Abstract Metabolic indices derived from the oral glucose tolerance test (OGTT) and mixed‐meal tolerance test (MMTT) are often interpreted interchangeably; however, these tests represent distinct physiological stimuli. In order to examine potential differential metabolic responses to these tests, we characterized the (dis)agreement between OGTT‐ and MMTT‐derived indices of insulin sensitivity, insulin secretion and β‐cell function. We also described their convergent validity in individuals with normal glucose tolerance (NGT) or type 2 diabetes (T2D). We conducted a post hoc analysis of eight trials with participants who underwent either OGTT or MMTT, or both. Insulin sensitivity, insulin secretion and β‐cell function were derived. Agreement was assessed using Bland–Altman regression approaches to estimate systematic and proportional bias and 95% limits of agreement. Linear mixed‐effects models were used to estimate means by glycaemic status (NGT vs. T2D), and area under the receiver operating characteristic (AUROC) curve analyses were used to evaluate discriminative ability between glycaemic status for the respective test indices. No systematic bias was observed. Proportional bias was present for insulin secretion and β‐cell function, with increasingly negative differences between methods (OGTT–MMTT) as outcome values increased. All indices exhibited relatively wide 95% limits of agreement, which widened further at higher magnitudes. The OGTT‐ and MMTT‐derived means were significantly different between NGT and T2D. We did not observe differences in AUROC between tolerance tests. Agreement between OGTT‐ and MMTT‐derived indices worsened as the respective value increased, suggesting differential stimulus–response characteristics in insulin secretion between tolerance tests. Despite this, descriptive analyses suggest that the test‐specific indices demonstrate convergent validity.

Impaired wound healing in type 2 diabetes (T2D) is associated with microvascular dysfunction and remains a significant clinical challenge. We aimed to determine whether primary human dermal microvascular endothelial cells (HDMVECs) from individuals with T2D exhibit abnormal cellular functions, and whether exposure to T2D serum impacts healthy endothelial function. In Experiment 1, T2D-HDMVECs displayed paradoxically higher migratory and angiogenic capacities than their healthy counterparts, despite markedly reduced eNOS expression and disrupted endothelial-identity gene expression. In Experiments 2 and 3, healthy HDMVECs showed decreased tube formation, nitric oxide production, and Notch/angiogenesis-related gene expression after exposure to both healthy and T2D serum, suggesting the presence of serum-derived factors that suppress these pathways. However, T2D-HDMVECs remained largely unresponsive to these serum-driven effects, reinforcing an intrinsic reprogramming of T2D endothelial cells. Additional analyses revealed selective alterations in redox and angiogenic signaling pathways (e.g., NOX4, FLT1), whereas canonical regulators such as VEGFA and PFKB3 were not affected by serum exposure. Overall, our data reveal a complex interplay between cell-autonomous alterations and extrinsic signals in diabetic endothelial dysfunction. Therapeutic strategies targeting both intrinsic cellular programs (e.g., eNOS, Notch signaling) and the circulating milieu may represent promising avenues for enhancing wound repair in patients with T2D.

“Active” heat acclimation (exercise-in-the-heat) can improve exercise performance but the efficacy of “passive” heat acclimation using post-exercise heat exposure is unclear. Therefore, we synthesised a systematic review and meta-analysis to answer whether post-exercise heat exposure improves exercise performance. Five databases were searched to identify studies including: (i) healthy adults; (ii) an exercise training intervention with post-exercise heat exposure via sauna or hot water immersion (treatment group); (iii) a non-heat exposure control group completing the same training; and (iv) outcomes measuring exercise performance in the heat (primary outcome), or performance in thermoneutral conditions, V̇O2max, lactate threshold, economy, heart rate, RPE, core temperature, sweat rate, and thermal sensations. Study quality was assessed using the Cochrane Risk of Bias 2 tool. To determine the effect of post-exercise heat exposure, between-group ratio of means or standardized mean differences (SMD) were calculated for each outcome and weighted by the inverse of their variance to calculate an overall effect estimate (ratio of mean or Hedges’g) in a random effects meta-analysis, with 95 https://doi.org/10.17605/OSF.IO/256XZ ).

BACKGROUND:Generative artificial intelligence (AI) chatbots are increasingly utilised in various domains, including sports nutrition. Despite their growing popularity, there is limited evidence on the accuracy, completeness, clarity, evidence quality, and test-retest reliability of AI-generated sports nutrition advice. This study evaluates the performance of ChatGPT, Gemini, and Claude's basic and advanced models across these metrics to determine their utility in providing sports nutrition information. MATERIALS AND METHODS:Two experiments were conducted. In Experiment 1, chatbots were tested with simple and detailed prompts in two domains: Sports nutrition for training and Sports nutrition for racing. Intraclass correlation coefficient (ICC) was used to assess interrater agreement and chatbot performance was assessed by measuring accuracy, completeness, clarity, evidence quality, and test-retest reliability. In Experiment 2, chatbot performance was evaluated by measuring the accuracy and test-retest reliability of chatbots' answers to multiple-choice questions based on a sports nutrition certification exam. ANOVAs and logistic mixed models were used to analyse chatbot performance. RESULTS:In Experiment 1, interrater agreement was good (ICC = 0.893) and accuracy varied from 74% (Gemini1.5pro) to 31% (ClaudePro). Detailed prompts improved Claude's accuracy but had little impact on ChatGPT or Gemini. Completeness scores were highest for ChatGPT-4o compared to other chatbots, which scored low to moderate. The quality of cited evidence was low for all chatbots when simple prompts were used but improved with detailed prompts. In Experiment 2, accuracy ranged from 89% (Claude3.5Sonnet) to 61% (ClaudePro). Test-retest reliability was acceptable across all metrics in both experiments. CONCLUSIONS:While generative AI chatbots demonstrate potential in providing sports nutrition guidance, their accuracy is moderate at best and inconsistent between models. Until significant advancements are made, athletes and coaches should consult registered dietitians for tailored nutrition advice.

Background:Fat loss mainly conveys the benefits of caloric restriction for people living with type 2 diabetes.The literature is equivocal regarding whether exercise facilitates fat loss during caloric restriction.This analysis aimed to assess the dose-response effects of exercise in combination with a caloric restriction on fat mass(FM)and FM percentage(FM％)in persons with diagnosed type 2 diabetes. Methods:In this secondary analysis of a 4-armed randomized trial,82 persons living with type 2 diabetes were randomly allocated to the control group(CON)(n=21),diet control(DCON)(25％caloric restriction;n=20),diet control and exercise 3 times per week(MED)(n=20),or diet control and exercise 6 times per week(HED)(n=21)for 16 weeks.The primary analysis was the change in FM％points.Secondary analyses included fat-free mass and visceral adipose tissue(VAT)volume(cm3). Results:FM％decreased compared to CON by a mean difference of-3.5％(95％confidence interval(95％CI):-5.6％to-1.4％),-6.3％(95％CI:-8.4％to-4.1％),and-8.0％(95％CI:-10.2％to-5.8％)for DCON,MED,and HED,respectively.Compared to DCON,MED,and HED decreased FM％by-2.8％(95％CI:-4.9％to-0.7％)and-4.5％(95％CI:-6.6％to-2.4％),respectively.The difference in FM％between HED and MED was-1.8％(95％CI:-3.9％to 0.4％).DCON and MED decreased fat-free mass compared to CON,whereas HED preserved fat-free mass(-0.2％;95％CI:-2.0％to 1.7％).Compared to CON,VAT volume decreased by-666.0 cm3(95％CI:-912.8 cm3 to-385.1 cm3),-1264.0 cm3(95％CI:-1679.6 cm3 to-655.9 cm3),and-1786.4 cm3(95％CI:-2264.6 cm3 to-1321.2 cm3)more for DCON,MED,and HED,respectively.HED decreased VAT volume more than DCON(-1120.4 cm3;95％CI:-1746.6 cm3 to-639.4 cm3)while the remaining comparisons did not reveal any differences. Conclusion:All interventions were superior in reducing FM％compared to standard care.Adding exercise to a caloric restriction was superior in reducing FM％compared to a caloric restriction alone.

"Active" heat acclimation (exercise-in-the-heat) can improve exercise performance in the heat. An alternative strategy is "passive" heat acclimation using post-exercise heat exposure, but its efficacy is unclear.

Interval walking training (IWT) is a free-living training intervention involving alternating fast and slow walking cycles. IWT is efficacious in improving physical fitness and muscle strength, and reducing factors associated with lifestyle-related diseases. In individuals with type 2 diabetes, IWT improves glycemic control directly through enhanced glucose effectiveness, challenging conventional views on mechanisms behind training-induced improvements in glycemic control. Whereas adherence to IWT in short-term studies is high, ensuring long-term adherence remains a challenge, particularly in populations with chronic diseases and/or overweight/obesity. Long-term studies in real-world settings are imperative to ascertain the widespread effectiveness of IWT and elucidate its impact on hard endpoints.

Diet-induced weight loss is associated with improved beta-cell function in people with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. Here, we carried out a four-armed randomized trial with a total of 82 persons (35% females, mean age (s.d.) of 58.2 years (9.8)) with newly diagnosed T2D (<7 years). Participants were randomly allocated to standard care (n = 20), calorie restriction (25% energy reduction; n = 21), calorie restriction and exercise three times per week (n = 20), or calorie restriction and exercise six times per week (n = 21) for 16 weeks. The primary outcome was beta-cell function as indicated by the late-phase disposition index (insulin secretion multiplied by insulin sensitivity) at steady-state hyperglycemia during a hyperglycemic clamp. Secondary outcomes included glucose-stimulated insulin secretion and sensitivity as well as the disposition, insulin sensitivity, and secretion indices derived from a liquid mixed meal tolerance test. We show that the late-phase disposition index during the clamp increases more in all three intervention groups than in standard care (diet control group, 58%; 95% confidence interval (CI), 16 to 116; moderate exercise dose group, 105%; 95% CI, 49 to 182; high exercise dose group, 137%; 95% CI, 73 to 225) and follows a linear dose-response relationship (P > 0.001 for trend). We report three serious adverse events (two in the control group and one in the diet control group), as well as adverse events in two participants in the diet control group, and five participants each in the moderate and high exercise dose groups. Overall, adding an exercise intervention to diet-induced weight loss improves glucose-stimulated beta-cell function in people with newly diagnosed T2D in an exercise dose-dependent manner (NCT03769883).

OBJECTIVE To assess the dose-response effects of exercise in combination with a diet-induced weight loss on fat mass (FM) percentage (FM%) in persons with diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS In this secondary analysis of a four-armed randomized trial ([Clinicaltrials.gov][1] [NCT03769883][2]) 82 persons (35% females, mean age and standard deviation (SD) 58.2 (9.8) years) living with type 2 diabetes were randomly allocated to the control group (N=21, CON), diet control (25% energy restriction; N =20, DCON), diet control and exercise three times/week (two sessions of aerobic and one session combining resistance and aerobic training; N =20, MED), or diet control and exercise six times/week (four sessions of aerobic and two sessions combining resistance and aerobic training; N =21, HED) for 16 weeks. The primary outcome was the change in FM percentage points (pp). Secondary outcomes included fat-free mass and visceral adipose tissue volume. RESULTS Type 2 diabetes duration was 4.0 years (interquartile range 1.9 to 5.5), body weight (SD) 101.4 kg (14.6), FM% (SD) 39.4 (6.7). FMpp decreased compared to standard care −3.5 pp (95% CI −5.6 to −1.4) p=0.002, −6.3 pp (CI −8.4 to −4.1) p<0.001, and −8.0 pp (95% CI −10.2 to −5.8) p<0.001, for DCON, MED, and HED, respectively. The difference between HED and MED was −1.8 pp [95% CI −3.9 to 0.4]; p=0.11). CONCLUSIONS All interventions were superior in reducing FMpp compared to standard care in a dose-dependent manner. Adding three or six sessions of exercise to a low-calorie diet was superior in reducing FM compared to a low-calorie diet alone. Article Highlights 1. Why did we undertake this study? Exercise and weight loss are recommended for persons with type 2 diabetes. It is unclear if adding exercise, and which amount of exercise, to a low-calorie diet supports additional fat mass loss. 2. What is the specific question(s) we wanted to answer? What is the dose-response effect of exercise combined with a moderate caloric restriction on changes in fat mass? 3. What did we find? Adding exercise to a diet-induced weight loss reduced fat mass and preserved fat-free mass in a dose-dependent manner. 4. What are the implications of our findings? Adding exercise to a moderate caloric restriction dose-dependently facilitates reductions in fat mass by enlarging weight loss and fat loss. ### Competing Interest Statement TPA owns stocks in NovoNordisk A/S. TPJS owns an academic consulting business (Blazon Scientific) and an endurance and nutrition consulting business (Veohtu). these companies had no control over the research design, data analysis, or publication outcomes of this work. ### Clinical Trial NCT03769883 ### Funding Statement The project was supported by a grant from TrygFonden and Svend Andersen Fonden. The Centre for Physical Activity Research is supported by TrygFonden (grants ID 101390, ID 20045, and ID 125132). Mark Preben Printz Lyngbaek was supported by a research grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406. Cody Durrer was supported by the Canadian Institutes of Health Research (MFE-176582). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study, which this study is a secondary analysis of, was approved by the Scientific Ethical Committee of the Capital Region of Denmark (approval number H-18038298). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are not available for download due to privacy/ethical restrictions under the EU GDPR. Specific requests for access to the trial and unique biological data as well as code may be sent to the corresponding author. Based on the request access may be provided to a named individual in agreement with the rules and regulations of the Danish Data Protection Agency and the National Committee on Health Research Ethics. [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03769883&atom=%2Fmedrxiv%2Fearly%2F2023%2F06%2F06%2F2023.06.04.23290749.atom

The benefits of exercise involve skeletal muscle redox state alterations of nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). We determined the fiber-specific effects of acute exercise on the skeletal muscle redox state in healthy adults. Muscle biopsies were obtained from 19 (11 M, 8 F; 26±4 yrs) at baseline (fasted), and 30-min and 3h after treadmill exercise at 80% VO2max. Muscle samples were fiber typed probed for autofluorescence of NADH (excitation at 340-360nm) and oxidized flavoproteins (Fp; excitation at 440-470nm) to quantify the redox signatures of individual muscle fibers. Redox state was calculated as the oxidation-to-reduction redox ratio: Fp/(Fp+NADH). At baseline, the redox ratio of MHC I fibers was 7.2% higher than MHC IIa (p = 0.023, 95% CI: 5.2, 9.2%) and the redox ratio of MHC IIa was 8.0% higher than MHC IIx (p = 0.035, 95% CI: 6.8, 9.2%). MHC I fibers also displayed greater NADH intensity than MHC IIx (p = 0.007) and greater Fp intensity than both MHC IIa (p = 0.019) and MHC IIx (p < 0.0001). Fp intensities increased in all fiber types (p = 0.039) but redox ratios did not change (p = 0.483) 30 min after exercise. The change in redox ratio was positively correlated with VO2max (ml/min/kg) in MHC I (rho = 0.809, p = 0.004) and MHC IIa (rho = 0.782, p = 0.006) but not MHC IIx fibers (rho = 0.571, p = 0.151). These findings support the use of redox autofluorescence to interrogate skeletal muscle metabolism.

Background Fibroblast growth factor 21 (FGF21) treatment improves metabolic homeostasis in diverse species, including humans. Physiologically, plasma FGF21 levels increase modestly after glucose ingestion, but it is unclear whether this is mediated by glucose itself or due to a secondary effect of postprandial endocrine responses. A refined understanding of the mechanisms that control FGF21 release in humans may accelerate the development of small-molecule FGF21 secretagogues to treat metabolic disease. This study aimed to determine whether FGF21 secretion is stimulated by elevations in plasma glucose, insulin, or glucagon-like peptide-1 (GLP-1) in humans. Methods Three groups of ten healthy participants were included in a parallel-group observational study. Group A underwent a hyperglycemic infusion; Group B underwent a 40 mU/m2/min hyperinsulinemic euglycemic clamp; Group C underwent two pancreatic clamps (to suppress endogenous insulin secretion) with euglycemic and hyperglycemic stages with an infusion of either saline or 0.5 pmol/kg/min GLP-1. Plasma FGF21 concentrations were measured at baseline and during each clamp stage by ELISA. Results Plasma FGF21 was unaltered during hyperglycemic infusion and hyperinsulinemic euglycemic clamps, compared to baseline. FGF21 was, however, increased by hyperglycemia under pancreatic clamp conditions (P < 0.05), while GLP-1 infusion under pancreatic clamp conditions did not change circulating FGF21 levels. Conclusion Increases in plasma FGF21 are likely driven directly by changes in plasma glucose independent of changes in insulin or GLP-1 secretion. Ecologically valid postprandial investigations are now needed to confirm our observations from basic science infusion models.

Background Lifestyle intervention, i.e. diet and physical activity, forms the basis for care of type 2 diabetes (T2D). The current physical activity recommendation for T2D is aerobic training for 150 min/week of moderate to vigorous intensity, supplemented with resistance training 2–3 days/week, with no more than two consecutive days without physical activity. The rationale for the recommendations is based on studies showing a reduction in glycated haemoglobin (HbA1c). This reduction is supposed to be caused by increased insulin sensitivity in muscle and adipose tissue, whereas knowledge about effects on abnormalities in the liver and pancreas are scarce, with the majority of evidence stemming from in vitro and animal studies. The aim of this study is to investigate the role of the volume of exercise training as an adjunct to dietary therapy in order to improve the pancreatic β-cell function in T2D patients less than 7 years from diagnosis. The objective of this protocol for the DOSE-EX trial is to describe the scientific rationale in detail and to provide explicit information about study procedures and planned analyses. Methods/design In a parallel-group, 4-arm assessor-blinded randomised clinical trial, 80 patients with T2D will be randomly allocated (1:1:1:1, stratified by sex) to 16 weeks in either of the following groups: (1) no intervention (CON), (2) dietary intervention (DCON), (3) dietary intervention and supervised moderate volume exercise (MED), or (4) dietary intervention and supervised high volume exercise (HED). Enrolment was initiated December 15th, 2018, and will continue until N = 80 or December 1st, 2021. Primary outcome is pancreatic beta-cell function assessed as change in late-phase disposition index (DI) from baseline to follow-up assessed by hyperglycaemic clamp. Secondary outcomes include measures of cardiometabolic risk factors and the effect on subsequent complications related to T2D. The study was approved by The Scientific Ethical Committee at the Capital Region of Denmark (H-18038298). Trial registration: The Effects of Different Doses of Exercise on Pancreatic β-cell Function in Patients With Newly Diagnosed Type 2 Diabetes (DOSE-EX), NCT03769883, registered 10 December 2018 https://clinicaltrials.gov/ct2/show/NCT03769883 ). Any modification to the protocol, study design, and changes in written participant information will be approved by The Scientific Ethical Committee at the Capital Region of Denmark before effectuation. Discussion The data from this study will add knowledge to which volume of exercise training in combination with a dietary intervention is needed to improve β-cell function in T2D. Secondarily, our results will elucidate mechanisms of physical activity mitigating the development of micro- and macrovascular complications correlated with T2D.

EDITORIAL article Front. Endocrinol., 27 May 2021Sec. Clinical Diabetes https://doi.org/10.3389/fendo.2021.699354

AIMS/HYPOTHESIS:This study aimed to examine if beta-aminoisobutyric acid (BAIBA) is (i) secreted by skeletal muscle in humans during exercise, (ii) associated with insulin secretory function in vivo, and (iii) directly linked with acute glucose-mediated insulin release by pancreatic beta cells in vitro. METHODS:Following 2-weeks of single-leg immobilization, plasma BAIBA concentrations were measured in the brachial artery and the femoral veins of each leg in healthy male subjects, at rest and during two-legged dynamic knee-extensor exercise. During a 2-h hyperglycamic clamp, insulin secretory function and levels of plasma BAIBA were assessed in non-diabetic individuals, non-diabetic individuals following 24-h hyperglycemia and patients with type 2 diabetes. Direct effects of BAIBA on acute glucose-mediated insulin release were probed in INS-1832/3 cells under normal and 'diabetes-like' conditions. Finally, the effect of BAIBA on mitochondrial function was assessed in INS-1832/3 cells using extracellular flux analysis. RESULTS:(i) BAIBA is released from skeletal muscle at rest and during exercise under healthy conditions but is suppressed during exercise following leg immobilization, (ii) plasma BAIBA concentrations inversely associate with insulin secretory function in humans, (iii) BAIBA lowers mitochondrial energy metabolism in INS-1 832/3 cells in parallel with decreased insulin secretionConclusion/interpretation: BAIBA is a myokine released by skeletal muscle during exercise and indepedantly alters the triggering pathway of insulin secretion in cultured INS-1832/3 cells.

BackgroundExercise improves glycemic control but the magnitude, and in some cases, the direction of this effect is variable. Ambient hyperglycemia has been implicated in this exercise response heterogeneity. The current study investigated whether pre-exercise hyperglycemia directly impacts the effect of exercise on glycemic control.MethodsTwelve healthy normal glucose-tolerant males completed four trials in a randomized, crossover design. Each trial consisted of 24-h pre-intervention monitoring, a 7-h intervention, and 24-h post-intervention monitoring. Glycemic control was measured throughout the study by continuous glucose monitoring. The four interventions were no exercise (CON) or 45 min of cycling exercise (70%HRmax) preceded by 3.5 h of either normoglycemia (NG-Ex), steady-state hyperglycemia induced by constant glucose infusion (HG-Ex) or fluctuating glycemia induced by repeated glucose bolus infusions (FG-Ex).ResultsPhysical activity and diet were similar between trials, and energy expenditure during exercise was matched between exercise trials (all P > 0.05). Mean glucose during the 3.5 h ± infusion period was higher in HG-Ex (mean ± SEM; 7.2 ± 0.4 mmol/L) and FG-Ex (7.3 ± 0.3 mmol/L) compared to CON (4.8 ± 0.2 mmol/L) and NG-Ex (5.0 ± 0.2 mmol/L) trials (P < 0.01). Glycemic variability was greatest in FG-Ex (P < 0.01). Following the interventions, the postprandial glucose response (iAUC) was reduced by exercise in NG-Ex compared to CON (321.1 ± 38.6 vs. 445.5 ± 49.7 mmol/L.8h, P < 0.05, d=0.81). This benefit was blunted when exercise was preceded by steady-state (HG-Ex, 425.3 ± 45.7 mmol/L.8h) and fluctuating (FG-Ex, 465.5 ± 39.3 mmol/L.8h) hyperglycemia (both P > 0.05 vs. CON).ConclusionPre-exercise hyperglycemia blunted the glucoregulatory benefits of acute exercise upon postprandial glucose response, suggesting that exposure to hyperglycemia contributes to exercise response heterogeneity.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03284216.

New Findings What is the topic of this review? This review discusses the evidence of the benefits of exercise training for beta-cell health through improvements in function, proliferation and survival which may have implications in the treatment of diabetes.

The optimal timing between meal ingestion and simple physical activity for improving blood glucose control is unknown. This study compared the effects of physical activity on postprandial interstitial glucose responses when the activity was conducted either immediately before, immediately after, or 30 min after breakfast. Forty-eight adults were randomized to three separate physical activity interventions: standing still (for 30 min), walking (for 30 min), and bodyweight exercises (3 sets of 10 squats, 10 push-ups, 10 lunges, 10 sit-ups). In each intervention, 16 participants completed four trials (A to D) during which a 500 kcal mixed nutrient liquid breakfast meal was consumed. Interstitial glucose responses were recorded using continuous glucose monitoring for 2 h after the meal. The activity was completed either after the glucose monitoring period (trial A; control) or immediately before (trial B), immediately after (trial C), or 30 min after (trial D) the breakfast. Mean, coefficient of variance (CV), and area under the curve (AUC) for glucose were calculated and compared between the four trials. Walking and bodyweight exercises immediately after the meal improved mean, CV, and AUC glucose (P ≤ 0.05 vs. control), while standing immediately after the meal only improved AUC glucose (P ≤ 0.05 vs. control) and nearly improved mean glucose (P = 0.06). Mean, CV, and AUC glucose were not affected by standing, walking, or bodyweight exercise conducted immediately before, or 30 min after the meal (all P > 0.05 vs. control). Energy intake (diet records) and energy expenditure (Actigraph) were consistent throughout the studies and did not influence the findings. Low- to moderate-intensity activity should be implemented soon after eating to improve glucose control following breakfast. The type of activity appears less important than the timing. These findings will help optimize exercise-meal timing in general health guidelines. ClinicalTrials.gov Identifier: NCT03730727

The purpose of this investigation was to evaluate the effects of experimental hyperglycemia on oxidative damage (OX), advanced glycation end products (AGEs), and the receptor for AGEs (RAGE) through an in vivo approach. Obese subjects (n = 10; 31.2 ± 1.2 kg·m−2; 56 ± 3 years) underwent 24 h of hyperglycemic clamp (+5.4 mM above basal), where plasma at basal and after 2 h and 24 h of hyperglycemic challenge were assayed for OX (methionine sulfoxide, MetSO, and aminoadipic acid, AAA) and AGE-free adducts (Ne-carboxymethyllysine, CML; Ne-carboxyethyllysine, CEL; glyoxal hydroimidazolone-1, GH-1; methylglyoxal hydroimidazolone-1, MG-H1; and 3-deoxyglucosone hydroimidazolone, 3DG-H) via liquid chromatography–tandem mass spectrometry (LC–MS/MS). Urine was also analyzed at basal and after 24 h for OX and AGE-free adducts and plasma soluble RAGE (sRAGE) isoforms (endogenous secretory RAGE, esRAGE, and cleaved RAGE, cRAGE), and inflammatory markers were determined via enzyme-linked immunosorbent assay (ELISA). Skeletal muscle tissue collected via biopsy was probed at basal, 2 h, and 24 h for RAGE and OST48 protein expression. Plasma MetSO, AAA, CEL, MG-H1, and G-H1 decreased (−18% to −47%; p < 0.05), while CML increased (72% at 24 h; p < 0.05) and 3DG-H remained unchanged (p > 0.05) with the hyperglycemic challenge. Renal clearance of MetSO, AAA, and G-H1 increased (599% to 1077%; p < 0.05), CML decreased (−30%; p < 0.05), and 3DG-H, CEL, and MG-H1 remained unchanged (p > 0.05). Fractional excretion of MetSO, AAA, CEL, G-H1, and MG-H1 increased (5.8% to 532%; p < 0.05) and CML and 3DG-H remained unchanged (p > 0.05). Muscle RAGE and OST48 expression, plasma sRAGE, IL-1β, IL-1Ra, and TNFα remained unchanged (p > 0.05), while IL-6 increased (159% vs. basal; p > 0.05). These findings suggest that individuals who are obese but otherwise healthy have the capacity to prevent accumulation of OX and AGEs during metabolic stress by increasing fractional excretion and renal clearance.

Obesity and type 2 diabetes (T2DM) are characterized by a blunted metabolic response to insulin, and strongly manifests in skeletal muscle insulin resistance. The orphan nuclear receptors, Nur77 and NOR1, regulate insulin-stimulated nutrient metabolism where Nur77 and NOR1 gene expression is increased with acute aerobic exercise and acute insulin stimulation. Whether Nur77 or NOR1 are associated with the insulin-sensitizing effects of chronic aerobic exercise training has yet to be elucidated. Fourteen lean healthy controls (LHC), 12 obese (OB), and 10 T2DM individuals (T2DM) underwent hyperinsulinemic-euglycemic clamps with skeletal muscle biopsies. Muscle was analyzed for Nur77 and NOR1 gene and protein expression at basal and insulin-stimulated conditions. Furthermore, a subcohort of 18 participants (OB, n = 12; T2DM, n = 6) underwent a 12-week aerobic exercise intervention (85% HRmax, 60 min/day, 5 days/week). In response to insulin infusion, LHC increased protein expression of Nur77 (8.7 +/- 3.2-fold) and NOR1 (3.6 +/- 1.1-fold), whereas OB and T2DM remained unaffected. Clamp-derived glucose disposal rates correlated with Nur77 (r(2) = 0.14) and NOR1 (r(2) = 0.12) protein expression responses to insulin, whereas age (Nur77: r(2) = 0.22; NOR1: r(2) = 0.25) and BMI (Nur77: r(2) = 0.22; NOR1: r(2) = 0.42) showed inverse correlations, corroborating preclinical data. In the intervention cohort, exercise improved Nur77 protein expression in response to insulin (PRE: -1.2 +/- 0.3%, POST: 6.2 +/- 1.5%). Also, insulin treatment of primary human skeletal muscle cells increased Nur77 and NOR1 protein. These findings highlight the multifactorial nature of insulin resistance in human obesity and T2DM. Understanding the regulation of Nur77 and NOR1 in skeletal muscle and other insulin-sensitive tissues will create opportunities to advance therapies for T2DM.

Exercise provides a cornerstone in the prevention and treatment of several chronic diseases. The use of in vivo exercise models alone cannot fully establish the skeletal muscle-specific mechanisms involved in such health-promoting effects. As such, models that replicate exercise-like effects in vitro provide useful tools to allow investigations that are not otherwise possible in vivo. In this review, we provide an overview of experimental models currently used to induce exercise-like effects in skeletal muscle in vitro. In particular, the appropriateness of electrical pulse stimulation and several pharmacological compounds to resemble exercise, as well as important technical considerations, are addressed. Each model covered herein provides a useful tool to investigate different aspects of exercise with a level of abstraction not possible in vivo. That said, none of these models are perfect under all circumstances, and the choice of model (and terminology) used should be informed by the specific research question whilst accounting for the several inherent limitations of each model. Further work is required to develop and optimise the current experimental models used, such as combination with complementary techniques during treatment, and thereby improve their overall utility and impact within muscle biology research.