Daily protein-polyphenol ingestion increases daily myofibrillar protein synthesis rates and promotes early muscle functional gains during resistance training.

Factors underpinning the time-course of resistance-type exercise training (RET) adaptations are not fully understood. This study hypothesized that consuming a twice-daily protein-polyphenol beverage (PPB; n = 15; age, 24 ± 1 yr; BMI, 22.3 ± 0.7 kg·m-2) previously shown to accelerate recovery from muscle damage and increase daily myofibrillar protein synthesis (MyoPS) rates would accelerate early (10 sessions) improvements in muscle function and potentiate quadriceps volume and muscle fiber cross-sectional area (fCSA) following 30 unilateral RET sessions in healthy, recreationally active, adults. Versus isocaloric placebo (PLA; n = 14; age, 25 ± 2 yr; BMI, 23.9 ± 1.0 kg·m-2), PPB increased 48 h MyoPS rates after the first RET session measured using deuterated water (2.01 ± 0.15 vs. 1.51 ± 0.16%·day-1, respectively; P < 0.05). In addition, PPB increased isokinetic muscle function over 10 sessions of training relative to the untrained control leg (%U) from 99.9 ± 1.8 pretraining to 107.2 ± 2.4%U at session 10 (vs. 102.6 ± 3.9 to 100.8 ± 2.4%U at session 10 in PLA; interaction P < 0.05). Pre to posttraining, PPB increased type II fCSA (PLA: 120.8 ± 8.2 to 109.5 ± 8.6%U; PPB: 92.8 ± 6.2 to 108.4 ± 9.7%U; interaction P < 0.05), but the gain in quadriceps muscle volume was similar between groups. Similarly, PPB did not further increase peak isometric torque, muscle function, or MyoPS measured posttraining. This suggests that although PPB increases MyoPS and early adaptation, it may not influence longer term adaptations to unilateral RET.NEW & NOTEWORTHY Using a unilateral model of resistance training, we show for the first time that a protein-polyphenol beverage increases initial rates of myofibrillar protein synthesis and promotes early functional improvements. Following a prolonged period of training, this strategy also increases type II fiber hypertrophy and causes large individual variation in gains in quadricep muscle cross-sectional area.

Reducing NF-κB Signaling Nutritionally is Associated with Expedited Recovery of Skeletal Muscle Function After Damage.

CONTEXT: The early events regulating the remodeling program following skeletal muscle damage are poorly understood. OBJECTIVE: The objective of this study was to determine the association between myofibrillar protein synthesis (myoPS) and nuclear factor-kappa B (NF-κB) signaling by nutritionally accelerating the recovery of muscle function following damage. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Healthy males and females consumed daily postexercise and prebed protein-polyphenol (PP; n = 9; 4 females) or isocaloric maltodextrin placebo (PLA; n = 9; 3 females) drinks (parallel design) 6 days before and 3 days after 300 unilateral eccentric contractions of the quadriceps during complete dietary control. MAIN OUTCOME MEASURES: Muscle function was assessed daily, and skeletal muscle biopsies were taken after 24, 27, and 36 hours for measurements of myoPS rates using deuterated water, and gene ontology and NF-κB signaling analysis using a quantitative reverse transcription PCR (RT-qPCR) gene array. RESULTS: Eccentric contractions impaired muscle function for 48 hours in PLA intervention, but just for 24 hours in PP intervention (P = 0.047). Eccentric quadricep contractions increased myoPS compared with the control leg during postexercise (24-27 hours; 0.14 ± 0.01 vs 0.11 ± 0.01%·h-1, respectively; P = 0.075) and overnight periods (27-36 hours; 0.10 ± 0.01 vs 0.07 ± 0.01%·h-1, respectively; P = 0.020), but was not further increased by PP drinks (P > 0.05). Protein-polyphenol drinks decreased postexercise and overnight muscle IL1R1 (PLA = 2.8 ± 0.4, PP = 1.1 ± 0.4 and PLA = 1.9 ± 0.4, PP = 0.3 ± 0.4 log2 fold-change, respectively) and IL1RL1 (PLA = 4.9 ± 0.7, PP = 1.6 ± 0.8 and PLA = 3.7 ± 0.6, PP = 0.7 ± 0.7 log2 fold-change, respectively) messenger RNA expression (P < 0.05) and downstream NF-κB signaling compared with PLA. CONCLUSION: Protein-polyphenol drink ingestion likely accelerates recovery of muscle function by attenuating inflammatory NF-κB transcriptional signaling, possibly to reduce aberrant tissue degradation rather than increase myoPS rates.

Improved recovery from skeletal muscle damage is largely unexplained by myofibrillar protein synthesis or inflammatory and regenerative gene expression pathways.

The contribution of myofibrillar protein synthesis (MyoPS) to recovery from skeletal muscle damage in humans is unknown. Recreationally active men and women consumed a daily protein-polyphenol beverage targeted at increasing amino acid availability and reducing inflammation (PPB; n = 9), both known to affect MyoPS, or an isocaloric placebo (PLA; n = 9) during 168 h of recovery from 300 maximal unilateral eccentric contractions (EE). Muscle function was assessed daily. Muscle biopsies were collected for 24, 27, 36, 72, and 168 h for MyoPS measurements using 2H2O and expression of 224 genes using RT-qPCR and pathway analysis. PPB improved recovery of muscle function, which was impaired for 5 days after EE in PLA (interaction P < 0.05). Acute postprandial MyoPS rates were unaffected by nutritional intervention (24-27 h). EE increased overnight (27-36 h) MyoPS versus the control leg (PLA: 33 ± 19%; PPB: 79 ± 25%; leg P < 0.01), and PPB tended to increase this further (interaction P = 0.06). Daily MyoPS rates were greater with PPB between 72 and 168 h after EE, albeit after function had recovered. Inflammatory and regenerative signaling pathways were dramatically upregulated and clustered after EE but were unaffected by nutritional intervention. These results suggest that accelerated recovery from EE is not explained by elevated MyoPS or suppression of inflammation.NEW & NOTEWORTHY The present study investigated the contribution of myofibrillar protein synthesis (MyoPS) and associated gene signaling to recovery from 300 muscle-damaging, eccentric contractions. Measured with 2H2O, MyoPS rates were elevated during recovery and observed alongside expression of inflammatory and regenerative signaling pathways. A nutritional intervention accelerated recovery; however, MyoPS and gene signaling were unchanged compared with placebo. These data indicate that MyoPS and associated signaling do not explain accelerated recovery from muscle damage.

A Randomised, Placebo-Controlled, Crossover Study Investigating the Optimal Timing of a Caffeine-Containing Supplement for Exercise Performance.

BACKGROUND: Pre-exercise supplements containing low doses of caffeine improve endurance exercise performance, but the most efficacious time for consumption before intense endurance exercise remains unclear, as does the contribution of caffeine metabolism. METHODS: This study assessed the timing of a commercially available supplement containing 200 mg of caffeine, 1600 mg of ß-alanine and 1000 mg of quercetin [Beachbody Performance Energize, Beachbody LLC, USA] on exercise performance, perception of effort and plasma caffeine metabolites. Thirteen cyclists (V̇O2max 64.5 ± 1.4 ml kg- 1 min- 1 (± SEM)) completed four experimental visits consisting of 30 min of steady-state exercise on a cycle ergometer at 83 ± 1% V̇O2max followed by a 15-min time trial, with perceived exertion measured regularly. On three of the visits, participants consumed caffeine either 35 min before steady-state exercise (PRE), at the onset of steady-state (ONS) or immediately before the time trial (DUR) phases, with a placebo consumed at the other two time points (i.e. three drinks per visit). The other visit (PLA) consisted of consuming the placebo supplement at all three time points. The placebo was taste-, colour- and calorie-matched. RESULTS: Total work performed during the time trial in PRE was 5% greater than PLA (3.53 ± 0.14 vs. 3.36 ± 0.13 kJ kg- 1 body mass; P = 0.0025), but not ONS (3.44 ± 0.13 kJ kg- 1; P = 0.3619) or DUR (3.39 ± 0.13 kJ kg- 1; P = 0.925), which were similar to PLA. Perceived exertion was lowest during steady-state exercise in the PRE condition (P < 0.05), which coincided with elevated plasma paraxanthine in PRE only (P < 0.05). CONCLUSION: In summary, ingestion of a pre-exercise supplement containing 200 mg caffeine 35 min before exercise appeared optimal for improved performance in a subsequent fatiguing time trial, possibly by reducing the perception of effort. Whether this was due to increased circulating paraxanthine requires further investigation. TRIAL REGISTRATION: ClinicalTrials.Gov, NCT02985606 ; 10/26/2016.

Response to Exercise Training and Outcomes in Patients With Heart Failure and Diabetes Mellitus: Insights From the HF-ACTION Trial.

BACKGROUND: In HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), exercise training improved functional capacity in heart failure with reduced ejection fraction (HFrEF). Previous studies have suggested that diabetes mellitus (DM) may be associated with an attenuated response to exercise. We explored whether DM attenuated the improvement in functional capacity with exercise. METHODS AND RESULTS: HF-ACTION randomized 2331 patients with HFrEF to medical therapy with or without exercise training over a median follow-up of 2.5 years. We examined the interaction between DM and exercise response measured by change in 6-minute walk distance (6MWD) and peak VO2. We also examined outcomes by DM status. In HF-ACTION, 748 (32%) patients had DM. DM patients had lower functional capacity at baseline and had lower exercise volumes at 3 months. There was a significant interaction between DM status and exercise training for change in peak VO2 (interaction P = .02), but not 6MWD. In the exercise arm, DM patients had a smaller mean increase in peak VO2 than non-DM patients (P = .03). There was no interaction between DM and exercise on clinical outcomes. After risk adjustment, DM was associated with increased all-cause mortality/hospitalization (P = .03). CONCLUSIONS: In HF-ACTION, DM was associated with lower baseline functional capacity, an attenuated improvement in peak VO2, and increased hospitalizations.

Adverse Cardiovascular Response to Aerobic Exercise Training: Is This a Concern?

PURPOSE: Aerobic exercise training in sedentary individuals improves physical fitness and various cardiovascular (CV) biomarkers. Nevertheless, there has been controversy as to whether exercise training may adversely affect some biomarkers in a small segment of the population. The purpose of this study was to investigate whether clinically significant worsening of CV biomarkers was more prevalent among individuals randomized to a supervised endurance training program as compared with those randomized to a control condition. METHODS: Baseline and end of study measurements of fasting insulin (FI), triglycerides (TG), resting systolic blood pressure (SBP), and HDL cholesterol (HDL-C) were obtained on 1188 healthy sedentary subjects from 4 clinical studies. Each study randomized subjects to 4- to 6-month supervised aerobic exercise programs or to a control group of no supervised exercise training. For each of the 4 CV biomarkers, we calculated the respective proportions of control and exercise group subjects whose baseline-to-follow-up changes were greater than or equal to previously reported adverse change (AC) thresholds. Those thresholds were increases of 24 pmol · L(-1) or greater for FI, 0.42 mmol · L(-1) or greater for TG, 10 mm Hg or greater for SBP, and a decrease of 0.12 mmol · L(-1) or greater for HDL-C. RESULTS: The respective proportions of subjects meeting the AC threshold in the control and exercise groups were 15.2% versus 9.6% (P = 0.02) for FI, 14.9% versus 13.1% (P = 0.37) for TG, 16.9% versus 15.8% (P = 0.52) for SBP, and 28.6% versus 22.5% (P = 0.03) for HDL-C. All were nonsignificant at the 0.0125 Bonferroni threshold adjusting for multiple comparisons. CONCLUSIONS: These findings do not support the concept that aerobic exercise training increases the risk of adverse changes in the CV biomarkers we studied.

The effects of exercise on the lipoprotein subclass profile: A meta-analysis of 10 interventions.

OBJECTIVE: The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts. METHODS: Nuclear magnetic resonance spectroscopy was used to quantify average particle size, total and subclass concentrations of very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles (VLDL-P, LDL-P, and HDL-P, respectively) before and after an exercise intervention in 1555 adults from six studies, encompassing 10 distinct exercise programs: APOE (N = 106), DREW (N = 385), GERS (N = 79), HERITAGE (N = 715), STRRIDE I (N = 168) and II (N = 102). Random-effects meta-analyses were performed to evaluate the overall estimate of mean change across the unadjusted and adjusted mean change values from each exercise group. RESULTS: Meta-analysis of unadjusted data showed that regular exercise induced significant decreases in the concentration of large VLDL-P, small LDL-P, and medium HDL-P and mean VLDL-P size, with significant increases in the concentration of large LDL-P and large HDL-P and mean LDL-P size. These changes remained significant in meta-analysis with adjustment for age, sex, race, baseline body mass index, and baseline trait value. CONCLUSIONS: Despite differences in exercise programs and study populations, regular exercise produced putatively beneficial changes in the lipoprotein subclass profile across 10 exercise interventions. Further research is needed to examine how exercise-induced changes in lipoprotein subclasses may be associated with (concomitant changes in) cardiovascular disease risk.

The effects of aerobic, resistance, and combination training on insulin sensitivity and secretion in overweight adults from STRRIDE AT/RT: a randomized trial.

Most health organizations recommend a combination of aerobic training (AT) and resistance training (RT), yet few studies have compared their acute (within 24 h of the last exercise bout) and sustained (after 14 days of no exercise training) effects alone and in combination on glucose metabolism. The present study (Studies Targeting Risk Reduction Interventions through Defined Exercise-Aerobic Training and/or Resistance Training) compared the effects of AT, RT, and the combination (AT/RT) on insulin action at both acute and sustained phases. Subjects (N = 196) were 18-70 yr old (mean age = 50 yr), overweight (mean body mass index = 30 kg/m2), sedentary with moderate dyslipidemia, and were randomized into one of three 8-mo exercise groups: 1) RT: 3 days/wk, 8 exercises, 3 sets/exercise, 8-12 repetitions/set; 2) AT: equivalent to ∼19.2 km/wk (12 miles/wk) at 75% peak O2 consumption; 3) AT/RT: the combination of AT and RT. One hundred forty-four subjects completed the intervention. Eighty-eight subjects completed all pre- and postintervention testing visits. Insulin sensitivity, glucose effectiveness, and disposition index were measured via a frequently sampled intravenous glucose tolerance test with subsequent minimal model analyses. AT/RT resulted in greater improvements in insulin sensitivity, ß-cell function (disposition index), and glucose effectiveness than either AT or RT alone (all P < 0.05). Approximately 52% of the improvement in insulin sensitivity by AT/RT was retained 14 days after the last exercise training bout. Neither AT or RT led to acute or chronic improvement in sensitivity index. In summary, only AT/RT (which required twice as much time as either alone) led to significant acute and sustained benefits in insulin sensitivity

Muscle-Specific Overexpression of PGC-1α Does Not Augment Metabolic Improvements in Response to Exercise and Caloric Restriction.

This study used mice with muscle-specific overexpression of PGC-1α, a transcriptional coactivator that promotes mitochondrial biogenesis, to determine whether increased oxidative potential facilitates metabolic improvements in response to lifestyle modification. MCK-PGC1α mice and nontransgenic (NT) littermates were fed a high-fat diet (HFD) for 10 weeks, followed by stepwise exposures to voluntary wheel running (HFD+Ex) and then 25% caloric restriction with exercise (Ex/CR), each for an additional 10 weeks with continued HFD. Running and CR improved weight and glucose control similarly in MCK-PGC1α and NT mice. Sedentary MCK-PGC1α mice were more susceptible to diet-induced glucose intolerance, and insulin action measured in isolated skeletal muscles remained lower in the transgenic compared with the NT group, even after Ex/CR. Comprehensive profiling of >200 metabolites and lipid intermediates revealed dramatic group-specific responses to the intervention but did not produce a lead candidate that tracked with changes in glucose tolerance irrespective of genotype. Instead, principal components analysis identified a chemically diverse metabolite cluster that correlated with multiple measures of insulin responsiveness. These findings challenge the notion that increased oxidative capacity defends whole-body energy homeostasis and suggest that the interplay between mitochondrial performance, lipotoxicity, and insulin action is more complex than previously proposed.

The effects of improved metabolic risk factors on bone turnover markers after 12 weeks of simvastatin treatment with or without exercise.

OBJECTIVE: Emerging evidence supports an association between metabolic risk factors and bone turnover. Statins and exercise independently improve metabolic risk factors; however whether improvements in metabolic risk factor affects bone turnover is unknown. The purpose of the present study was to: 1) evaluate the relationship between metabolic risk factors and bone turnover; and 2) determine if improvements in metabolic risk factors after 12 weeks of statin treatment, exercise or the combination affect bone turnover. METHODS: Fifty participants with ≥2 metabolic syndrome defining characteristics were randomly assigned to one of three groups: statin (STAT: simvastatin, 40 mg/day), exercise (EX: brisk walking and/or slow jogging, 45 minutes/day, 5 days/week), or the combination (STAT+EX). Body composition and whole body bone mineral density were measured with dual energy X-ray absorptiometry. Serum markers of bone formation (bone specific alkaline phosphatase, BAP; osteocalcin, OC), resorption (C-terminal peptide of type I collagen, CTX) and metabolic risk factors were determined. Two-factor (time, group) repeated-measures ANCOVA was used to examine changes of metabolic risk factors and bone turnover. General linear models were used to determine the effect of pre-treatment metabolic risk factors on post-treatment bone turnover marker outcomes. RESULTS: Participants with ≥4 metabolic syndrome defining characteristics had lower pre-treatment OC than those with 3 or fewer. OC was negatively correlated with glucose, and CTX was positively correlated with cholesterol. STAT or STAT+EX lowered total and LDL cholesterol. The OC to CTX ratio decreased in all groups with no other significant changes in bone turnover. Higher pre-treatment insulin or body fat predicted a greater CTX reduction and a greater BAP/CTX increase. CONCLUSION: Metabolic risk factors were negatively associated with bone turnover markers. Short-term statin treatment with or without exercise lowered cholesterol and all treatments had a small effect on bone turnover.

Aerobic and strength training in concomitant metabolic syndrome and type 2 diabetes.

PURPOSE: Concomitant type 2 diabetes (T2D) and metabolic syndrome exacerbates mortality risk; yet, few studies have examined the effect of combining (AER + RES) aerobic (AER) and resistance (RES) training for individuals with T2D and metabolic syndrome. METHODS: We examined AER, RES, and AER + RES training (9 months) commensurate with physical activity guidelines in individuals with T2D (n = 262; 63% female, 44% black). Primary outcomes were change in, and prevalence of, metabolic syndrome score at follow-up (mean and 95% confidence interval [CI]). Secondary outcomes included maximal cardiorespiratory fitness (VO2peak) and estimated METs from time-to-exhaustion (TTE) and exercise efficiency calculated as the slope of the line between ventilatory threshold, respiratory compensation, and maximal fitness. General linear models and bootstrapped Spearman correlations were used to examine changes in metabolic syndrome associated with training primary and secondary outcome variables. RESULTS: We observed a significant decrease in metabolic syndrome scores (P for trend = 0.003) for AER (-0.59, 95% CI = -1.00 to -0.21) and AER + RES (-0.79, 95% CI = -1.40 to -0.35), both being significant (P ≤ 0.02) versus control (0.26, 95% CI = -0.58 to 0.40) and RES (-0.13, 95% CI = -1.00 to 0.24). This led to a reduction in metabolic syndrome prevalence for the AER (56% vs 43%) and AER + RES (55% vs 46%) groups between baseline and follow-up. The observed decrease in metabolic syndrome was mediated by significant improvements in exercise efficiency for the AER and AER + RES training groups (P < 0.05), which was more strongly related to TTE (25%-30%; r = -0.38, 95% CI = -0.55 to -0.19) than VO2peak (5%-6%; r = -0.24, 95% CI = -0.45 to -0.01). CONCLUSIONS: AER and AER + RES training significantly improved metabolic syndrome scores and prevalence in patients with T2D. These improvements appear to be associated with improved exercise efficiency and are more strongly related to improved TTE versus VO2peak.

One bout of exercise alters free-living postprandial glycemia in type 2 diabetes.

PURPOSE: Elevated postprandial glycemic (PPG) excursions are significant risk factors for cardiovascular disease in type 2 diabetes patients. In this study, we tested if and for how many meals a single bout of exercise would reduce PPG responses to subsequent meals in type 2 diabetes (T2D) patients using a continuous glucose monitor system (CGMS). METHODS: We recruited nine sedentary (<30 min·wk(-1) of exercise) individuals with T2D (mean ± SD; body mass index = 36.0 ± 1.1 kg·m(-2), age = 60.3 ± 1.0 yr, HbA1c = 6.3% ± 0.2%). The subjects consumed a eucaloric diet (51% carbohydrate, 31% fat, and 18% protein) consisting of three meals, identical in composition, for a 2-d period while wearing a continuous glucose monitor system in two different conditions (exercise [EX], one 60-min bout at 60%-75% of heart rate reserve performed before breakfast), vs a sedentary [SED] condition). We quantified 24-h average glucose, PPG area under the curve (AUC; 4-h glucose AUC after meals), and PPG-2 h (2 h postprandial glucose). RESULTS: EX significantly reduced average [glucose] during the first 24-h period (P = 0.03). EX caused a reduction in PPG-AUC (P = 0.02) for all of the meals during the 2 d (main effect between conditions). A comparison between the EX and the SED conditions at each meal revealed that EX reduced PPG-AUC after the second meal of day 1 (lunch) (P = 0.04). PPG-2 h was not significantly different between EX and SED. CONCLUSIONS: Although a single EX bout does lower 24-h average [glucose], it only significantly lowered PPG-AUC at the second meal after the bout, suggesting that daily exercise may be needed to most effectively improve PPG at the advent of exercise training in T2D patients.

Simvastatin impairs exercise training adaptations.

OBJECTIVES: This study sought to determine if simvastatin impairs exercise training adaptations. BACKGROUND: Statins are commonly prescribed in combination with therapeutic lifestyle changes, including exercise, to reduce cardiovascular disease risk in patients with metabolic syndrome. Statin use has been linked to skeletal muscle myopathy and impaired mitochondrial function, but it is unclear whether statin use alters adaptations to exercise training. METHODS: This study examined the effects of simvastatin on changes in cardiorespiratory fitness and skeletal muscle mitochondrial content in response to aerobic exercise training. Sedentary overweight or obese adults with at least 2 metabolic syndrome risk factors (defined according to National Cholesterol Education Panel Adult Treatment Panel III criteria) were randomized to 12 weeks of aerobic exercise training or to exercise in combination with simvastatin (40 mg/day). The primary outcomes were cardiorespiratory fitness and skeletal muscle (vastus lateralis) mitochondrial content (citrate synthase enzyme activity). RESULTS: Thirty-seven participants (exercise plus statins: n = 18; exercise only: n = 19) completed the study. Cardiorespiratory fitness increased by 10% (p < 0.05) in response to exercise training alone, but was blunted by the addition of simvastatin resulting in only a 1.5% increase (p < 0.005 for group by time interaction). Similarly, skeletal muscle citrate synthase activity increased by 13% in the exercise-only group (p < 0.05), but decreased by 4.5% in the simvastatin-plus-exercise group (p < 0.05 for group-by-time interaction). CONCLUSIONS: Simvastatin attenuates increases in cardiorespiratory fitness and skeletal muscle mitochondrial content when combined with exercise training in overweight or obese patients at risk of the metabolic syndrome. (Exercise, Statins, and the Metabolic Syndrome; NCT01700530).

Voluntary wheel running selectively augments insulin-stimulated vasodilation in arterioles from white skeletal muscle of insulin-resistant rats.

BACKGROUND: Exercise (RUN) prevents declines in insulin-mediated vasodilation, an important component of insulin-mediated glucose disposal, in rats prone to obesity and insulin resistance. OBJECTIVE: Determine whether RUN (1) improves insulin-stimulated vasodilation after insulin resistance has been established, and (2) differentially affects arterioles from red and white muscle. METHODS: Insulin signaling and vasoreactivity to insulin (1-1000 µIU/mL) were assessed in 2A from the Gw and Gr of SED OLETF rats at 12 and 20 weeks of age (SED12, SED20) and those undergoing RUN (RUN20) or caloric restriction (CR20; to match body weight of RUN) from 12 to 20 weeks. RESULTS: Glucose and insulin responses to i.p. glucose were reduced in RUN20, elevated in SED20 (p < 0.05 vs. SED12), and maintained in CR20. Insulin-stimulated vasodilation was greater in Gw but not Gr, 2As of RUN20 (p < 0.01 vs. all groups), and was improved by ET-1 receptor inhibition in Gw 2As from SED20 and CR20 (p < 0.05). There were no differences in microvascular insulin signaling among groups or muscle beds. CONCLUSIONS: RUN selectively improved insulin-mediated vasodilation in Gw 2As, in part through attenuated ET-1 sensitivity/production, an adaptation that was independent of changes in adiposity and may contribute to enhanced insulin-stimulated glucose disposal.

Lowering physical activity impairs glycemic control in healthy volunteers.

INTRODUCTION: Postprandial glucose (PPG) is an independent predictor of cardiovascular events and death, regardless of diabetes status. Whereas changes in physical activity produce changes in insulin sensitivity, it is not clear whether changes in daily physical activity directly affect PPG in healthy free-living persons. METHODS: We used continuous glucose monitors to measure PPG and PPG excursions (ΔPPG, postmeal - premeal blood glucose) at 30-min increments after meals in healthy habitually active volunteers (n = 12, age = 29 ± 1 yr, body mass index = 23.6 ± 0.9 kg·m(-2), VO2max = 53.6 ± 3.0 mL·kg(-1)·min(-1)) during 3 d of habitual (≥10,000 steps per day) and reduced (<5000 steps per day) physical activity. Diets were standardized across monitoring periods, and fasting-state oral glucose tolerance tests (OGTT) were performed on the fourth day of each monitoring period. RESULTS: During 3 d of reduced physical activity (12,956 ± 769 to 4319 ± 256 steps per day), PPG increased at 30 and 60 min after a meal (6.31 ± 0.19 to 6.68 ± 0.23 mmol·L(-1) and 5.75 ± 0.16 to 6.26 ± 0.28 mmol·L(-1), P < 0.05 relative to corresponding active time point), and ΔPPG increased by 42%, 97%, and 33% at 30, 60, and 90 min after a meal, respectively (P < 0.05). Insulin and C-peptide responses to the OGTT increased after 3 d of reduced activity (P < 0.05), and the glucose response to the OGTT did not change significantly. CONCLUSIONS: Thus, despite evidence of compensatory increases in plasma insulin during an OGTT, ΔPPG assessed by continuous glucose monitoring systems increased markedly during 3 d of reduced physical activity in otherwise healthy free-living individuals. These data indicate that daily physical activity is an important mediator of glycemic control, even among healthy individuals, and reinforce the utility of physical activity in preventing pathologies associated with elevated PPG.

Seven days of aerobic exercise training improves conduit artery blood flow following glucose ingestion in patients with type 2 diabetes.

The vasodilatory effects of insulin account for up to 40% of insulin-mediated glucose disposal; however, insulin-stimulated vasodilation is impaired in individuals with type 2 diabetes, limiting perfusion and delivery of glucose and insulin to target tissues. To determine whether exercise training improves conduit artery blood flow following glucose ingestion, a stimulus for increasing circulating insulin, we assessed femoral blood flow (FBF; Doppler ultrasound) during an oral glucose tolerance test (OGTT; 75 g glucose) in 11 overweight or obese (body mass index, 34 ± 1 kg/m²), sedentary (peak oxygen consumption, 23 ± 1 ml·kg⁻¹·min⁻¹) individuals (53 ± 2 yr) with non-insulin-dependent type 2 diabetes (HbA1c, 6.63 ± 0.18%) before and after 7 days of supervised treadmill and cycling exercise (60 min/day, 60-75% heart rate reserve). Fasting glucose, insulin, and FBF were not significantly different after 7 days of exercise, nor were glucose or insulin responses to the OGTT. However, estimates of whole body insulin sensitivity (Matsuda insulin sensitivity index) increased (P < 0.05). Before exercise training, FBF did not change significantly during the OGTT (1 ± 7, -7 ± 5, 0 ± 6, and 0 ± 5% of fasting FBF at 75, 90, 105, and 120 min, respectively). In contrast, after exercise training, FBF increased by 33 ± 9, 39 ± 14, 34 ± 7, and 48 ± 18% above fasting levels at 75, 90, 105, and 120 min, respectively (P < 0.05 vs. corresponding preexercise time points). Additionally, postprandial glucose responses to a standardized breakfast meal consumed under "free-living" conditions decreased during the final 3 days of exercise (P < 0.05). In conclusion, 7 days of aerobic exercise training improves conduit artery blood flow during an OGTT in individuals with type 2 diabetes.

Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial.

CONTEXT: Exercise guidelines for individuals with diabetes include both aerobic and resistance training although few studies have directly examined this exercise combination. OBJECTIVE: To examine the benefits of aerobic training alone, resistance training alone, and a combination of both on hemoglobin A(1c) (HbA(1c)) in individuals with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial in which 262 sedentary men and women in Louisiana with type 2 diabetes and HbA(1c) levels of 6.5% or higher were enrolled in the 9-month exercise program between April 2007 and August 2009. INTERVENTION: Forty-one participants were assigned to the nonexercise control group, 73 to resistance training 3 days a week, 72 to aerobic exercise in which they expended 12 kcal/kg per week; and 76 to combined aerobic and resistance training in which they expended 10 kcal/kg per week and engaged in resistance training twice a week. Main Outcome Change in HbA(1c) level. Secondary outcomes included measures of anthropometry and fitness. RESULTS: The study included 63.0% women and 47.3% nonwhite participants who were a mean (SD) age of 55.8 years (8.7 years) with a baseline HbA(1c) level of 7.7% (1.0%). Compared with the control group, the absolute mean change in HbA(1c) in the combination training exercise group was -0.34% (95% confidence interval [CI], -0.64% to -0.03%; P = .03). The mean changes in HbA(1c) were not statistically significant in either the resistance training (-0.16%; 95% CI, -0.46% to 0.15%; P = .32) or the aerobic (-0.24%; 95% CI, -0.55% to 0.07%; P = .14) groups compared with the control group. Only the combination exercise group improved maximum oxygen consumption (mean, 1.0 mL/kg per min; 95% CI, 0.5-1.5, P < .05) compared with the control group. All exercise groups reduced waist circumference from -1.9 to -2.8 cm compared with the control group. The resistance training group lost a mean of -1.4 kg fat mass (95% CI, -2.0 to -0.7 kg; P < .05) and combination training group lost a mean of -1.7 (-2.3 to -1.1 kg; P < .05) compared with the control group. CONCLUSIONS: Among patients with type 2 diabetes mellitus, a combination of aerobic and resistance training compared with the nonexercise control group improved HbA(1c) levels. This was not achieved by aerobic or resistance training alone. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00458133.

Daily physical activity enhances reactivity to insulin in skeletal muscle arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats.

Insulin-mediated glucose disposal is dependent on the vasodilator effects of insulin. In type 2 diabetes, insulin-stimulated vasodilation is impaired as a result of an imbalance in NO and ET-1 production. We tested the hypothesis that chronic voluntary wheel running (RUN) prevents impairments in insulin-stimulated vasodilation associated with obesity and type 2 diabetes independent of the effects of RUN on adiposity by randomizing Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of hyperphagia-induced obesity and type 2 diabetes, to 1) RUN, 2) caloric restriction (CR; diet adjusted to match body weights of RUN group), or 3) sedentary control (SED) groups (n = 8/group) at 4 wk. At 40 wk, NO- and ET-1-mediated vasoreactivity to insulin (1-1,000 µIU/ml) was assessed in the presence of a nonselective ET-1 receptor blocker (tezosentan) or a NO synthase (NOS) inhibitor [N(G)-nitro-L-arginine methyl ester (L-NAME)], respectively, in second-order arterioles isolated from the white portion of the gastrocnemius muscle. Body weight, fasting plasma glucose, and hemoglobin A1c were lower in RUN and CR than SED (P < 0.05); however, the glucose area under the curve (AUC) following the intraperitoneal glucose tolerance test was lower only in the RUN group (P < 0.05). Vasodilator responses to all doses of insulin were greater in RUN than SED or CR in the presence of a tezosentan (P < 0.05), but group differences in vasoreactivity to insulin with coadministration of L-NAME were not observed. We conclude daily wheel running prevents obesity and type 2 diabetes-associated declines in insulin-stimulated vasodilation in skeletal muscle arterioles through mechanisms that appear to be NO mediated and independent of attenuating excess adiposity in hyperphagic rats.

Skeletal muscle mitochondrial and metabolic responses to a high-fat diet in female rats bred for high and low aerobic capacity.

Rats selected artificially to be low-capacity runners (LCR) possess a metabolic syndrome phenotype that is worsened by a high-fat diet (HFD), whereas rats selected to be high-capacity runners (HCR) are protected against HFD-induced obesity and insulin resistance. This study examined whether protection against, or susceptibility to, HFD-induced insulin resistance in the HCR-LCR strains is associated with contrasting metabolic adaptations in skeletal muscle. HCR and LCR rats (generation 20; n = 5-6; maximum running distance approximately 1800 m vs. approximately 350 m, respectively (p < 0.0001)) were divided into HFD (71.6% energy from fat) or normal chow (NC) (16.7% energy from fat) groups for 7 weeks (from 24 to 31 weeks of age). Skeletal muscle (red gastrocnemius) mitochondrial-fatty acid oxidation (FAO), mitochondrial-enzyme activity, mitochondrial-morphology, peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), and peroxisome proliferator-activated receptor delta (PPARdelta) expression and insulin sensitivity (intraperitoneal glucose tolerance tests) were measured. The HFD caused increased adiposity and reduced insulin sensitivity only in the LCR and not the HCR strain. Isolated mitochondria from the HCR skeletal muscle displayed a 2-fold-higher rate of FAO on NC, but both groups increased FAO following HFD. PGC-1alpha mRNA expression and superoxide dismutase activity were significantly reduced with the HFD in the LCR rats, but not in the HCR rats. PPARdelta expression did not differ between strains or dietary conditions. These results do not provide a clear connection between protection of insulin sensitivity and HFD-induced adaptive changes in mitochondrial function or transcriptional responses but do not dismiss the possibility that elevated mitochondrial FAO in the HCR may play a protective role.

Changes in skeletal muscle mitochondria in response to the development of type 2 diabetes or prevention by daily wheel running in hyperphagic OLETF rats.

The temporal changes in skeletal muscle mitochondrial content and lipid metabolism that precede type 2 diabetes are largely unknown. Here we examined skeletal muscle mitochondrial fatty acid oxidation (MitoFAOX) and markers of mitochondrial gene expression and protein content in sedentary 20- and 40-wk-old hyperphagic, obese Otsuka Long-Evans Tokushima fatty (OLETF-SED) rats. Changes in OLETF-SED rats were compared with two groups of rats who maintained insulin sensitivity: age-matched OLETF rats given access to voluntary running wheels (OLETF-EX) and sedentary, nonobese Long-Evans Tokushima Otsuka (LETO-SED) rats. As expected, glucose tolerance tests revealed insulin resistance at 20 wk that progressed to type 2 diabetes at 40 wk in the OLETF-SED, whereas both the OLETF-EX and LETO-SED maintained whole body insulin sensitivity. At 40 wk, complete MitoFAOX (to CO(2)), beta-hydroxyacyl-CoA dehydrogenase activity, and citrate synthase activity did not differ between OLETF-SED and LETO-SED but were significantly (P < 0.05) higher in OLETF-EX compared with OLETF-SED rats. Genes controlling skeletal muscle MitoFAOX (PGC-1alpha, PPARdelta, mtTFA, cytochrome c) were not different between OLETF-SED and LETO-SED at any age. Compared with the OLETF-SED, the OLETF-EX rats had significantly (P < 0.05) higher skeletal muscle PGC-1alpha, cytochrome c, and mtTFA mRNA levels at 20 and 40 wk and PPARdelta at 40 wk; however, protein content for each of these markers did not differ between groups at 40 wk. Limited changes in skeletal muscle mitochondria were observed during the transition from insulin resistance to type 2 diabetes in the hyperphagic OLETF rat. However, diabetes prevention through increased physical activity appears to be mediated in part through maintenance of skeletal muscle mitochondrial function.