · Article · Jun 2015 · The Journal of Clinical Endocrinology and Metabolism
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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.
    No preview · Article · Jan 2015 · AJP Endocrinology and Metabolism
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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.
    No preview · Article · Nov 2014 · Journal of Clinical Endocrinology & Metabolism
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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.
    No preview · Article · Nov 2014 · AJP Regulatory Integrative and Comparative Physiology
  • 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.
    No preview · Article · Oct 2014 · Journal of Mass Spectrometry
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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.
    Full-text · Article · Aug 2014
  • 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.
    No preview · Article · Aug 2014 · Journal of Mass Spectrometry
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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.
    Full-text · Article · Jul 2014 · Diabetes
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    ABSTRACT: AimIt is an ongoing discussion the extent to which oxygen delivery and oxygen extraction contribute to an increased 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. Methods In nine healthy volunteers (seven males, two females), haemodynamic and metabolic responses to incremental arm cycling were measured by the Fick method and biopsy of the deltoid and triceps muscles before and after 42days of skiing for 6hday(-1) at 60% max heart rate. ResultsPeak pulmonary VO2 during arm crank was unchanged after training (2.380.19 vs. 2.18 +/- 0.2Lmin(-1) pre-training) yet arm VO2 (1.04 +/- 0.08 vs. 0.83 +/- 0.1Lmin(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 +/- 0.6Lmin(-1), P<0.05) and expanded muscle capillary volume (76 +/- 7 vs. 62 +/- 4mL, P<0.05). Muscle O-2 diffusion capacity (16.2 +/- 1 vs. 12.5 +/- 0.9mLmin(-1)mHg(-1), P<0.05) and O-2 extraction (68 +/- 1 vs. 62 +/- 1%, P<0.05) were enhanced at a similar mean capillary transit time (569 +/- 43 vs. 564 +/- 31ms) and P-50 (35.8 +/- 0.7 vs. 35 +/- 0.8), whereas mitochondrial O-2 flux capacity was unchanged (147 +/- 6mLkgmin(-1) vs. 146 +/- 8mLkgmin(-1)). Conclusion The mechanisms underlying the increase in peak arm VO2 with prolonged low-intensity training in previously untrained subjects are an increased convective O-2 delivery specifically to the muscles of the arm combined with a larger capillary-muscle surface area that enhance diffusional O-2 conductance, with no apparent role of mitochondrial respiratory capacity.
    No preview · Article · Feb 2014 · Acta Physiologica
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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.
    Full-text · Article · Feb 2014 · Mediators of Inflammation
  • 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.
    No preview · Article · Jan 2014 · Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
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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.
    Full-text · Article · Jul 2013 · Diabetologia
  • Tina D Jeppesen · Mette C Orngreen · Gerrit Van Hall · John Vissing
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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.
    No preview · Article · Jul 2013 · Neuromuscular Disorders