Immediate post-breakfast physical activity improves interstitial postprandial glycemia: a comparison of different activity-meal timings.

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 benefits of physical exercise for the health of the pancreatic ß-cell: a review of the evidence.

NEW FINDINGS: What is the topic of this review? This review discusses the evidence of the benefits of exercise training for ß-cell health through improvements in function, proliferation and survival which may have implications in the treatment of diabetes. What advances does it highlight? This review highlights how exercise may modulate ß-cell health in the context of diabetes and highlights the need for further exploration of whether ß-cell preserving effects of exercise translates to T1D. ABSTRACT: Physical exercise is a core therapy for type 1 and type 2 diabetes. Whilst the benefits of exercise for different physiological systems are recognised, the effect of exercise specifically on the pancreatic ß-cell is not well described. Here we review the effects of physical exercise on ß-cell health. We show that exercise improves ß-cell mass and function. The improved function manifests primarily through the increased insulin content of the ß-cell and its increased ability to secrete insulin in response to a glucose stimulus. We review the evidence relating to glucose sensing, insulin signalling, ß-cell proliferation and ß-cell apoptosis in humans and animal models with acute exercise and following exercise training programmes. Some of the mechanisms through which these benefits manifest are discussed.

In vitro experimental models for examining the skeletal muscle cell biology of exercise: the possibilities, challenges and future developments.

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.

Probing the Effect of Physiological Concentrations of IL-6 on Insulin Secretion by INS-1 832/3 Insulinoma Cells under Diabetic-Like Conditions.

Exercise improves insulin secretion by pancreatic beta cells (ß-cells) in patients with type 2 diabetes, but molecular mechanisms of this effect are yet to be determined. Given that contracting skeletal muscle causes a spike in circulating interleukin-6 (IL-6) levels during exercise, muscle-derived IL-6 is a possible endocrine signal associated with skeletal muscle to ß-cell crosstalk. Evidence to support a role of IL-6 in regulating the health and function of ß-cells is currently inconsistent and studies investigating the role of IL-6 on the function of ß-cells exposed to type 2 diabetic-like conditions are limited and often confounded by supraphysiological IL-6 concentrations. The purpose of this study is to explore the extent by which an exercise-relevant concentration of IL-6 influences the function of pancreatic ß-cells exposed to type 2 diabetic-like conditions. Using insulin-secreting INS-1 832/3 cells as an experimental ß-cell model, we show that 1-h IL-6 (10 pg/mL) has no effect on insulin secretion under normal conditions and does not restore the loss of insulin secretion caused by elevated glucose ± palmitate or IL-1ß. Moreover, treatment of INS-1 832/3 cells to medium collected from C2C12 myotubes conditioned with electrical pulse stimulation does not alter insulin secretion despite significant increases in IL-6. Since insulin secretory defects caused by diabetic-like conditions are neither improved nor worsened by exposure to physiological IL-6 levels, we conclude that the beneficial effect of exercise on ß-cell function is unlikely to be driven by muscle-derived IL-6.

The effects of 2 weeks of interval vs continuous walking training on glycaemic control and whole-body oxidative stress in individuals with type 2 diabetes: a controlled, randomised, crossover trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the effects of oxygen consumption-matched short-term interval walking training (IWT) vs continuous walking training (CWT) on glycaemic control, including glycaemic variability, in individuals with type 2 diabetes. We also assessed whether any training-induced improvements in glycaemic control were associated with systemic oxidative stress levels. METHODS: Participants (n = 14) with type 2 diabetes completed a crossover trial using three interventions (control intervention [CON], CWT and IWT), each lasting 2 weeks. These were performed in a randomised order (computerised generated randomisation) and separated by washout periods of 4 or 8 weeks after CON or training interventions, respectively. Training included ten supervised treadmill sessions, lasting 60 min/session, and was performed at the research facility. CWT was performed at moderate walking speed (75.6% ± 2.5% of walking peak oxygen consumption [[Formula: see text]]), while IWT was performed as alternating 3 min repetitions at slow (58.9% ± 2.0% [Formula: see text]) and fast (90.0% ± 3.6% [Formula: see text]) walking speed. Before and after each intervention, the following was assessed: 24 h continuous glucose monitoring (CGM) and urinary free 8-iso prostaglandin F2α (8-iso PGF2α; a marker for oxidative stress), physical fitness and body composition. Neither participants nor assessors were blinded to the interventions. RESULTS: No intervention-induced changes were seen in physical fitness or body composition. Compared with baseline, IWT reduced mean glucose levels non-significantly (-0.7 ± 0.3 mmol/l, p = 0.08) and significantly reduced maximum glucose levels (-1.8 ± 0.5 mmol/l, p = 0.04) and mean amplitude of glycaemic excursions (MAGE; -1.7 ± 0.4 mmol/l, p = 0.02), whereas no significant within-group changes were seen with CON or CWT. Although 8-iso PGF2α was associated with minimum glucose levels at baseline, no change in 8-iso PGF2α was seen with any intervention, nor were there any associations between changes in 8-iso PGF2α and changes in glycaemic control (p > 0.05 for all). No adverse effects were observed with any of the interventions. CONCLUSIONS/INTERPRETATION: Short-term IWT, but not CWT, improves CGM-derived measures of glycaemic control independent of changes in physical fitness and body composition in individuals with type 2 diabetes. Systemic oxidative stress levels are unaffected by short-term walking and changes in oxidative stress levels are not associated with changes in glycaemic control. TRIAL REGISTRATION: ClinicalTrials.gov NCT02320526 FUNDING : The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The study was further supported by grants from Diabetesforeningen, Augustinusfonden and Krista og Viggo Petersens Fond. CIM/CFAS is a member of the Danish Center for Strategic Research in Type 2 Diabetes (DD2; the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724). MR-L was supported by a post-doctoral grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation.

Glucose effectiveness, but not insulin sensitivity, is improved after short-term interval training in individuals with type 2 diabetes mellitus: a controlled, randomised, crossover trial.

AIMS/HYPOTHESIS: The role of glucose effectiveness (S G) in training-induced improvements in glucose metabolism in individuals with type 2 diabetes is unknown. The objectives and primary outcomes of this study were: (1) to assess the efficacy of interval walking training (IWT) and continuous walking training (CWT) on S G and insulin sensitivity (S I) in individuals with type 2 diabetes; and (2) to assess the association of changes in S G and S I with changes in glycaemic control. METHODS: Fourteen participants with type 2 diabetes underwent three trials (IWT, CWT and no training) in a crossover study. Exclusion criteria were exogenous insulin treatment, smoking, pregnancy, contraindications to structured physical activity and participation in recurrent training (>90 min/week). The trials were performed in a randomised order (computerised-generated randomisation). IWT and CWT consisted of ten supervised treadmill walking sessions, each lasting 60 min, over 2 weeks. IWT was performed as repeated cycles of 3 min slow walking and 3 min fast walking (aiming for 54% and 89% of [Formula: see text], respectively, which was measured during the last minute of each interval), and CWT was performed aiming for a moderate walking speed (73% of [Formula: see text]). A two-step (pancreatic and hyperinsulinaemic) hyperglycaemic clamp was implemented before and after each trial. All data were collected in a hospitalised setting. Neither participants nor assessors were blinded to the trial interventions. RESULTS: Thirteen individuals completed all procedures and were included in the analyses. IWT improved S G (mean ± SEM: 0.6 ± 0.1 mg kg-1 min-1, p < 0.05) but not S I (p > 0.05), whereas CWT matched for energy expenditure and time duration improved neither S G nor S I (both p > 0.05). Changes in S G, but not in S I, were associated with changes in mean (ß = -0.62 ± 0.23, r 2 = 0.17, p < 0.01) and maximum (ß = -1.18 ± 0.52, r 2 = 0.12, p < 0.05) glucose levels during 24 h continuous glucose monitoring. CONCLUSIONS/INTERPRETATION: Two weeks of IWT, but not CWT, improves S G but not S I in individuals with type 2 diabetes. Moreover, changes in S G are associated with changes in glycaemic control. Therefore, increased S G is likely an important mechanism by which training improves glycaemic control in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02320526 FUNDING: CFAS is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The study was further supported by grants from Diabetesforeningen, Augustinusfonden and Krista og Viggo Petersens Fond. CIM/CFAS is a member of DD2-the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724).

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes.

The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA, and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, vs. normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower (P < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (P < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; P < 0.01) and cRAGE (odds ratio, 0.84; P < 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes.

Effect of a 2-year home-based endurance training intervention on physiological function and PSA doubling time in prostate cancer patients.

AIM: Physical activity after prostate cancer diagnosis has been shown to reduce the risk of disease progression. Here, we aimed to evaluate the effect of a 2-year home-based endurance training intervention on body composition, biomarkers levels, and prostate-specific antigen (PSA) doubling time as a surrogate end-point for progressing disease. METHODS: Out-clinic patients with either biochemical recurrence following radical prostatectomy or patients managed on active surveillance were randomized to either 24 months (3 times/week) of home-based endurance training or usual care. Aerobic fitness, body composition, insulin sensitivity, and biomarkers were measured at 0, 6, and 24 months of intervention. PSA doubling time (PSADT) was calculated based on monthly PSA measurements. RESULTS: Twenty-five patients were enrolled, and 19 patients completed the study. PSADT increased in the training group from 28 to 76 months (p < 0.05) during the first 6 months and was correlated with changes in VO2max (p < 0.01, r (2) = 0.41). The training group lost 3.6 ± 1.0 kg (p < 0.05) exclusively as fat mass, yet the changes in body composition were not associated with the increased PSADT. The training group showed significant improvements in plasma triglycerides, adiponectin, IGF-1, IGFBP-1, and fasting glucose levels, but no changes in insulin sensitivity (measured as Matsuda index), testosterone, cholesterols, fasting insulin, plasma TNF-alpha, IL-6, or leptin levels. The control group showed no changes in any of the evaluated parameters across the 2-year intervention. CONCLUSION: In this small randomized controlled trial, we found that improvements in fitness levels correlated with increasing PSADT, suggesting a link between training and disease progression.

Direct effect of incretin hormones on glucose and glycerol metabolism and hemodynamics.

The objective of this study was to assess the insulin-independent effects of incretin hormones on glucose and glycerol metabolism and hemodynamics under euglycemic and hyperglycemic conditions. Young, healthy men (n=10) underwent three trials in a randomized, controlled, crossover study. Each trial consisted of a two-stage (euglycemia and hyperglycemia) pancreatic clamp (using somatostatin to prevent endogenous insulin secretion). Glucose and lipid metabolism was measured via infusion of stable glucose and glycerol isotopic tracers. Hemodynamic variables (femoral, brachial, and common carotid artery blood flow and flow-mediated dilation of the brachial artery) were also measured. The three trials differed as follows: 1) saline [control (CON)], 2) glucagon-like peptide (GLP-1, 0.5 pmol·kg(-1)·min(-1)), and 3) glucose-dependent insulinotropic polypeptide (GIP, 1.5 pmol·kg(-1)·min(-1)). No between-trial differences in glucose infusion rates (GIR) or glucose or glycerol kinetics were seen during euglycemia, whereas hyperglycemia resulted in increased GIR and glucose rate of disappearance during GLP-1 compared with CON and GIP (P<0.01 for all). However, when normalized to insulin levels, no differences between trials were seen for GIR or glucose rate of disappearance. Besides a higher femoral blood flow during hyperglycemia with GIP (vs. CON and GLP-1, P<0.001), no between-trial differences were seen for the hemodynamic variables. In conclusion, GLP-1 and GIP have no direct effect on whole body glucose metabolism or hemodynamics during euglycemia. On the contrary, during hyperglycemia, GIP increases femoral artery blood flow with no effect on glucose metabolism, whereas GLP-1 increases glucose disposal, potentially due to increased insulin levels.

Mechanisms behind the superior effects of interval vs continuous training on glycaemic control in individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: By use of a parallel and partly crossover randomised, controlled trial design we sought to elucidate the underlying mechanisms behind the advantageous effects of interval walking training (IWT) compared with continuous walking training (CWT) on glycaemic control in individuals with type 2 diabetes. We hypothesised that IWT, more than CWT, would improve insulin sensitivity including skeletal muscle insulin signalling, insulin secretion and disposition index (DI). METHODS: By simple randomisation (sequentially numbered, opaque sealed envelopes), eligible individuals (diagnosed with type 2 diabetes, no exogenous insulin treatment) were allocated to three groups: a control group (CON, n = 8), an IWT group (n = 12) and an energy expenditure-matched CWT group (n = 12). Training groups were prescribed free-living training, five sessions per week (60 min/session). A three-stage hyperglycaemic clamp, including glucose isotope tracers and skeletal muscle biopsies, was performed before and after a 4 month intervention in a hospitalised setting. No blinding was performed. RESULTS: The improved glycaemic control, which was only seen in the IWT group, was consistent with IWT-induced increases in insulin sensitivity index (49.8 ± 14.6%; p < 0.001), peripheral glucose disposal (14.5 ± 4.9%; p < 0.05) and DI (66.2 ± 21.8%; p < 0.001), with no changes in the CWT or CON group. Moreover, only IWT improved insulin signalling in skeletal muscle via increased insulin-stimulated phosphorylation of AS160 (29.0 ± 10.8%; p < 0.05). No changes were seen in insulin secretion during hyperglycaemia alone, hyperglycaemia + glucagon-like peptide 1 infusion or arginine injection. CONCLUSIONS/INTERPRETATION: IWT maintains insulin secretion and improves insulin sensitivity and DI, in contrast to energy expenditure-matched CWT. These results suggest that training with alternating intensity, and not just training volume and mean intensity, is a key determinant of changes in whole body glucose disposal in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials (NCT01234155).

Hyperglycemia abolishes meal-induced satiety by a dysregulation of ghrelin and peptide YY3-36 in healthy overweight/obese humans.

Satiety and satiety-regulating gut hormone levels are abnormal in hyperglycemic individuals. We aimed to determine whether these abnormalities are secondary to hyperglycemia. Ten healthy overweight/obese subjects (age: 56 ± 3 yr; BMI: 30.3 ± 1.2 kg/m(2)) received three equicaloric meals at t = 0, 4, and 8 h in the absence (control trial) and presence of experimental hyperglycemia (hyperglycemia trial; 5.4 mM above basal). Circulating levels of glucose, insulin, ghrelin, and peptide YY (PYY)3-36 and visual analog scale ratings of satiety were measured throughout each trial. In the control trial, glucose, insulin, PYY3-36, and the feeling of fullness were increased in the postprandial periods, whereas ghrelin was decreased. In the hyperglycemia trial, in which plasma glucose was increased to 11.2 ± 0.1 mmol/l, postprandial meal responses (AUC: 0-2, 4-6, and 8-10 h) of PYY3-36 were lower (meal 1, P < 0.0001; meal 2, P < 0.001; meal 3, P < 0.05), whereas insulin (meal 1, P < 0.01; meal 2, P < 0.001; meal 3, P < 0.05) and ghrelin (meal 1, P < 0.05; meal 2, P > 0.05; meal 3, P > 0.05) were higher compared with the control trial. Furthermore, the incremental (Δ0-0.5, 4-4.5, and 8-8.5 h) ghrelin response to the first and third meals was higher in the hyperglycemia trial in contrast to control (Δ: 2.3 ± 8.0, P = 0.05; Δ: 14.4 ± 2.5, P < 0.05). Also, meal-induced fullness was prevented (meal 1, P = 0.06; meal 2, P = 0.01; meal 3, P = 0.08) by experimental hyperglycemia. Furthermore, trends in ghrelin, PYY3-36, and fullness were described by different polynomial functions between the trials. In conclusion, hyperglycemia abolishes meal-induced satiety and dysregulates postprandial responses of the gut hormones PYY3-36 and ghrelin in overweight/obese healthy humans.

Determining pancreatic ß-cell compensation for changing insulin sensitivity using an oral glucose tolerance test.

Plasma glucose, insulin, and C-peptide responses during an OGTT are informative for both research and clinical practice in type 2 diabetes. The aim of this study was to use such information to determine insulin sensitivity and insulin secretion so as to calculate an oral glucose disposition index (DI(OGTT)) that is a measure of pancreatic ß-cell insulin secretory compensation for changing insulin sensitivity. We conducted an observational study of n = 187 subjects, representing the entire glucose tolerance continuum from normal glucose tolerance to type 2 diabetes. OGTT-derived insulin sensitivity (S(I OGTT)) was calculated using a novel multiple-regression model derived from insulin sensitivity measured by hyperinsulinemic euglycemic clamp as the independent variable. We also validated the novel S(I OGTT) in n = 40 subjects from an independent data set. Plasma C-peptide responses during OGTT were used to determine oral glucose-stimulated insulin secretion (GSIS(OGTT)), and DI(OGTT) was calculated as the product of S(I OGTT) and GSIS(OGTT). Our novel S(I OGTT) showed high agreement with clamp-derived insulin sensitivity (typical error = +3.6%; r = 0.69, P < 0.0001) and that insulin sensitivity was lowest in subjects with impaired glucose tolerance and type 2 diabetes. GSIS(OGTT) demonstrated a significant inverse relationship with S(I OGTT). GSIS(OGTT) was lowest in normal glucose-tolerant subjects and greatest in those with impaired glucose tolerance. DI(OGTT) was sequentially lower with advancing glucose intolerance. We hereby derive and validate a novel OGTT-derived measurement of insulin sensitivity across the entire glucose tolerance continuum and demonstrate that ß-cell compensation for changing insulin sensitivity can be readily calculated from clinical variables collected during OGTT.

Effects of caloric restriction with different doses of exercise on fat loss in people living with type 2 diabetes: A secondary analysis of the DOSE-EX randomized clinical trial.

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 wk (MED) (n = 20), or diet control and exercise 6 times per wk (HED) (n = 21) for 16 wk. 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 (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.

Pancreatic ß-cell function increases in a linear dose-response manner following exercise training in adults with prediabetes.

Although some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic ß-cell function is unknown. Thirty-five older obese adults with prediabetes underwent a progressive 12-wk supervised exercise intervention (5 days/wk for 60 min at ~85% HRmax). Insulin and C-peptide responses to an OGTT were used to define the first- and second-phase disposition index (DI; ß-cell function = glucose-stimulated insulin secretion × clamp-derived insulin sensitivity). Maximum oxygen consumption (Vo2max) and body composition (dual-energy X-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using Vo2/heart-rate derived linear regression equations. Subjects expended 474.5 ± 8.8 kcal/session (2,372.5 ± 44.1 kcal/wk) during the intervention and lost ~8% body weight. Exercise increased first- and second-phase DI (P < 0.05), and these changes in DI were linearly related to exercise dose (DIfirst phase: r = 0.54, P < 0.001; DIsecond phase: r = 0.56, P = 0.0005). Enhanced DI was also associated with increased Vo2max (DIfirst phase: r = 0.36, P = 0.04; DIsecond phase: r = 0.41, P < 0.02) but not lower body fat (DIfirst phase: r = -0.21, P = 0.25; DIsecond phase: r = -0.30, P = 0.10) after training. Low baseline DI predicted an increase in DI after the intervention (DIfirst phase: r = -0.37; DIsecond phase: r = -0.41, each P < 0.04). Thus, exercise training plus weight loss increased pancreatic ß-cell function in a linear dose-response manner in adults with prediabetes. Our data suggest that higher exercise doses (i.e., >2,000 kcal/wk) are necessary to enhance ß-cell function in adults with poor insulin secretion capacity.

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes.

Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 ± 0.8 yr) obese (34.2 ± 0.9 kg/m(2)) adults were categorized as IFG (n = 8), IGT (n = 8), or IFG + IGT (n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ∼85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m(2)·min(-1)) with [6,6-(2)H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT (P < 0.05). Exercise reduced glucose iAUCOGTT in IGT only (P < 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity (P < 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P < 0.05). Adults with IFG + IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training.

Tumour necrosis factor-alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. METHODS: We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m(2) ). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated. RESULTS: TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. CONCLUSION: In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect.

Exercise-induced changes to the fiber type-specific redox state in human skeletal muscle are associated with aerobic capacity.

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 participants (11 M, 8 F; 26 ± 4 yr) at baseline (fasted) and 30 min and 3 h after treadmill exercise at 80% maximal oxygen consumption (V̇o2max). Muscle samples were probed for autofluorescence of NADH (excitation at 340-360 nm) and oxidized flavoproteins (Fp; excitation at 440-470 nm) and subsequently, fiber typed 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, pair-wise comparisons revealed that the redox ratio of myosin heavy chain (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 (main effect, P = 0.039) but redox ratios did not change (main effect, P = 0.483) 30 min after exercise. The change in redox ratio was positively correlated with capillary density in MHC I (rho = 0.762, P = 0.037), MHC IIa fibers (rho = 0.881, P = 0.007), and modestly in MHC IIx fibers (rho = 0. 771, P = 0.103). These findings support the use of redox autofluorescence to interrogate skeletal muscle metabolism.NEW & NOTEWORTHY This study is the first to use autofluorescent imaging to describe differential redox states within human skeletal muscle fiber types with exercise. Our findings highlight an easy and efficacious technique for assessing skeletal muscle redox in humans.

Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial.

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).

Exercise training with weight loss and either a high- or low-glycemic index diet reduces metabolic syndrome severity in older adults.

BACKGROUND: The efficacy of combining carbohydrate quality with exercise on metabolic syndrome risk is unclear. Thus, we determined the effects of exercise training with a low (LoGIx)- or high (HiGIx)-glycemic index diet on the severity of the metabolic syndrome (Z-score). METHODS: Twenty-one adults (66.2±1.1 years; BMI=35.3±0.9 kg/m2) with the metabolic syndrome were randomized to 12 weeks of exercise (60 min/day for 5 days/week at about 85% HRmax) and provided a LoGIx (n=11) or HiGIx (n=10) diet. Z-scores were determined from: blood pressure, triglycerides (TGs), high-density lipoproteins (HDLs), fasting plasma glucose (FPG), and waist circumference (WC) before and after the intervention. Body composition, aerobic fitness, insulin resistance, and nonesterfied fatty acid (NEFA) suppression were also assessed. RESULTS: LoGIx and HiGIx diets decreased body mass and insulin resistance and increased aerobic fitness comparably (p<0.05). LoGIx and HiGIx diets decreased the Z-score similarly as each intervention decreased blood pressure, TGs, FPG and WC (p<0.05). The HiGIx diet tended to suppress NEFA during insulin stimulation compared with the LoGIx diet (p=0.06). CONCLUSIONS: Our findings highlight that exercise with weight loss reduces the severity of the metabolic syndrome whether individuals were randomized to a HiGIx or a LoGIx diet.

Plasma FGF21 concentrations are regulated by glucose independently of insulin and GLP-1 in lean, healthy humans.

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.