The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia

Sylow, Lykke; Tokarz, Victoria L.; Richter, Erik A.; Klip, Amira

doi:10.1016/j.cmet.2021.03.020

Cited by 162 publications

(155 citation statements)

References 319 publications

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“…Resistance exercise coupled with leucine-enriched essential amino acid supplements or whey protein food supplements (when the diet is inadequate in energy and/or protein) are recommended to treat sarcopenia (172), although recent reviews have not found additional benefit for protein above resistance training alone in older adults who are not malnourished (173). There is evidence from various epidemiological and experimental studies that muscle weakness, decreased muscle mass, reduced activation of glycogen synthase, and alterations in numbers of glycolytic skeletal muscle fibres are related to, and may precede, insulin resistance, glucose intolerance, and type 2 diabetes expression (174,175).…”

Section: Role Of Physical Activity and Exercise In Preserving Muscle Mass With Agementioning

confidence: 99%

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines

Izquierdo

Merchant

Morley

et al. 2021

The Journal of nutrition, health and aging

536

377

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The human ageing process is universal, ubiquitous and inevitable. Every physiological function is being continuously diminished. There is a range between two distinct phenotypes of ageing, shaped by patterns of living - experiences and behaviours, and in particular by the presence or absence of physical activity (PA) and structured exercise (i.e., a sedentary lifestyle). Ageing and a sedentary lifestyle are associated with declines in muscle function and cardiorespiratory fitness, resulting in an impaired capacity to perform daily activities and maintain independent functioning. However, in the presence of adequate exercise/PA these changes in muscular and aerobic capacity with age are substantially attenuated. Additionally, both structured exercise and overall PA play important roles as preventive strategies for many chronic diseases, including cardiovascular disease, stroke, diabetes, osteoporosis, and obesity; improvement of mobility, mental health, and quality of life; and reduction in mortality, among other benefits. Notably, exercise intervention programmes improve the hallmarks of frailty (low body mass, strength, mobility, PA level, energy) and cognition, thus optimising functional capacity during ageing. In these pathological conditions exercise is used as a therapeutic agent and follows the precepts of identifying the cause of a disease and then using an agent in an evidence-based dose to eliminate or moderate the disease. Prescription of PA/structured exercise should therefore be based on the intended outcome (e.g., primary prevention, improvement in fitness or functional status or disease treatment), and individualised, adjusted and controlled like any other medical treatment. In addition, in line with other therapeutic agents, exercise shows a dose-response effect and can be individualised using different modalities, volumes and/or intensities as appropriate to the health state or medical condition. Importantly, exercise therapy is often directed at several physiological systems simultaneously, rather than targeted to a single outcome as is generally the case with pharmacological approaches to disease management. There are diseases for which exercise is an alternative to pharmacological treatment (such as depression), thus contributing to the goal of deprescribing of potentially inappropriate medications (PIMS). There are other conditions where no effective drug therapy is currently available (such as sarcopenia or dementia), where it may serve a primary role in prevention and treatment. Therefore, this consensus statement provides an evidence-based rationale for using exercise and PA for health promotion and disease prevention and treatment in older adults. Exercise prescription is discussed in terms of the specific modalities and doses that have been studied in randomised controlled trials for their effectiveness in attenuating physiological changes of ageing, disease prevention, and/or improvement of older adults with chronic disease and disability. Recommendations are proposed to bridge gaps in the current literature and to optimise the use of exercise/PA both as a preventative medicine and as a therapeutic agent.

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Section: Role Of Physical Activity and Exercise In Preserving Muscle Mass With Agementioning

confidence: 99%

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines

Izquierdo

Merchant

Morley

et al. 2021

The Journal of nutrition, health and aging

536

377

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show abstract

“…During insulin‐induced glucose uptake, these can modulate the cytoskeleton via concomitant severing and polymerisation of actin filaments, thereby facilitating the movement of GLUT4‐containing vesicles to the cell membrane (Sylow et al . 2021). Therefore, Rac1 could potentially facilitate skeletal muscle actin remodelling in response to exercise or contraction.…”

Section: Introductionmentioning

confidence: 99%

β‐Catenin is required for optimal exercise‐ and contraction‐stimulated skeletal muscle glucose uptake

Masson

Woodhead

D’Souza

et al. 2021

The Journal of Physiology

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Key points Loss of β‐catenin impairs in vivo and isolated muscle exercise/contraction‐stimulated glucose uptake. β‐Catenin is required for exercise‐induced skeletal muscle actin cytoskeleton remodelling. β‐Catenin675 phosphorylation during exercise may be intensity dependent. Abstract The conserved structural protein β‐catenin is an emerging regulator of vesicle trafficking in multiple tissues and supports insulin‐stimulated glucose transporter 4 (GLUT4) translocation in skeletal muscle by facilitating cortical actin remodelling. Actin remodelling may be a convergence point between insulin and exercise/contraction‐stimulated glucose uptake. Here we investigated whether β‐catenin is involved in regulating exercise/contraction‐stimulated glucose uptake. We report that the muscle‐specific deletion of β‐catenin induced in adult mice (BCAT‐mKO) impairs both exercise‐ and contraction (isolated muscle)‐induced glucose uptake without affecting running performance or canonical exercise signalling pathways. Furthermore, high intensity exercise in mice and contraction of myotubes and isolated muscles led to the phosphorylation of β‐cateninS675, and this was impaired by Rac1 inhibition. Moderate intensity exercise in control and Rac1 muscle‐specific knockout mice did not induce muscle β‐cateninS675 phosphorylation, suggesting exercise intensity‐dependent regulation of β‐cateninS675. Introduction of a non‐phosphorylatable S675A mutant of β‐catenin into myoblasts impaired GLUT4 translocation and actin remodelling stimulated by carbachol, a Rac1 and RhoA activator. Exercise‐induced increases in cross‐sectional phalloidin staining (F‐actin marker) of gastrocnemius muscle was impaired in muscle from BCAT‐mKO mice. Collectively our findings suggest that β‐catenin is required for optimal glucose transport in muscle during exercise/contraction, potentially via facilitating actin cytoskeleton remodelling.

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“…An important effect of insulin is to stimulate the transportation of glucose into insulin-sensitive tissue, such as skeletal muscle, and thereby reduce the circulating level of glucose ( 1 ). However, glucose disposal may also be regulated by insulin-independent mechanisms, as was initially reported in 1937 ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Impact of Incretin Hormone Receptors on Insulin-Independent Glucose Disposal in Model Experiments in Mice

Ovlund

Pacini²,

Åhrén

2021

Front. Endocrinol.

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A large contribution to glucose elimination from the circulation is achieved by insulin-independent processes. We have previously shown that the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) increase this process and, therefore, seem to contribute to glucose disposal both through this effect and through the classical incretin effect resulting in enhanced insulin levels. We have now explored in more detail the potential contribution by incretin hormone receptors to insulin-independent processes for glucose elimination. To that end, we have performed intravenous glucose tests (0.35g/kg) in C57BL/6J mice and analyzed glucose elimination rate and glucose effectiveness (i.e., insulin-independent glucose disposal, SG) in wildtype mice and in mice with genetic deletion of GIP receptors or GLP-1 receptors. We performed studies with or without complete blockade of insulin secretion by the drug diazoxide (25 mg/kg). The mice were anesthetized with a novel fentanyl citrate/fluanisone formulation, called Fluafent, together with midazolam. Initially we demonstrated that glucose and insulin data after intravenous and oral glucose were not different using this anesthesia compared to the previously commonly used combination of HypnormR and midazolam. The results show that SG was reduced in GLP-1 receptor knockout mice, whereas there was no difference between GIP receptor knockout mice and wildtype mice, and this was evident both under normal conditions and after complete inhibition of insulin secretion. The study therefore indicates that insulin-independent glucose elimination requires active GLP-1 receptors and thus that the two incretin hormone receptor types show dissociated relevance for this process.

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The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia

Cited by 162 publications

References 319 publications

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines

β‐Catenin is required for optimal exercise‐ and contraction‐stimulated skeletal muscle glucose uptake

Impact of Incretin Hormone Receptors on Insulin-Independent Glucose Disposal in Model Experiments in Mice

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