11 research outputs found
Exercising with insulin action:the “condition” of skeletal muscle and its influence on the insulin-sensitizing effect of a single bout of exercise
No full textDet er velkendt, at de gavnlige effekter af fysisk aktivitet medfører en generel øget sundhedstilstand samt bidrager til forebyggelsen og behandlingen af en lang række sygdomme. For eksempel medfører regelmæssig træning øget glykemisk kontrol, hvilket til dels skyldes øget insulinstimuleret glukoseoptagelse i muskler både hos raske og insulinresistente individer. Skeletmuskulaturen er et af de største organer i kroppen og er derfor kvantitativt det vigtigste væv for insulinstimuleret glukoseoptagelse og dermed kroppens regulering af glukosehomeostasen. Ud over effekterne ved regelmæssig træning så er det vist, at også et enkeltsående arbejde øger insulins virkning i de tidligere arbejdende muskler. Dette som følge af en lokal kontraktionsmedieret mekanisme. Dog så er de bagvedliggende molekylære mekanismer for ovenstående fænomen ikke helt klarlagt. Derudover er det stadig uklart, hvilke faktorer der påvirker graden af insulins virkning både i muskler og på helkropsniveau. Derfor er formålet med denne Ph.d. afhandling, at undersøge faktorer der er vigtige for insulins virkning i muskler samt den øgede insulinfølsomhed efter et enkeltstående arbejde. I studie 1 fandt vi, at musklens evne til at øge insulins virkning efter et enkeltstående arbejde var afhængig af musklens træningstilstand med en nedsat evne i den trænede muskel. Dette betyder at øget insulin virkning i musklen som følge af regelmæssig træning, mindsker musklernes evne til at øge insulins virkning yderligere efter et enkeltstående arbejde. Samtidig fandt vi, at arbejdsinducerede fosforylering af TBC1D4 var lavere efter det enkeltstående arbejde formegentlig på grund af en nedsat aktivering af AMPK α2β2γ3. Tilsammen tyder dette på, at AMPK-TBC1D4 signaleringsaksen også spiller en afgørende rolle for den øgede insulinfølsomhed efter et enkeltstående arbejde i mennesker, som det tidligere er blevet vist i gnavere. I studie 2 fandt vi, at virkningen af insulin på helkropsniveau efter et enkeltstående arbejde var afhængig af insulins virkning i de tidligere arbejdende muskler men også de ikke-arbejdende muskler. Et enkeltstående arbejde til udmattelse med en lille muskelgruppe medførte øget insulinfølsomhed i de tidligere arbejdende muskler, men samtidig medførte det også systemiske forandringer, der reducerede insulins virkning i de ikke-arbejdende muskler. På grund af den store mængde inaktiv muskelmasse resulterede det i en nedsat helkrops insulinfølsomhed efter et enkeltstående arbejde. Ved brug af proteomics kunne vi i studie 3 identificere >4000 proteiner i pools af type I og type II muskelfibre taget før og efter en træningsperiode. Denne enorme database vedrørende fiber typer og træningsadaptationer bidrager til forståelse for musklers metabolisme og derudover medfører det mange muligheder for fremtidig forskning. I denne afhandling blev disse data brugt til at undersøge fibertype-specifikke forskelle i kapaciteten for insulinstimuleret glukoseoptagelse i human skeletmuskulatur. På baggrund af dette tyder det ikke på, at kapaciteten for glukosetransport og glykogensyntese er forskellig mellem fibertyper, mens kapaciteten for glukosefosforylering og oxidering ser ud til at være højere i type I fibre. Den træningsinducerede øgede ekspression af proteiner vigtige for insulinstimuleret glukoseoptagelse var ikke forskellig mellem fibertyper. På baggrund af data opnået i studierne kan det konkluderes, at den øgede insulinfølsomhed efter et enkeltstående arbejde afhænger af træningsstatus, mængden af inaktiv vs. aktiv muskel og muligvis også fibertypefordelingen og -rekrutteringen. Resultaterne fra de tre studier vil i afhandlingen blive diskuteret i forhold til den eksisterende litteratur med det formål at identificere faktorer og mekanismer, der har betydning for den øgede insulinfølsomhed efter et enkeltstående arbejde.The benefits of exercise for the prevention and treatment of various diseases and overall health are well known. For instance, exercise training improves glycemic control in part due to enhanced insulin action on glucose uptake in skeletal muscle of both healthy and insulin resistant individuals. As skeletal muscle is one of the largest tissues in the human body and hence the predominant site forinsulin-stimulated glucose disposal, it is essential for maintaining glucose homeostasis. In addition to the effects of regular exercise training, a single bout of exercise also improves insulin action of the prior exercised muscle due to local contraction-induced mechanisms. However, the underlying molecular mechanisms for this phenomenon are not fully elucidated. Furthermore, factorsdetermining the magnitude of the response to a single bout of exercise on insulin action both within the muscle and at a whole-body level are not completely known. Thus the aim of the present thesis was to investigate factors important for insulin action in muscle and the enhancement of insulin actionby a single bout of exercise.In study 1, we demonstrated that the ability of muscle to enhance insulin action in response to a single bout of exercise is dependent on the training status of the muscle with a lower ability to enhance insulin action in the exercised trained state. This suggest that increased insulin action of the muscle by regular exercise training reduces the ability of a single bout of exercise to enhance insulin actionfurther. The reduced ability to enhance insulin action in response to a single bout of exercise in the trained state was accompanied by a compromised TBC1D4 signaling likely due to a lower activation of AMPK α2β2γ3 during exercise. Thus, our findings in humans also support a role for the AMPKTBC1D4 signaling axis in the insulin-sensitizing effect of a single bout of exercise, as previouslydemonstrated in rodents.In study 2, we demonstrated that whole-body insulin action following a single bout of exercise is dependent of the insulin action in both the prior exercised muscle as well as the non-exercised muscle. As expected, exhaustive exercise of a small muscle group was found to increase insulin action in the prior exercised muscle while, surprisingly, at the same time induce systemic changes that impaired insulin action in non-exercised muscle. Due to the large amount of inactive muscles this resulted in reduced whole-body insulin action after a single bout of exercise. Thus, the magnitude of the response on whole-body insulin action following a single bout of exercise seems to be dependent on the amountof inactive vs. active muscle mass.Lastly, using a proteomic approach we were able to identify >4000 proteins in pools of type I and type II human muscle fibers in study 3. The fibers were obtained before and after a period of endurance exercise training. The fiber type-specific database on adaptations to training provided a unique insight into muscle metabolism, which offers inspiration and possibilities for future research. For the PhD thesis, the database was used to evaluate fiber type-specific differences in the capacity for insulin-stimulated glucose uptake in human skeletal muscle. Based on this, it was suggested that the capacity for glucose transport and glucose incorporation into glycogen was not different between fiber types, whereas the capacity for glucose phosphorylation and oxidation was higher in type I fibers. In response to training, the adaptations important for insulin-stimulated glucose uptake occurred to the same extent between fiber types. In conclusion, the insulin-sensitizing effect of a single bout of exercise is affected by training status, non-exercised vs. exercised muscle mass and perhaps also fiber type composition and recruitment. In the present thesis, results obtained from three studies are discussed in the context of the existing literature with the purpose to elucidate the insulin-sensitizing effect of a single bout of exercise as well as factors and mechanisms contributing to this phenomenon. </p
Exercise training reduces the insulin-sensitizing effect of acute exercise in human skeletal muscle
No full textNot only chronic exercise training, but also a single bout of exercise, increase insulin-stimulated glucose uptake in skeletal muscle. However, it is not well described how adaptations to exercise training affect the ability of a single bout of exercise to increase insulin sensitivity. Rodent studies suggest that the insulin-sensitizing effect of a single bout of exercise is AMPK-dependent (presumably via the α2 β2 γ3 AMPK complex). Whether this is also the case in humans is unknown. Previous studies have shown that exercise training decreases expression of the α2 β2 γ3 AMPK complex and diminishes the activation of this complex during exercise. Thus, we hypothesized that exercise training diminishes the ability of a single bout of exercise to enhance muscle insulin sensitivity. We investigated nine, healthy male subjects who performed one-legged knee-extensor exercise at the same relative intensity before and after 12 weeks of exercise training. Training increased VO2peak and expression of mitochondrial proteins in muscle, while expression of AMPKγ3 was decreased. Training also increased whole body as well as muscle insulin sensitivity. Interestingly, insulin-stimulated glucose uptake in the acutely exercised leg was not further enhanced by training. Thus, the increase in insulin-stimulated glucose uptake following a single bout of one-legged exercise was lower in the trained vs. untrained state. This was associated with reduced signalling through confirmed α2 β2 γ3 AMPK downstream targets (ACC and TBC1D4). These results suggest that the insulin-sensitizing effect of a single bout of exercise is also AMPK-dependent in human skeletal muscle.</p
The insulin-sensitizing effect of a single exercise bout is similar in type I and type II human muscle fibres
No full textHuman skeletal muscle consists of slow-twitch (type I) and fast-twitch (type II) muscle fibres. Muscle insulin action, regulating glucose uptake and metabolism, is improved following a single exercise bout. Rodent studies suggest that this phenomenon is confined to specific muscle fibre types. Whether this phenomenon is also confined to specific fibre types in humans has not been described. To investigate this, nine healthy men underwent a euglycemic hyperinsulinemic clamp (EHC) in the recovery from a single bout of one-legged knee-extensor exercise. Pools of type I and type II fibres were prepared from muscle biopsies taken in the rested and prior exercised leg before and after theEHC. AMPK γ3 and TBC1D4 – two key proteins regulating muscle insulin action following exercise – were higher expressed in type II compared to type I fibres. However, phosphor-regulation of TBC1D4 was similar between fibre types when related to the total amount of TBC1D4 protein. The activating dephosphorylation of glycogen synthase was also similar in the two fibre types. Thus, insulin-induced regulation of key proteins important for transport and intracellular flux of glucose towards glycogen storage in the recovery from exercise, does not differ between fibre types. In conclusion, the insulinsensitizing effect of a single bout of exercise includes both type I and type II fibres in human skeletal muscle. This may be an important observation for future pharmacological strategies targeting muscle insulin sensitivity in humans
Deep muscle-proteomic analysis of freeze-dried human muscle biopsies reveals fiber type-specific adaptations to exercise training
No full textSkeletal muscle conveys several of the health-promoting effects of exercise; yet the underlying mechanisms are not fully elucidated. Studying skeletal muscle is challenging due to its different fiber types and the presence of non-muscle cells. This can be circumvented by isolation of single muscle fibers. Here, we develop a workflow enabling proteomics analysis of pools of isolated muscle fibers from freeze-dried human muscle biopsies. We identify more than 4000 proteins in slow- and fast-twitch muscle fibers. Exercise training alters expression of 237 and 172 proteins in slow- and fast-twitch muscle fibers, respectively. Interestingly, expression levels of secreted proteins and proteins involved in transcription, mitochondrial metabolism, Ca2+ signaling, and fat and glucose metabolism adapts to training in a fiber type-specific manner. Our data provide a resource to elucidate molecular mechanisms underlying muscle function and health, and our workflow allows fiber type-specific proteo..
A single bout of one-legged exercise to local exhaustion decreases insulin action in non-exercised muscle leading to decreased whole-body insulin action
No full textA single bout of exercise enhances insulin action in the exercised muscle. However, not all human studies find that this translates into increased whole-body insulin action, suggesting that insulin action in rested muscle or other organs may be decreased by exercise. To investigate this, eight healthy men underwent a euglycemic hyperinsulinemic clamp on two separate days: One day with prior one-legged knee-extensor exercise to local exhaustion (∼2.5 hours) and another day without exercise. Whole-body glucose disposal was ∼18% lower on the exercise day as compared to the resting day due to decreased (-37%) insulin-stimulated glucose uptake in the non-exercised muscle. Insulin signaling at the level of Akt2 was impaired in the non-exercised muscle on the exercise day suggesting that decreased insulin action in non-exercised muscle may reduce GLUT4 translocation in response to insulin.Thus, the effect of a single bout of exercise on whole-body insulin action depends on the balance between local effects increasing and systemic effects decreasing insulin action. Physiologically, this mechanism may serve to direct glucose into the muscles in need of glycogen replenishment. For insulin-treated patients this complex relationship may explain the difficulties in predicting the adequate insulin dose for maintaining glucose homeostasis following physical activity.</p
Effects of menopause and high-intensity training on insulin sensitivity and muscle metabolism
No full textTo investigate peripheral insulin sensitivity and skeletal muscle glucose metabolism in premenopausal and postmenopausal women, and evaluate whether exercise training benefits are maintained after menopause. Sedentary, healthy, normal-weight, late premenopausal (n = 21), and early postmenopausal (n = 20) women were included in a 3-month high-intensity exercise training intervention. Body composition was assessed by magnetic resonance imaging and dual-energy x-ray absorptiometry, whole body glucose disposal rate (GDR) by hyperinsulinemic euglycemic clamp (40 mU/m/min), and femoral muscle glucose uptake by positron emission tomography/computed tomography, using the glucose analog fluorodeoxyglucose, expressed as estimated metabolic rate (eMR). Insulin signaling was investigated in muscle biopsies. Age difference between groups was 4.5 years, and no difference was observed in body composition. Training increased lean body mass (estimate [95% confidence interval] 0.5 [0.2-0.9] kg, P
Illumination of the endogenous insulin-regulated TBC1D4 interactome in human skeletal muscle
No full textInsulin-stimulated muscle glucose uptake is a key process in glycemic control. This process depends on the redistribution of glucose transporters to the surface membrane, a process which involves regulatory proteins such as TBC1D1 and TBC1D4. Accordingly, a TBC1D4 loss-of-function mutation in human skeletal muscle is associated with increased risk of type 2 diabetes, and observations from carriers of a TBC1D1 variant associate this protein to a severe obesity phenotype. Here, we identified interactors of the endogenous TBC1D4 in human skeletal muscle by an unbiased proteomics approach. We detected 76 proteins as candidate TBC1D4 interactors. The binding of 12 of these interactors were regulated by insulin, including proteins known to be involved in glucose metabolism (e.g. 14-3-3 proteins and ACTN4). TBC1D1 also co-precipitated with TBC1D4 and vice versa in both human and mouse skeletal muscle. This interaction was not regulated by insulin nor exercise in young, healthy, lean individuals. Similarly, the exercise- and insulin-regulated phosphorylation of the TBC1D1-TBC1D4 complex was intact. In contrast, we observed an altered interaction as well as compromised insulin-stimulated phospho-regulation of the TBC1D1-TBC1D4 complex in muscle of obese individuals with type 2 diabetes. Altogether, we provide a repository of TBC1D4 interactors in human and mouse skeletal muscle, which serve as potential regulators of TBC1D4 function and, thus, insulin-stimulated glucose uptake in human skeletal muscle.</p
Prior exercise in humans redistributes intramuscular GLUT4 and enhances insulin-stimulated sarcolemmal and endosomal GLUT4 translocation
No full textObjective: Exercise is a cornerstone in the management of skeletal muscle insulin-resistance. A well-established benefit of a single bout of exercise is increased insulin sensitivity for hours post-exercise in the previously exercised musculature. Although rodent studies suggest that the insulin-sensitization phenomenon involves enhanced insulin-stimulated GLUT4 cell surface translocation and might involve intramuscular redistribution of GLUT4, the conservation to humans is unknown.Methods: Healthy young males underwent an insulin-sensitizing one-legged kicking exercise bout for 1 hour followed by fatigue bouts to exhaustion. Muscle biopsies were obtained 4h post-exercise before and after a 2h hyperinsulinemic-euglycemic clamp.Results: A detailed microscopy-based analysis of GLUT4 distribution muscle specimen in 7 different myocellular compartments revealed that prior exercise increased GLUT4 localization in insulin-responsive storage vesicles and T-tubuli. Furthermore, insulin-stimulated GLUT4 localization was augmented at the sarcolemma and in the endosomal compartments.Conclusion: An intracellular redistribution of GLUT4 post-exercise is proposed as a molecular mechanism contributing to the insulin-sensitizing effect of prior exercise in human skeletal muscle.</p
Insulin sensitization following a single exercise bout is uncoupled to glycogen in human skeletal muscle: A meta-analysis of 13 single-center human studies
No full textExercise profoundly influences glycemic control by enhancing muscle insulin sensitivity, thus promoting glucometabolic health. While prior glycogen breakdown so far has been deemed integral for muscle insulin sensitivity to be potentiated by exercise, the mechanisms underlying this phenomenon remain enigmatic. We have combined original data from 13 of our studies that investigated insulin action in skeletal muscle either under rested conditions or following a bout of one-legged knee extensor exercise in healthy young male individuals (n = 106). Insulin-stimulated glucose uptake was potentiated and occurred substantially faster in the prior contracted muscles. In this otherwise homogenous group of individuals, a remarkable biological diversity in the glucometabolic responses to insulin is apparent both in skeletal muscle and at the whole-body level. In contrast to the prevailing concept, our analyses reveal that insulin-stimulated muscle glucose uptake and the potentiation thereof by exercise are not associated with muscle glycogen synthase activity, muscle glycogen content, or degree of glycogen utilization during the preceding exercise bout. Our data further suggest that the phenomenon of improved insulin sensitivity in prior contracted muscle is not regulated in a homeostatic feedback manner from glycogen. Instead, we put forward the idea that this phenomenon is regulated by cellular allostatic mechanisms that elevate the muscle glycogen storage set point and enhance insulin sensitivity to promote the uptake of glucose toward faster glycogen resynthesis without development of glucose overload/toxicity or feedback inhibition.</p
