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Featured researches published by Thorkil Ploug.


Diabetes | 1995

Insulin-Stimulated Muscle Glucose Clearance in Patients With NIDDM: Effects of One-Legged Physical Training

Flemming Dela; Jens Jørn Larsen; K. J. Mikines; Thorkil Ploug; Lone Petersen; Henrik Galbo

Physical training increases insulin action in skeletal muscle in healthy men. In non-insulin-dependent diabetes mellitus (NIDDM), only minor improvements in whole-body insulin action are seen. We studied the effect of training on insulin-mediated glucose clearance rates (GCRs) in the whole body and in leg muscle in seven patients with NIDDM and in eight healthy control subjects. One-legged training was performed for 10 weeks. GCR in whole body and in both legs were measured before, the day after, and 6 days after training by hyperinsulinemic (28, 88, and 480 mU · min−1 · m−2), isoglycemic clamps combined with the leg balance technique. On the 5th day of detraining, one bout of exercise was performed with the nontraining leg. Muscle biopsies were obtained before and after training. Whole-body GCRs were always lower (P < 0.05) in NIDDM patients compared with control subjects and increased (P < 0.05) in response to training. In untrained muscle, GCR was lower (P < 0.05) in NIDDM patients (13 ± 4, 91 ± 9, and 148 ± 12 ml/min) compared with control subjects (56 ± 12, 126 ± 14, and 180 ± 14 ml/min). It Increased (P < 0.05) in both groups in response to training (43 ± 10, 144 ± 17, and 205 ± 24 [NIDDM patients] and 84 ± 10, 212 ± 20, and 249 ± 16 ml/min [control subjects]). Acute exercise did not increase leg GCR. In NIDDM patients, the effect of training was lost after 6 days, while the effect lasted longer in control subjects. Training increased (P < 0.05) muscle lactate production and glucose storage as well as glycogen synthase (GS) mRNA in both groups. We conclude that training increases insulin action in skeletal muscle in control subjects and NIDDM patients, and in NIDDM patients normal values may be obtained. The increase in trained muscle cannot fully account for the increase in whole-body GCR. Improvements in GCR involve enhancement of insulin-mediated increase in muscle blood flow and the ability to extract glucose. They are accompanied by enhanced nonoxidative glucose disposal and increases in GS mRNA. The improvements in insulin action are short-lived.


Diabetes | 1994

Physical Training Increases Muscle GLUT4 Protein and mRNA in Patients With NIDDM

Flemming Dela; Thorkil Ploug; Aase Handberg; Lone Petersen; Jens Jørn Larsen; K. J. Mikines; Henrik Galbo

Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit insulin resistance and decreased glucose transport in skeletal muscle. Total content of muscle GLUT4 protein is not affected by NIDDM, whereas GLUT4 mRNA content is reported, variously, to be unaffected or increased. Physical training is recommended in the treatment of NIDDM, but the effect of training on muscle GLUT4 protein and mRNA content is unknown. To clarify the effect of training in NIDDM, seven men with NIDDM (58 ± 2 years of age [mean ± SE]) and eight healthy men (59 ± 1 years of age) (control group) performed one-legged ergometer bicycle training for 9 weeks, 6 days/week, 30 min/day. Biopsies were obtained from the vastus lateralis leg muscle before and after training. GLUT4 protein analyses was performed along with analyses of muscle biopsies from five young (23 ± 1 years of age) (young group), healthy subjects who participated in a previously published identical study. In response to training, maximal oxygen uptake increased (Δ 3.3 ± 1.8 in NIDDM subjects and 4.5 ± 1.2 ml.min−1·kg−1 in control subjects [both P < 0.05]). Before training, GLUT4 protein content was similar in NIDDM, control, and young subjects (0.35 ± 0.02, 0.34 ± 0.03, and 0.41 ± 0.03 arbitrary units, respectively), and it increased (P < 0.05) in all groups during training (to 0.43 ± 0.03, 0.40 ± 0.03, and 0.57 ± 0.08 arbitrary units, respectively). GLUT4 mRNA content was always lower in NIDDM compared with control subjects (P < 0.05) and increased in both groups (P < 0.05) during training (94 ± 6 to 122 ± 8 and 151 ± 5 to 170 ± 4 arbitrary units/10 μg total RNA, respectively). We conclude that muscle GLUT4 protein and mRNA increase in both NIDDM and control subjects in response to training. GLUT4 mRNA content is lower in NIDDM subjects compared with control subjects. GLUT4 protein content does not change with age.


Biochemical Journal | 1999

Expression of hormone-sensitive lipase and its regulation by adrenaline in skeletal muscle.

Józef Langfort; Thorkil Ploug; Jacob Ihlemann; Michele Saldo; Cecilia Holm; Henrik Galbo

The enzymic regulation of triacylglycerol breakdown in skeletal muscle is poorly understood. Western blotting of muscle fibres isolated by collagenase treatment or after freeze-drying demonstrated the presence of immunoreactive hormone-sensitive lipase (HSL), with the concentrations in soleus and diaphragm being more than four times the concentrations in extensor digitorum longus and epitrochlearis muscles. Neutral lipase activity determined under conditions optimal for HSL varied directly with immunoreactivity. Expressed relative to triacylglycerol content, neutral lipase activity in soleus muscle was about 10 times that in epididymal adipose tissue. In incubated soleus muscle, both neutral lipase activity against triacylglycerol (but not against a diacylglycerol analogue) and glycogen phosphorylase activity increased in response to adrenaline (epinephrine). The lipase activation was completely inhibited by anti-HSL antibody and by propranolol. The effect of adrenaline could be mimicked by incubation of crude supernatant from control muscle with the catalytic subunit of cAMP-dependent protein kinase, while no effect of the kinase subunit was seen with supernatant from adrenaline-treated muscle. The results indicate that HSL is present in skeletal muscle and is stimulated by adrenaline via beta-adrenergic activation of cAMP-dependent protein kinase. The concentration of HSL is higher in oxidative than in glycolytic muscle, and the enzyme is activated in parallel with glycogen phosphorylase.


The Journal of Physiology | 2001

Glycogen synthase localization and activity in rat skeletal muscle is strongly dependent on glycogen content.

Jakob Nielsen; Wim Derave; Søren Kristiansen; Evelyn Ralston; Thorkil Ploug; Erik A. Richter

1 The influence of muscle glycogen content on glycogen synthase (GS) localization and GS activity was investigated in skeletal muscle from male Wistar rats. 2 Two groups of rats were obtained, preconditioned with a combination of exercise and diet to obtain either high (HG) or low (LG) muscle glycogen content. The cellular distribution of GS was studied using subcellular fractionation and confocal microscopy of immunostained single muscle fibres. Stimulation of GS activity in HG and LG muscle was obtained with insulin or contractions in the perfused rat hindlimb model. 3 We demonstrate that GS translocates from a glycogen‐enriched membrane fraction to a cytoskeleton fraction when glycogen levels are decreased. Confocal microscopy supports the biochemical observations that the subcellular localization of GS is influenced by muscle glycogen content. GS was not found in the nucleus. 4 Investigation of the effect of glycogen content on GS activity in basal and insulin‐ and contraction‐stimulated muscle shows that glycogen has a strong inhibitory effect on GS activity. Our data demonstrate that glycogen is a more potent regulator of glycogen synthase activity than insulin. Furthermore we show that the contraction‐induced increase in GS activity is merely a result of a decrease in muscle glycogen content. 5 In conclusion, the present study shows that GS localization is influenced by muscle glycogen content and that not only basal but also insulin‐ and contraction‐stimulated GS activity is strongly regulated by glycogen content in skeletal muscle.


FEBS Journal | 2005

Expression profiling reveals differences in metabolic gene expression between exercise‐induced cardiac effects and maladaptive cardiac hypertrophy

Claes C. Strøm; Mark Aplin; Thorkil Ploug; Tue E. H. Christoffersen; Józef Langfort; Michael Viese; Henrik Galbo; Stig Haunsø; Søren P. Sheikh

While cardiac hypertrophy elicited by pathological stimuli eventually leads to cardiac dysfunction, exercise‐induced hypertrophy does not. This suggests that a beneficial hypertrophic phenotype exists. In search of an underlying molecular substrate we used microarray technology to identify cardiac gene expression in response to exercise. Rats exercised for seven weeks on a treadmill were characterized by invasive blood pressure measurements and echocardiography. RNA was isolated from the left ventricle and analysed on DNA microarrays containing 8740 genes. Selected genes were analysed by quantitative PCR. The exercise program resulted in cardiac hypertrophy without impaired cardiac function. Principal component analysis identified an exercise‐induced change in gene expression that was distinct from the program observed in maladaptive hypertrophy. Statistical analysis identified 267 upregulated genes and 62 downregulated genes in response to exercise. Expression changes in genes encoding extracellular matrix proteins, cytoskeletal elements, signalling factors and ribosomal proteins mimicked changes previously described in maladaptive hypertrophy. Our most striking observation was that expression changes of genes involved in β‐oxidation of fatty acids and glucose metabolism differentiate adaptive from maladaptive hypertrophy. Direct comparison to maladaptive hypertrophy was enabled by quantitative PCR of key metabolic enzymes including uncoupling protein 2 (UCP2) and fatty acid translocase (CD36). DNA microarray analysis of gene expression changes in exercise‐induced cardiac hypertrophy suggests that a set of genes involved in fatty acid and glucose metabolism could be fundamental to the beneficial phenotype of exercise‐induced hypertrophy, as these changes are absent or reversed in maladaptive hypertrophy.


Diabetes | 1985

Increased Muscle Glucose Uptake After Exercise: No Need for Insulin During Exercise

Erik A. Richter; Thorkil Ploug; Henrik Galbo

It has recently been shown that insulin sensitivity of skeletal muscle glucose uptake and glycogen synthesis is increased after a single exercise session. The present study was designed to determine whether insulin is necessary during exercise for development of these changes found after exercise. Diabetic rats and controls ran on a treadmill and their isolated hindquarters were subsequently perfused at insulin concentrations of 0, 100, and 20,000 μU/ml. Exercise increased insulin sensitivity of glucose uptake and glycogen synthesis equally in diabetic and control rats, but insulin responsiveness of glucose uptake was noted only in controls. Analysis of intracellular glucose-6-phosphate, glucose, glycogen synthesis, and glucose transport suggested that the exercise effect on responsiveness might be due to enhancement of glucose disposal. After electrical stimulation of diabetic hindquarters in the presence of insulin antiserum, insulin sensitivity of 3-O-methylglucose transport was increased to the same extent as in muscle from healthy rats stimulated in the presence of insulin at 50 μU/ml. Furthermore, in muscle depleted of glycogen by contractions, transport of 3-O-methylglucose was increased in the presence of insulin antiserum and in the absence of increased regional perfusate flow. It is concluded that after exercise, increased sensitivity of muscle glucose metabolism to insulin can be found in the absence of insulin during exercise, but still involves increased membrane transport of glucose. At maximal insulin concentrations, the enhancing effect of exercise on glucose uptake may involve enhancement of glucose disposal, an effect that is probably less in muscle from diabetic rats. Finally, after exercise, increased glucose transport in glycogen-depleted muscle does not require increased muscle blood flow and, therefore, involves increased membrane permeability for glucose. The presence of insulin is not necessary for this effect of exercise.


Journal of Lipid Research | 2006

Decrease in intramuscular lipid droplets and translocation of HSL in response to muscle contraction and epinephrine

Clara Prats; Morten Donsmark; Klaus Qvortrup; Constantine Londos; Carole Sztalryd; Cecilia Holm; Henrik Galbo; Thorkil Ploug

A better understanding of skeletal muscle lipid metabolism is needed to identify the molecular mechanisms relating intramuscular triglyceride (IMTG) to muscle metabolism and insulin sensitivity. An increasing number of proteins have been reported to be associated with intracellular triglyceride (TG), among them the PAT family members: perilipin, ADRP (for adipocyte differentiation-related protein), and TIP47 (for tail-interacting protein of 47 kDa). Hormone-sensitive lipase (HSL) is thought to be the major enzyme responsible for IMTG hydrolysis in skeletal muscle. In adipocytes, regulation of HSL by intracellular redistribution has been demonstrated. The existence of such regulatory mechanisms in skeletal muscle has long been hypothesized but has never been demonstrated. The aim of this study was to characterize the PAT family proteins associated with IMTG and to investigate the effect of epinephrine stimulation or muscle contraction on skeletal muscle TG content and HSL intracellular distribution. Rat soleus muscles were either incubated with epinephrine or electrically stimulated for 15 min. Single muscle fibers were used for morphological analysis by confocal and transmission electron microscopy. We show a decrease in IMTG in response to both lipolytic stimuli. Furthermore, we identify two PAT family proteins, ADRP and TIP47, associated with IMTG. Finally, we demonstrate HSL translocation to IMTG and ADRP after stimulation with epinephrine or contraction.


American Journal of Physiology-regulatory Integrative and Comparative Physiology | 2012

Body fat loss and compensatory mechanisms in response to different doses of aerobic exercise—a randomized controlled trial in overweight sedentary males

Mads Rosenkilde; Pernille Auerbach; Michala Holm Reichkendler; Thorkil Ploug; Bente Stallknecht; Anders Sjödin

The amount of weight loss induced by exercise is often disappointing. A diet-induced negative energy balance triggers compensatory mechanisms, e.g., lower metabolic rate and increased appetite. However, knowledge about potential compensatory mechanisms triggered by increased aerobic exercise is limited. A randomized controlled trial was performed in healthy, sedentary, moderately overweight young men to examine the effects of increasing doses of aerobic exercise on body composition, accumulated energy balance, and the degree of compensation. Eighteen participants were randomized to a continuous sedentary control group, 21 to a moderate-exercise (MOD; 300 kcal/day), and 22 to a high-exercise (HIGH; 600 kcal/day) group for 13 wk, corresponding to ∼30 and 60 min of daily aerobic exercise, respectively. Body weight (MOD: -3.6 kg, P < 0.001; HIGH: -2.7 kg, P = 0.01) and fat mass (MOD: -4.0 kg, P < 0.001 and HIGH: -3.8 kg, P < 0.001) decreased similarly in both exercise groups. Although the exercise-induced energy expenditure in HIGH was twice that of MOD, the resulting accumulated energy balance, calculated from changes in body composition, was not different (MOD: -39.6 Mcal, HIGH: -34.3 Mcal, not significant). Energy balance was 83% more negative than expected in MOD, while it was 20% less negative than expected in HIGH. No statistically significant changes were found in energy intake or nonexercise physical activity that could explain the different compensatory responses associated with 30 vs. 60 min of daily aerobic exercise. In conclusion, a similar body fat loss was obtained regardless of exercise dose. A moderate dose of exercise induced a markedly greater than expected negative energy balance, while a higher dose induced a small but quantifiable degree of compensation.


The Journal of Clinical Endocrinology and Metabolism | 2010

Diet-Induced Weight Loss and Exercise Alone and in Combination Enhance the Expression of Adiponectin Receptors in Adipose Tissue and Skeletal Muscle, but Only Diet-Induced Weight Loss Enhanced Circulating Adiponectin

Tore Christiansen; Søren K. Paulsen; Jens M. Bruun; Thorkil Ploug; Steen B. Pedersen; Bjørn Richelsen

OBJECTIVE The aim of the study was to investigate the effect of weight loss and exercise independently and in combination on circulating levels of adiponectin including low molecular weight, medium molecular weight, and high molecular weight adiponectin and expression of adiponectin and adiponectin receptors (AdipoR) in adipose tissue (AT) and skeletal muscle (SM). DESIGN AND METHODS Seventy-nine obese males and females were randomized into the following: 1) exercise only (12 wk of exercise without diet restriction); 2) hypocaloric diet [8 wk of very low energy diet (600 kcal/d) followed by 4 wk with a weight maintenance diet]; and 3) hypocaloric diet and exercise (DEX; 8 wk very low energy diet 800 kcal/d followed by 4 wk weight maintenance diet combined with exercise throughout the 12 wk). Blood samples and biopsies from sc abdominal AT and SM were collected at baseline and after 12 wk. The molecular subforms of adiponectin in serum were determined by Western blot. RESULTS The mRNA expression of AdipoR1 and -2 in SM was increased significantly in the exercise-only and DEX groups (both P < 0.05). The mRNA expression of adiponectin and AdipoRs in AT was increased significantly in all three groups (all P < 0.01), whereas serum total circulating adiponectin was significantly increased only in the DEX and hypocaloric diet groups (both P < 0.01). All the adiponectin subforms changed in a similar manner as total adiponectin, indicating no specific regulation of any of the subforms by the intervention. CONCLUSION Exercise alone and in combination with a diet-induced weight loss enhance the mRNA expression of adiponectin receptors in AT and in SM but only a pronounced hypocaloric-induced weight-loss increases circulating adiponectin in obese subjects.


Diabetes | 2006

Imaging of Insulin Signaling in Skeletal Muscle of Living Mice Shows Major Role of T-Tubules

Hans P.M.M. Lauritzen; Thorkil Ploug; Clara Prats; Jeremy M. Tavaré; Henrik Galbo

Insulin stimulates glucose transport in skeletal muscle by glucose transporter GLUT4 translocation to sarcolemma and membrane invaginations, the t-tubules. Although muscle glucose uptake plays a key role in insulin resistance and type 2 diabetes, the dynamics of GLUT4 translocation and the signaling involved are not well described. We have now developed a confocal imaging technique to follow trafficking of green fluorescent protein–labeled proteins in living muscle fibers in situ in anesthetized mice. Using this technique, by imaging the dynamics of GLUT4 translocation and phosphatidylinositol 3,4,5 P3 (PIP3) production in response to insulin, here, for the first time, we delineate the temporal and spatial distribution of these processes in a living animal. We find a 10-min delay of maximal GLUT4 recruitment and translocation to t-tubules compared with sarcolemma. Time-lapse imaging of a fluorescent dye after intravenous injection shows that this delay is similar to the time needed for insulin diffusion into the t-tubule system. Correspondingly, immunostaining of muscle fibers shows that insulin receptors are present throughout the t-tubule system. Finally, PIP3 production, an early event in insulin signaling, progresses slowly along the t-tubules with a 10-min delay between maximal PIP3 production at sarcolemma compared with deep t-tubules following the appearance of dye-labeled insulin. Our findings in living mice indicate a major role of the t-tubules in insulin signaling in skeletal muscle and show a diffusion-associated delay in insulin action between sarcolemma and inner t-tubules.

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Henrik Galbo

University of Copenhagen

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Anders Sjödin

University of Copenhagen

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Clara Prats

University of Copenhagen

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Flemming Dela

University of Copenhagen

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Józef Langfort

Polish Academy of Sciences

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