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Aims/hypothesisExercise is recommended for the treatment and prevention of type 2 diabetes. However, the most effective time of day to achieve beneficial effects on health remains unknown. We aimed to determine whether exercise training at two distinct times of day would have differing effects on 24 h blood glucose levels in men with type 2 diabetes.MethodsEleven men with type 2 diabetes underwent a randomised crossover trial. Inclusion criteria were 45–68 years of age and BMI between 23 and 33 kg/m2. Exclusion criteria were insulin treatment and presence of another systemic illness. Researchers were not blinded to the group assignment. The trial involved 2 weeks of either morning or afternoon high-intensity interval training (HIIT) (three sessions/week), followed by a 2 week wash-out period and a subsequent period of the opposite training regimen. Continuous glucose monitor (CGM)-based data were obtained.ResultsMorning HIIT increased CGM-based glucose concentration (6.9 ± 0.4 mmol/l; mean ± SEM for the exercise days during week 1) compared with either the pre-training period (6.4 ± 0.3 mmol/l) or afternoon HIIT (6.2 ± 0.3 mmol/l for the exercise days during week 1). Conversely, afternoon HIIT reduced the CGM-based glucose concentration compared with either the pre-training period or morning HIIT. Afternoon HIIT was associated with elevated thyroid-stimulating hormone (TSH; 1.9 ± 0.2 mU/l) and reduced T4 (15.8 ± 0.7 pmol/l) concentrations compared with pre-training (1.4 ± 0.2 mU/l for TSH; 16.8 ± 0.6 pmol/l for T4). TSH was also elevated after morning HIIT (1.7 ± 0.2 mU/l), whereas T4 concentrations were unaltered.Conclusions/interpretationAfternoon HIIT was more efficacious than morning HIIT at improving blood glucose in men with type 2 diabetes. Strikingly, morning HIIT had an acute, deleterious effect, increasing blood glucose. However, studies of longer training regimens are warranted to establish the persistence of this adverse effect. Our data highlight the importance of optimising the timing of exercise when prescribing it as treatment for type 2 diabetes.

Time-restricted feeding (TRF) improves metabolism independent of dietary macronutrient composition or energy restriction. To elucidate mechanisms underpinning the effects of short-term TRF, we investigated skeletal muscle and serum metabolic and transcriptomic profiles from 11 men with overweight/obesity after TRF (8 h day −1 ) and extended feeding (EXF, 15 h day −1 ) in a randomised cross-over design (trial registration: ACTRN12617000165381). Here we show that muscle core clock gene expression was similar after both interventions. TRF increases the amplitude of oscillating muscle transcripts, but not muscle or serum metabolites. In muscle, TRF induces rhythmicity of several amino acid transporter genes and metabolites. In serum, lipids are the largest class of periodic metabolites, while the majority of phase-shifted metabolites are amino acid related. In conclusion, short-term TRF in overweight men affects the rhythmicity of serum and muscle metabolites and regulates the rhythmicity of genes controlling amino acid transport, without perturbing core clock gene expression. Time restricted feeding has several health benefits. Here the authors perform a randomised cross-over study with 11 men with overweight/obesity to investigate how time restricted feeding affects skeletal muscle and serum, and report that it does not affect the core circadian machinery, but modifies periodicity in amino acid related metabolites and transporters.

Aims/hypothesis Insulin-mediated glucose disposal rates (R d) are reduced in type 2 diabetic patients, a process in which intrinsic signalling defects are thought to be involved. Phosphorylation of TBC1 domain family, member 4 (TBC1D4) is at present the most distal insulin receptor signalling event linked to glucose transport. In this study, we examined insulin action on site-specific phosphorylation of TBC1D4 and the effect of exercise training on insulin action and signalling to TBC1D4 in skeletal muscle from type 2 diabetic patients. Methods During a 3 h euglycaemic-hyperinsulinaemic (80 mU min⁻¹ m⁻²) clamp, we obtained M. vastus lateralis biopsies from 13 obese type 2 diabetic and 13 obese, non-diabetic control individuals before and after 10 weeks of endurance exercise-training. Results Before training, reductions in insulin-stimulated R d, together with impaired insulin-stimulated glycogen synthase fractional velocity, Akt Thr³⁰⁸ phosphorylation and phosphorylation of TBC1D4 at Ser³¹⁸, Ser⁵⁸⁸ and Ser⁷⁵¹ were observed in skeletal muscle from diabetic patients. Interestingly, exercise-training normalised insulin-induced TBC1D4 phosphorylation in diabetic patients. This happened independently of increased TBC1D4 protein content, but exercise-training did not normalise Akt phosphorylation in diabetic patients. In both groups, training-induced improvements in insulin-stimulated R d (~20%) were associated with increased muscle protein content of Akt, TBC1D4, α2-AMP-activated kinase (AMPK), glycogen synthase, hexokinase II and GLUT4 (20-75%). Conclusions/interpretation Impaired insulin-induced site-specific TBC1D4 phosphorylation may contribute to skeletal muscle insulin resistance in type 2 diabetes. The mechanisms by which exercise-training improves insulin sensitivity in type 2 diabetes may involve augmented signalling of TBC1D4 and increased skeletal muscle content of key insulin signalling and effector proteins, e.g., Akt, TBC1D4, AMPK, glycogen synthase, GLUT4 and hexokinase II.

Perturbed diurnal rhythms are becoming increasingly evident as deleterious events in the pathology of metabolic diseases. Exercise is well characterized as a crucial intervention in the prevention and treatment of individuals with metabolic diseases. Little is known, however, regarding optimizing the timing of exercise bouts in order to maximize their health benefits. Furthermore, exercise is a potent modulator of skeletal muscle metabolism, and it is clear that skeletal muscle has a strong circadian profile. In humans, mitochondrial function peaks in the late afternoon, and the circadian clock might be inherently impaired in myotubes from patients with metabolic disease. Timing exercise bouts to coordinate with an individual’s circadian rhythms might be an efficacious strategy to optimize the health benefits of exercise. The role of exercise as a Zeitgeber can also be used as a tool in combating metabolic disease. Shift work is known to induce acute insulin resistance, and appropriately timed exercise might improve health markers in shift workers who are at risk of metabolic disease. In this Review, we discuss the literature regarding diurnal skeletal muscle metabolism and the interaction with exercise bouts at different times of the day to combat metabolic disease.Exercise is used to prevent and treat metabolic diseases. Finding the optimum time for exercise is important as skeletal muscle has many clock-controlled genes. This Review summarizes the current literature regarding the consequence of exercise at different times of the day.

Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.Skeletal muscles show high metabolic flexibility and functional plasticity in their response to different exercise modalities. Recent findings have advanced our understanding of signalling, transcriptional and epigenetic mechanisms that regulate muscle adaptation to exercise and their impact on muscle physiology.

Exercise elicits high energy demands, stimulating cardiorespiratory function and substrate mobilisation and oxidation. Repeated bouts of exercise lead to whole-body adaptations, which improve athletic performance. Distinct exercise modalities and intensities and nutritional conditions pose specific physiological challenges, subsequently inducing different adaptations to training. Athletes often modify these variables to achieve individualised training goals and maximise performance. Exercise training improves glycaemic control in individuals with type 2 diabetes; however, the precise training regimen that confers the most beneficial metabolic adaptations in this population is unknown. In this review, we discuss how modifying exercise type, intensity and modality and nutritional status affects the beneficial effects of exercise on glycaemic control in individuals with type 2 diabetes. Evidence indicates that greater improvements in glycaemic control can be achieved through combined aerobic and resistance training regimens compared with either training type alone. However, the increased frequency of training and a greater number of exercise bouts during combined programmes could be responsible for apparent advantages over a single training modality. The beneficial effects of aerobic exercise on glycaemic control seem to rise with training intensity, with superior adaptations achieved by high-intensity interval training (HIT). In addition, training with low carbohydrate availability (‘training low’) improves cardiorespiratory function and skeletal muscle oxidative capacity more than conventional training in healthy untrained individuals. Examinations of various training regimens are warranted to assess the safety, efficacy, feasibility and beneficial effects in the type 2 diabetes population. Just like competitive athletes, individuals with type 2 diabetes should be encouraged to adopt training regimens that improve fitness and metabolism.

The molecular mechanisms underlying the response to exercise and inactivity are not fully understood. We propose an innovative approach to profile the skeletal muscle transcriptome to exercise and inactivity using 66 published datasets. Data collected from human studies of aerobic and resistance exercise, including acute and chronic exercise training, were integrated using meta-analysis methods ( www.metamex.eu ). Here we use gene ontology and pathway analyses to reveal selective pathways activated by inactivity, aerobic versus resistance and acute versus chronic exercise training. We identify NR4A3 as one of the most exercise- and inactivity-responsive genes, and establish a role for this nuclear receptor in mediating the metabolic responses to exercise-like stimuli in vitro. The meta-analysis (MetaMEx) also highlights the differential response to exercise in individuals with metabolic impairments. MetaMEx provides the most extensive dataset of skeletal muscle transcriptional responses to different modes of exercise and an online interface to readily interrogate the database. The pathways that underlie the effects of exercise on metabolism remain incompletely described. Here, the authors perform a meta-analysis of transcriptomic data from 66 published datasets of human skeletal muscle. They identify pathways selectively activated by inactivity, aerobic or resistance exercise, and characterize NR4A3 as one of the genes responsive to inactivity.

Key Points Epigenetic processes have been implicated in the pathogenesis of type 2 diabetes mellitus Diet and exercise might affect the epigenome over several generations Epigenetic changes can be driven by DNA methylation and histone modification in response to environmental stressors Regulation of gene expression by DNA methylation and histone modification occurs by a mechanism that impairs the access of transcriptional machinery to the promoters Studying the epigenetic signatures of insulin resistance and the adaptive response to exercise might provide insight into gene–environment networks that control glucose and energy homeostasis. In this Review, Romain Barrès and Juleen Zierath outline the current understanding of the mechanisms underlying how lifestyle factors affect epigenetic changes involved in the risk of type 2 diabetes mellitus. The latest findings on the mechanisms by which diet and exercise affect the epigenome are also discussed. Epigenetic changes are caused by biochemical regulators of gene expression that can be transferred across generations or through cell division. Epigenetic modifications can arise from a variety of environmental exposures including undernutrition, obesity, physical activity, stress and toxins. Transient epigenetic changes across the entire genome can influence metabolic outcomes and might or might not be heritable. These modifications direct and maintain the cell-type specific gene expression state. Transient epigenetic changes can be driven by DNA methylation and histone modification in response to environmental stressors. A detailed understanding of the epigenetic signatures of insulin resistance and the adaptive response to exercise might identify new therapeutic targets that can be further developed to improve insulin sensitivity and prevent obesity. This Review focuses on the current understanding of mechanisms by which lifestyle factors affect the epigenetic landscape in type 2 diabetes mellitus and obesity. Evidence from the past few years about the potential mechanisms by which diet and exercise affect the epigenome over several generations is discussed.

The proliferation in the rate of diagnosis of obesity and type 2 diabetes mellitus continues unabated, with current recommendations for primary lifestyle changes (i.e. modification to dietary patterns) having a limited impact in reducing the incidence of these metabolic diseases. Part of the reason for the failure to alter nutritional practices is that current dietary recommendations may be unrealistic for the majority of adults. Indeed, round-the-clock access to energy-dense, nutrient-poor food makes long-term changes to dietary habits challenging. Hence, there is urgent need for innovations in the delivery of evidence-based diet interventions to rescue some of the deleterious effects on circadian biology induced by our modern-day lifestyle. With the growing appreciation that the duration over which food is consumed during a day has profound effects on numerous physiological and metabolic processes, we discuss dietary protocols that modify the timing of food intake to deliberately alter the feeding–fasting cycle. Such chrono-nutrition functions to optimise metabolism by timing nutrient intake to the acrophases of metabolic rhythms to improve whole-body insulin sensitivity and glycaemic control, and thereby positively impact metabolic health.

The effect of metformin or rosiglitazone monotherapy versus placebo on insulin signaling and gene expression in skeletal muscle of patients with newly diagnosed type 2 diabetes was determined. A euglycemic-hyperinsulinemic clamp, combined with skeletal muscle biopsies and glucose uptake measurements over rested and exercised muscle, was performed before and after 26 weeks of metformin (n = 9), rosiglitazone (n = 10), or placebo (n = 11) treatment. Insulin-mediated whole-body and leg muscle glucose uptake was enhanced 36 and 32%, respectively, after rosiglitazone (P < 0.01) but not after metformin or placebo treatment. Insulin increased insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and phosphorylation of Akt Ser473 and AS160, a newly described Akt substrate that plays a role in GLUT4 exocytosis, approximately 2.3 fold before treatment. These insulin signaling parameters were unaltered after metformin, rosiglitazone, or placebo treatment. Expression of selected genes involved in glucose and fatty acid metabolism in skeletal muscle was unchanged between the treatment groups. Low-intensity acute exercise increased insulin-mediated glucose uptake but was without effect on insulin signaling. In conclusion, the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/AS160 in patients with newly diagnosed type 2 diabetes.