Direct assessment of leukocyte signalling and cytokine secretion reveals exercise intensity-dependent reductions in anti-inflammatory cytokine action.

Circulating interleukin (IL)-6 and IL-10 concentrations are widely used to evaluate the anti-inflammatory effects of exercise but do not capture cytokine action at the cellular level. Whether and how acute exercise impacts anti-inflammatory cytokine action in humans is unknown. To determine how exercise intensity and pattern impact IL-6 and IL-10 action in blood leukocytes, 16 active adults (eight males/eight females; age: 30 ± 3 years; body mass index: 22.8 ± 2.3 kg/m2; V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ : 51 ± 6 mL/kg/min) completed a no-exercise control condition (CTL) or isocaloric bouts of cycling performed below (moderate continuous exercise; MCE) or above (heavy continuous or heavy intermittent exercise; HCE or HIE, respectively) lactate threshold. Venous blood (before, after, 30 min after and 90 min after exercise) was analysed for immune cell subpopulations, plasma cytokine concentrations, anti-inflammatory cytokine action and monocyte phenotype. Exercise induced rapid leukocytosis (P < 0.001) and increased plasma IL-6 (P < 0.001), IL-10 (P = 0.0145) and tumour necrosis factor-⍺ (TNF-⍺) (P = 0.0338) concentrations in an intensity-dependent manner (HCE and/or HIE vs. CTL). These systemic changes coincided with a diminished ability of IL-10/6 to phosphorylate STAT3 (P < 0.001) and inhibit TNF-⍺ secretion (P = 0.0238) in blood leukocytes following HCE and HIE. Monocyte polarization experiments revealed lower CD80 [MCE (P = 0.0933) and HIE (P = 0.0187) vs. CTL] and a tendency for higher CD163 expression (HCE vs. CTL, P = 0.0985), suggesting that hyporesponsiveness to anti-inflammatory cytokine action does not impede the ability of exercise to promote an anti-inflammatory monocyte phenotype. These findings provide novel insights into the immunomodulatory effects of exercise in humans and highlight the importance of directly measuring cellular cytokine action when evaluating the anti-inflammatory effects of exercise. KEY POINTS: Circulating cytokine concentrations are frequently used to evaluate the anti-inflammatory effects of exercise but may not capture changes in cytokine action occurring at the cellular level. We directly assessed anti-inflammatory cytokine action - measured using a combination of intracellular signalling and cytokine secretion ex vivo - in distinct immune cell subpopulations after acute calorie-matched exercise bouts differing in intensity and pattern. Anti-inflammatory cytokine action was blunted following higher intensity exercise despite corresponding increases in circulating cytokine concentrations and immune cell counts. Changes in cytokine action were not explained by changes in cytokine receptor expression on circulating immune cells. Our findings provide new insights into the immunomodulatory effects of exercise in humans and highlight the importance of directly measuring cellular cytokine action when evaluating the anti-inflammatory effects of exercise.

A bout of aerobic exercise in the heat increases carbohydrate use but does not enhance the disposal of an oral glucose load, in healthy active individuals.

We investigated if a bout of exercise in a hot environment (HEAT) would reduce the postprandial hyperglycemia induced by glucose ingestion. The hypothesis was that HEAT stimulating carbohydrate oxidation and glycogen use would increase the disposal of an ingested glucose load [i.e., oral glucose tolerance test (OGTT); 75 g of glucose]. Separated by at least 1 wk, nine young healthy individuals underwent three trials after an overnight fast in a randomized order. Two trials included 50 min of pedaling at 58 ± 5% V̇o2max either in a thermoneutral (21 ± 1°C; NEUTRAL) or in a hot environment (33 ± 1°C; HEAT) eliciting similar energy expenditure (503 ± 101 kcal). These two trials were compared with a no-exercise trial (NO EXER). Twenty minutes after exercise (or rest), subjects underwent an OGTT, while carbohydrate oxidation (CHOxid, using indirect calorimetry) plasma blood glucose, insulin concentrations (i.e., [glucose], [insulin]), and double tracer glucose kinetics ([U-13C] glucose ingestion and [6,6-2H2] glucose infusion) were monitored for 120 min. At rest, [glucose], [insulin], and rates of appearance/disappearance of glucose in plasma (glucose Ra/Rd) were similar among trials. During exercise, heart rate, tympanic temperature, [glucose], glycogen oxidation, and total CHOxid were higher during HEAT than NEUTRAL (i.e., 149 ± 35 vs. 124 ± 31 µmol·kg-1·min-1, P = 0.010). However, during the following OGTT, glucose Rd was similar in HEAT and NEUTRAL trials (i.e., 25.1 ± 3.6 vs. 25.2 ± 5.3 µmol·kg-1·min-1, P = 0.981). Insulin sensitivity (i.e., ISIndexMATSUDA) only improved in NEUTRAL compared with NO EXER (10.1 ± 4.6 vs. 8.8 ± 3.7 au; P = 0.044). In summary, stimulating carbohydrate use with exercise in a hot environment does not improve postprandial plasma glucose disposal or insulin sensitivity in a subsequent OGTT.NEW & NOTEWORTHY Exercise in the heat increases estimated muscle glycogen use. Reduced muscle glycogen after exercise in the heat could increase insulin-mediated glucose uptake during a subsequent oral glucose tolerance test (OGTT). However, plasma glucose kinetics are not improved during the OGTT in response to a bout of exercise in the heat, and insulin sensitivity worsens. Heat stress activates glucose counterregulatory hormones whose actions may linger during the OGTT, preventing increased glucose uptake.

Glucose volume of distribution affects insulin sensitivity measured by intravenous glucose tolerance test.

AIM: To determine whether glucose volume of distribution (VdGLUCOSE ) affects the diagnosis of impaired insulin sensitivity (IS) when using an intravenous glucose tolerance test (IVGTT). METHODS: Individuals with distinct levels of IS underwent IVGTT after an overnight fast. The prediabetic group (Prediab; n = 33) differed from the healthy group (Healthy; n = 14) in their larger glycosylated hemoglobin (HbA1c of 5.9 ± 0.3 vs. 5.4 ± 0.1%; 41 ± 4 vs. 36 ± 1 mmol/mol; p < 0.001), percent body fat (37 ± 6 vs. 24 ± 3%; p < 0.001) and cardiovascular fitness level (VO2MAX 22 ± 5 vs. 44 ± 5 mL of O2 ·kg-1 ·min-1 ; p < 0.001). Ten minutes after intravenous infusion of the glucose bolus (i.e., 35 g in a 30% solution), VdGLUCOSE was assessed from the increases in plasma glucose concentration. IS was calculated during the next 50 min using the slope of glucose disappearance and the insulin time-response curve. RESULTS: VdGLUCOSE was higher in Healthy than in Prediab (230 ± 49 vs. 185 ± 21 mL·kg-1 ; p < 0.001). VdGLUCOSE was a strong predictor of IS (ß standardized coefficient 0.362; p = 0.004). VO2MAX was associated with VdGLUCOSE and IS (Pearson r = 0.582 and 0.704, respectively; p < 0.001). However, body fat was inversely associated with VdGLUCOSE and IS (r = -0.548 and -0.555, respectively; p < 0.001). CONCLUSIONS: Since fat mass is inversely related to VdGLUCOSE and in turn, VdGLUCOSE affects the calculations of IS, the IV glucose bolus dose should be calculated based on fat-free mass rather than body weight for a more accurate diagnosis of impaired IS.

Effect of the ketone beta-hydroxybutyrate on markers of inflammation and immune function in adults with type 2 diabetes.

Pre-clinical and cell culture evidence supports the role of the ketone beta-hydroxybutyrate (BHB) as an immunomodulatory molecule that may inhibit inflammatory signalling involved in several chronic diseases such as type 2 diabetes (T2D), but studies in humans are lacking. Therefore, we investigated the anti-inflammatory effect of BHB in humans across three clinical trials. To investigate if BHB suppressed pro-inflammatory cytokine secretion, we treated LPS-stimulated leukocytes from overnight-fasted adults at risk for T2D with BHB (Study 1). Next (Study 2), we investigated if exogenously raising BHB acutely in vivo by ketone monoester supplementation (KME) in adults with T2D would suppress pro-inflammatory plasma cytokines. In Study 3, we investigated the effect of BHB on inflammation via ex vivo treatment of LPS-stimulated leukocytes with BHB and in vivo thrice-daily pre-meal KME for 14 days in adults with T2D. Ex vivo treatment with BHB suppressed LPS-stimulated IL-1ß, TNF-α, and IL-6 secretion and increased IL-1RA and IL-10 (Study 1). Plasma IL-10 increased by 90 min following ingestion of a single dose of KME in T2D, which corresponded to peak blood BHB (Study 2). Finally, 14 days of thrice-daily KME ingestion did not significantly alter plasma cytokines or leukocyte subsets including monocyte and T-cell polarization (Study 3). However, direct treatment of leukocytes with BHB modulated TNF-α, IL-1ß, IFN-γ, and MCP-1 secretion in a time- and glucose-dependent manner (Study 3). Therefore, BHB appears to be anti-inflammatory in T2D, but this effect is transient and is modulated by the presence of disease, glycaemia, and exposure time.

Efficacy of morning versus afternoon aerobic exercise training on reducing metabolic syndrome components: A randomized controlled trial.

A supervised intense aerobic exercise program improves the health of individuals with metabolic syndrome (MetS). However, it is unclear whether the timing of training within the 24 h day would influence those health benefits. The present study aimed to determine the influence of morning vs. afternoon exercise on body composition, cardiometabolic health and components of MetS. One hundred thirty-nine individuals with MetS were block randomized into morning (AMEX; n = 42) or afternoon (PMEX; n = 59) exercise training groups, or a non-training control group (Control; n = 38). Exercise training was comprised of 48 supervised high-intensity interval sessions distributed over 16 weeks. Body composition, cardiorespiratory fitness (assessed by V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ), maximal fat oxidation (FOmax ), blood pressure and blood metabolites were assessed before and after the intervention. Compared with the non-training Control, both exercise groups improved similarly body composition (-0.7% fat loss; P = 0.002), waist circumference (-2.1 cm; P < 0.001), diastolic blood pressure (-3.8 mmHg; P = 0.004) and V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ (3.5 mL kg-1   min-1 ; P < 0.001) with no differences between training groups. AMEX, in comparison with PMEX, reduced systolic blood pressure (-4% vs. -1%; P = 0.019), plasma fasting insulin concentration (-12% vs. -5%; P = 0.001) and insulin resistance (-14% vs. -4%; P = 0.006). Furthermore, MetS Z score was further reduced in the AMEX compared to PMEX (-52% vs. -19%; P = 0.021) after training. In summary, high-intensity aerobic exercise training in the morning in comparison to training in the afternoon is somewhat more efficient at reducing cardiometabolic risk factors (i.e. systolic blood pressure and insulin sensitivity). KEY POINTS: The effect of exercise time of day on health promotion is an area that has gained interest in recent years; however, large-scale, randomized-control studies are scarce. People with metabolic syndrome (MetS) are at risk of developing cardiometabolic diseases and reductions in this risk with exercise training can be precisely gauged using a compound score sensitive to subtle evolution in each MetS component (i.e. Z score). Supervised aerobic exercise for 16 weeks (morning and afternoon), without dietary restriction, improved cardiorespiratory and metabolic fitness, body composition and mean arterial pressure compared to a non-exercise control group. However, training in the morning, without changes in exercise dose or intensity, reduced systolic blood pressure and insulin resistance further compared to when training in the afternoon. Thus, high-intensity aerobic exercise training in the morning is somewhat more efficient in improving the health of individuals with metabolic syndrome.

Role of prior feeding status in mediating the effects of exercise on blood glucose kinetics.

Changes in blood glucose concentrations are underpinned by blood glucose kinetics (endogenous and exogenous glucose appearance rates and glucose disappearance rates). Exercise potently alters blood glucose kinetics and can thereby be used as a tool to control blood glucose concentration. However, most studies of exercise-induced changes in glucose kinetics are conducted in a fasted state, and therefore less is known about the effects of exercise on glucose kinetics when exercise is conducted in a postprandial state. Emerging evidence suggests that food intake prior to exercise can increase postprandial blood glucose flux compared with when meals are consumed after exercise, whereby both glucose appearance rates and disappearance rates are increased. The mechanisms underlying the mediating effect of exercise conducted in the fed versus the fasted state are yet to be fully elucidated. Current evidence demonstrates that exercise in the postprandial state increased glucose appearance rates due to both increased exogenous and endogenous appearance and may be due to changes in splanchnic blood flow, intestinal permeability, and/or hepatic glucose extraction. On the other hand, increased glucose disappearance rates after exercise in the fed state have been shown to be associated with increased intramuscular AMPK signaling via a mismatch between carbohydrate utilization and delivery. Due to differences in blood glucose kinetics and other physiological differences, studies conducted in the fasted state cannot be immediately translated to the fed state. Therefore, conducting studies in the fed state could improve the external validity of data pertaining to glucose kinetics and intramuscular signaling in response to nutrition and exercise.

Metformin and exercise effects on postprandial insulin sensitivity and glucose kinetics in pre-diabetic and diabetic adults.

The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin and/or exercise on fasting and postprandial insulin sensitivity in individuals with pre-diabetes and type 2 diabetes (T2D). Eight T2D adults (60 ± 4 yr) with overweight/obesity (32 ± 4 kg·m-2) under chronic metformin treatment (9 ± 6 yr; 1281 ± 524 mg·day-1) underwent four trials; 1) taking their habitual metformin treatment (MET), 2) substituting during 96 h their metformin medication by placebo (PLAC), 3) placebo combined with 50 min bout of high-intensity interval exercise (PLAC + EX), and 4) metformin combined with exercise (MET + EX). Plasma glucose kinetics using stable isotopes (6,6-2H2 and [U-13C] glucose), and glucose oxidation by indirect calorimetry, were assessed at rest, during exercise, and in a subsequent oral glucose tolerance test (OGTT). Postprandial glucose and insulin concentrations were analyzed as mean and incremental area under the curve (iAUC), and insulin sensitivity was calculated (i.e., MATSUDAindex and OGISindex). During OGTT, metformin reduced glucose iAUC (i.e., MET and MET + EX lower than PLAC and PLAC + EX, respectively; P = 0.023). MET + EX increased MATSUDAindex above PLAC (4.8 ± 1.4 vs. 3.3 ± 1.0, respectively; P = 0.018) and OGISindex above PLAC (358 ± 52 vs. 306 ± 46 mL·min-1·m-2, respectively; P = 0.006). Metformin decreased the plasma appearance of the ingested glucose (Ra OGTT; MET vs. PLAC, -3.5; 95% CI -0.1 to -6.8 µmol·kg-1·min-1; P = 0.043). Metformin combined with exercise potentiates insulin sensitivity during an OGTT in individuals with pre-diabetes and type 2 diabetes. Metformin's blood glucose-lowering effect seems mediated by decreased oral glucose entering the circulation (gut-liver effect) an effect partially blunted after exercise.NEW & NOTEWORTHY Metformin is the most prescribed oral antidiabetic medicine in the world but its mechanism of action and its interactions with exercise are not fully understood. Our stable isotope tracer data suggested that metformin reduces the rates of oral glucose entering the circulation (gut-liver effect). Exercise, in turn, tended to reduce postprandial insulin blood levels potentiating metformin improvements in insulin sensitivity. Thus, exercise potentiates metformin improvements in glycemic control and should be advised to metformin users.

Acute Statin Withdrawal Does not Interfere With the Improvements of a Session of Exercise in Postprandial Metabolism.

BACKGROUND: The risk for atherogenic plaque formation is high after ingestion of meals in individuals with high blood lipid levels (ie, dyslipidemia). Statins and exercise reduce the rise of blood triglyceride concentrations after a meal, but the effect of their combination is unclear. METHODS: In a randomized crossover design, 11 individuals with dyslipidemia and metabolic syndrome treated with statins underwent a mixed-meal (970 ± 111 kcal, 24% fat, and 34% carbohydrate) tolerance test. Plasma lipid concentrations, fat oxidation, glucose, and glycerol kinetics were monitored immediately prior and during the meal test. Trials were conducted with participants under their habitual statin treatment and 96 hours after blinded statin withdrawal. Trials were duplicated after a prolonged bout of low-intensity exercise (75 minutes at 53 ± 4% maximal oxygen consumption) to study the interactions between exercise and statins. RESULTS: Statins reduced postprandial plasma triglycerides from 3.03 ± 0.85 to 2.52 ± 0.86 mmol·L-1 (17%; P = .015) and plasma glycerol concentrations (ie, surrogate of whole-body lipolysis) without reducing plasma free fatty acid concentration or fat oxidation. Prior exercise increased postprandial plasma glycerol levels (P = .029) and fat oxidation rates (P = .024). Exercise decreased postprandial plasma insulin levels (241 ± 116 vs 301 ± 172 ρmol·L-1; P = .026) but not enough to increase insulin sensitivity (P = .614). Neither statins nor exercise affected plasma glucose appearance rates from exogenous or endogenous sources. CONCLUSIONS: In dyslipidemic individuals, statins reduce blood triglyceride concentrations after a meal, but without limiting fat oxidation. Statins do not interfere with exercise lowering the postprandial insulin that likely promotes fat oxidation. Last, statins do not restrict the rates of plasma incorporation or oxidation of the ingested glucose.

Effects of statin therapy on glycemic control and insulin resistance: A systematic review and meta-analysis.

AIMS: To update the evidence about the diabetogenic effect of statins. METHODS: We searched for randomized-controlled trials reporting the effects of statin therapy on glycosylated hemoglobin (HbA1c) and/or homeostatic model insulin resistance (i.e., HOMA-IR) as indexes of diabetes. Studies were classified between the ones testing normal vs individuals with already altered glycemic control (HbA1c ≥ 6.5%; and HOMA-IR ≥ 2.15). Furthermore, studies were separated by statin type and dosage prescribed. Data are presented as mean difference (MD) and 95% confidence intervals. RESULTS: A total of 67 studies were included in the analysis (>25,000 individuals). In individuals with altered glycemic control, statins increased HbA1c levels (MD 0.21%, 95% CI 0.16-to-0.25) and HOMA-IR index (MD 0.31, 95% CI 0.24-to-0.38). In individuals with normal glycemic control, statin increased HbA1c (MD 1.33%, 95% CI 1.31-to-1.35) and HOMA-IR (MD 0.49, 95% CI 0.41-to-0.58) in comparison to the placebo groups. The dose or type of statins did not modulate the diabetogenic effect. CONCLUSIONS: Statins, slightly but significantly raise indexes of diabetes in individuals with adequate or altered glycemic control. The diabetogenic effect does not seem to be influenced by the type or dosage of statin prescribed.

Chronic Statin Treatment Does Not Impair Exercise Lipolysis or Fat Oxidation in Exercise-Trained Individuals With Obesity and Dyslipidemia.

OBJECTIVE: To determine whether statin medication in individuals with obesity, dyslipidemia, and metabolic syndrome affects their capacity to mobilize and oxidize fat during exercise. METHODS: Twelve individuals with metabolic syndrome pedaled during 75 min at 54 ± 13% V˙O2max (5.7 ± 0.5 metabolic equivalents) while taking statins (STATs) or after 96-hr statin withdrawal (PLAC) in a randomized double-blind fashion. RESULTS: At rest, PLAC increased low-density lipoprotein cholesterol (i.e., STAT 2.55 ± 0.96 vs. PLAC 3.16 ± 0.76 mmol/L; p = .004) and total cholesterol blood levels (i.e., STAT 4.39 ± 1.16 vs. PLAC 4.98 ± 0.97 mmol/L; p = .008). At rest, fat oxidation (0.99 ± 0.34 vs. 0.76 ± 0.37 µmol·kg-1·min-1 for STAT vs. PLAC; p = .068) and the rates of plasma appearance of glucose and glycerol (i.e., Ra glucose-glycerol) were not affected by PLAC. After 70 min of exercise, fat oxidation was similar between trials (2.94 ± 1.56 vs. 3.06 ± 1.94 µmol·kg-1·min-1, STA vs. PLAC; p = .875). PLAC did not alter the rates of disappearance of glucose in plasma during exercise (i.e., 23.9 ± 6.9 vs. 24.5 ± 8.2 µmol·kg-1·min-1 for STAT vs. PLAC; p = .611) or the rate of plasma appearance of glycerol (i.e., 8.5 ± 1.9 vs. 7.9 ± 1.8 µmol·kg-1·min-1 for STAT vs. PLAC; p = .262). CONCLUSIONS: In patients with obesity, dyslipidemia, and metabolic syndrome, statins do not compromise their ability to mobilize and oxidize fat at rest or during prolonged, moderately intense exercise (i.e., equivalent to brisk walking). In these patients, the combination of statins and exercise could help to better manage their dyslipidemia.

Effects of Statins on Fat Oxidation Improvements After Aerobic Exercise Training.

CONTEXT: Statins blunt cardiorespiratory fitness improvements after exercise training and may affect fat oxidation adaptations to training. OBJECTIVE: To determine if long-term statin use in dyslipidemic individuals restricts the improvements in fat oxidation typically observed after an intense exercise-training program. METHODS: A total of 106 metabolic syndrome individuals either chronically medicated with statins (ie, statin group; n = 46) or statin naive (ie, control group; n = 60) completed a 16-week supervised high-intensity interval training program. Maximal rates of oxygen consumption (V˙O2MAX), fat oxidation (FOMAX), and the shape of the workload-fat oxidation curve were assessed before and 48 hours after training in an overnight fasted state. RESULTS: Starting from a similar value at baseline, both groups increased V˙O2MAX after training, but the increase was larger in the control than in the statin group (19.4% vs 12.6%; P = .013). Before training, FOMAX in the statin group was lower (0.19 ± 0.08 vs 0.23 ± 0.07 g·min-1; P = .023) and took place at a lower workload (33 ± 21 vs 37 ± 19 W; P = .015) than in the control group. After training, FOMAX improved similarly in both groups (0.06 ± 0.08; 95% CI, 0.03-0.08 g·min-1 and 0.05 ± 0.09; 95% CI, 0.03-0.07 g·min-1, for statin and control groups, respectively; (P < .001). Still, after training, FOMAX occurred at a 28% lower workload in the statin group (38 ± 26 vs 53 ± 32 W; P = .048). The V˙O2-workload slope decreased after training in both groups (both P < .001) along with reductions in the respiratory exchange ratio-workload slope. Fat oxidation increased at all workloads after training regardless of the use of statins. CONCLUSION: Long-term statin treatment is associated with blunted exercise fat oxidation before exercise training. However, statin use does not attenuate the improvements in exercise fat oxidation (FOMAX) derived from intense aerobic exercise training. This finding should encourage statin users to exercise-train to benefit from increased fat oxidation once their fitness level improves.

Effect of Yearly Exercise on Medication Expense and Benefit-Cost Ratio in Individuals with Metabolic Syndrome: A Randomized Clinical Trial.

INTRODUCTION: Lifestyle modification through incorporation of exercise training could improve metabolic syndrome (MetS) clinical components (hypertension, dyslipidemia, hyperglycemia, and visceral abdominal obesity). We aimed to assess if long-term exercise training could restrain the increased pharmacological cost of the clinical management of the MetS. METHODS: Medicine cost during a 5-yr-long randomized controlled exercise intervention trial was analyzed. After a per-protocol analysis, a group of 64 individuals 53 ± 2 yr old, with overweight (body mass index, 33.4 ± 0.9 kg·m -2 ) and MetS (3.6 ± 0.2 factors) were randomized to a training (4 months·yr -1 for 5 yr; EXERCISE, n = 25) or to a control group (CONTROL, n = 26). Subjects were studied on three occasions during the 5-yr follow-up. Participants continued their routine medication managed by their general practitioner. The main outcome is the 5-yr evolution of medication cost to treat MetS (hyperglycemia, hypertension, and hyperlipidemia). A secondary outcome is the benefit-cost ratio of the exercise intervention. RESULTS: In CONTROL, medicine cost increased 160% from baseline ( P < 0.001), whereas in EXERCISE, it remained unchanged (33%; P = 0.25). After the 5-yr follow-up, medicine use was 60% and medicine cost 74% higher in CONTROL than EXERCISE ( P < 0.05 in both cases). However, MetS z score was similarly reduced over time in both groups ( P = 0.244 for group-time interaction). The number of prescribed medications increased after 5 yr in CONTROL (89%; P < 0.001), whereas it remained stable with yearly training (17%; P = 0.72 in EXERCISE). Ten-year atherosclerotic cardiovascular disease risk estimation increased only in CONTROL (15%; P = 0.05 for group-time interaction). The benefit in medicine savings (€153 per year and patient) triplicated the estimated cost (€50.8 per year and patient) of the exercise intervention. CONCLUSIONS: A 5-yr-long supervised exercise training program in middle-age individuals with MetS prevents the need for increasing medicine use. The savings in pharmacological therapy outweighs the estimated costs of implementing the exercise program.

Statins effect on insulin resistance after a meal and exercise in hypercholesterolemic pre-diabetic individuals.

AIM: To study if statins, a widely prescribed, inexpensive medication to prevent coronary artery diseases may cause insulin resistance (IR). METHODS: Fasted (HOMA-IR) and post-meal insulin resistance were assessed in 21 pre-diabetic hypercholesterolemic individuals treated with statins (STA trial). Measurements were compared to another trial conducted 96 h after statin withdrawal using placebo pills (PLAC trial). Trials were duplicated 16-18 h after a bout of moderate-intensity exercise (500 kcal of energy expenditure) to reduce IR and better appreciate statin effects (EXER+STA and EXER+PLAC trials). RESULTS: Statin withdrawal did not affect fasting (HOMA-IR; 2.35 ± 1.05 vs. 2.18 ± 0.87 for STA vs. PLAC trials; p = 0.150) or post-meal insulin resistance (i.e., Matsuda-index, STA 6.23 ± 2.83 vs. PLAC 6.49 ± 3.74; p = 0.536). A bout of aerobic exercise lowered post-meal IR (p = 0.043), but statin withdrawal did not add to the exercise actions (p = 0.564). Statin withdrawal increased post-meal plasma free glycerol concentrations (0.136 ± 0.073 vs. 0.185 ± 0.090 mmol·L-1 for STA vs. PLAC trials; p < 0.001) but not plasma free fatty acids or fat oxidation (p = 0.981, and p = 0.621, respectively). Post-meal fat oxidation was higher in the exercise trials (p = 0.002). CONCLUSIONS: Withdrawal of statin medication does not affect fasting or post-meal insulin resistance in pre-diabetic hypercholesterolemic individuals. Furthermore, statin use does not interfere with the beneficial effects of exercise on lowering IR.

Effects of metabolic syndrome on fuel utilization during exercise on middle-aged moderately trained individuals.

People with the metabolic syndrome (MetS) may have blunted exercise stimulation of metabolism explaining their resistance to lower blood glucose and triglycerides with exercise training. Glycerol and glucose rate of appearance (Ra) in plasma and substrate oxidation were determined at rest and during cycle ergometer exercise at three increasing intensities (55, 80 and 95% of maximal heart rate) in 9 middle-aged (61±7 yr) individuals with MetS. Data were compared to 8 healthy-younger (29±10 yr) individuals matched for habitual exercise training and fat free mass (Healthy-young). At rest, fasting plasma triglycerides (TG), blood glucose and insulin were higher in MetS than in Healthy-young (38%, 42% and 85%, respectively; all p<0.05). At rest, and during low intensity exercise (32-43% VO2MAX), plasma glycerol Ra (index of whole-body lipolysis) and glucose Ra and Rd (index of glucose appearance and disposal) were similar in MetS and Healthy-young. Fat oxidation peaked at low intensity exercise similarly in MetS and Healthy-young (0.273±0.082 vs 0.272±0.078 g·min-1, respectively; p = 0.961). Ra glycerol increased with exercise intensity but was lower in MetS at moderate and high exercise intensities (i.e., 60-100% VO2MAX; p<0.05). Metabolic clearance rate of glucose at high intensity (85-100% VO2MAX) was lower in MetS compared to Healthy-young (p = 0.029). The MetS that develops in middle adulthood, reduces exercise lipolysis and plasma glucose clearance at high exercise intensities, but does not blunt fat or carbohydrate metabolism at low exercise intensity.

Effects of chronic metformin treatment on training adaptations in men and women with hyperglycemia: A prospective study.

OBJECTIVE: This study aimed to determine whether chronic metformin use interferes with the improvements in insulin resistance (IR) and cardiorespiratory fitness with aerobic training in people with hyperglycemia and metabolic syndrome (MetS). METHODS: A total of 63 middle-aged (53 [7] years) individuals with MetS and obesity (BMI = 32.8 [4.5] kg/m2 ) completed 16 weeks of supervised high-intensity interval training (3 d/wk, 43 min/session). Participants were either taking metformin (EXER+MET; n = 29) or were free of any pharmacological treatment for their MetS factors (EXER; n = 34). Groups were similar in their initial cardiorespiratory fitness (maximal oxygen uptake [VO2MAX ]), age, percentage of women, BMI, and MetS factors (z score). The effects of exercise training on IR (homeostatic model assessment of insulin resistance [HOMA-IR]), MetS z score, VO2MAX , maximal fat oxidation during exercise, and maximal aerobic power output were measured. RESULTS: Fasting insulin and HOMA-IR decreased similarly in both groups with training (EXER+MET: -4.3% and -10.6%; EXER: -5.3% and -14.5%; p value for time = 0.005). However, metformin use reduced VO2MAX improvements by half (i.e., EXER+MET: 12.7%; EXER: 25.3%; p value for time × group = 0.012). Maximal fat oxidation during exercise increased similarly in both groups (EXER+MET: 20.7%; EXER: 25.3%; p value for time = 0.040). VO2MAX gains were not associated with HOMA-IR reductions (EXER+MET: r = -0.098; p = 0.580; EXER: r = -0.255; p = 0.182). CONCLUSIONS: Metformin use was associated with attenuated VO2MAX improvements but did not affect fasting IR reductions with aerobic training in individuals with hyperglycemia and high cardiovascular risk (i.e., MetS).

Aerobic exercise training improves nocturnal blood pressure dipping in medicated hypertensive individuals.

OBJECTIVE: The absence of nocturnal blood pressure (BP) reduction at night in hypertensive individuals is associated with an increased cardiovascular risk. The main purpose of the present study was to investigate the effects of an aerobic training intervention on nocturnal BP dipping in medicated hypertensive individuals. METHODS: At baseline, hypertensive individuals under pharmacological treatment underwent 24-h ambulatory BP monitoring and a morning urine sample to analyze albumin creatinine ratio (UACR). Then, participants were divided into nocturnal dippers ( N = 15; 59 ± 6 years) and nondippers ( N = 20; 58 ± 5 years) according to a day-to-night BP reduction of >10% or <10%, respectively. Next, participants underwent a 3-weekly, 4-month aerobic interval training intervention. RESULTS: Follow-up measurements revealed a reduction in daytime diastolic BP in dippers and nondippers ( Ptime < 0.001), whereas nighttime systolic BP was reduced only in nondippers ( P = 0.004). Regarding dipping pattern, nocturnal systolic BP dipping increased after training in nondippers (5 ± 3 to 9 ± 7%; P = 0.018), whereas in dippers, there was a decrease in nocturnal dipping after training (14 ± 4 to 10 ± 7%, P = 0.016). Nocturnal diastolic BP dipping did not change in nondippers (8 ± 5 to 10 ± 7%; P = 0.273) but decreased in dippers (17 ± 6 to 12 ± 8%; P = 0.004). In addition, UACR was significantly reduced in both groups after training ( Ptime = 0.020). CONCLUSION: Aerobic exercise training is associated with nocturnal BP dipping as nighttime BP was lower than before the program in medicated hypertensive individuals with an initial nondipping phenotype. The lack of improvement in individuals with a dipping phenotype warrants further investigation to discern whether dipping phenotypes influence BP responses to exercise training.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

One Bout of Resistance Training Does Not Enhance Metformin Actions in Prediabetic and Diabetic Individuals.

PURPOSE: This study aimed to determine the separated and combined effects of metformin and resistance exercise on glycemic control, insulin sensitivity, and insulin-like growth factor 1 (IGF-1) in overweight/obese individuals with prediabetes and type 2 diabetes mellitus. METHODS: Fourteen adults with a body mass index of 32.1 ± 4.1 kg·m-2, insulin resistance (HOMA-2 1.6 ± 0.6), and poor glycemic control (glycated hemoglobin, 6.9% ± 0.9%; 51.9 ± 10.7 mmol·mol-1) while taking metformin (1561 ± 470 g·d-1) were recruited. Participants underwent four 72-h long experimental trials in a randomized counterbalanced order, either 1) taking metformin (MET), 2) replacing metformin by placebo pills (PLAC), 3) taking placebo and undergoing a resistance training bout (RT + PLAC), and 4) taking metformin and undergoing the same RT bout (RT + MET). Interstitial fluid glucose concentration was frequently sampled to obtain 72-h glucose area under the curve (GAUC) and the percentage hyperglycemic glucose readings (>180 mg·dL-1; GPEAKS). Insulin sensitivity (i.e., HOMA-2) and IGF-1 were also assessed. RESULTS: HOMA-2 was not affected by treatments. GAUC and GPEAKS were similarly reduced below PLAC during RT + MET and MET (all P < 0.05). In contrast, RT + PLAC did not affect glucose concentration. Metformin decreased serum IGF-1 concentrations (P = 0.006), and RT did not reverse this reduction. CONCLUSIONS: A bout of full-body RT does not interfere or aid on metformin's blood glucose-lowering actions in individuals with prediabetes and type 2 diabetes mellitus.

Endurance Exercise Training reduces Blood Pressure according to the Wilder's Principle.

The effect of antihypertensive medicine (AHM) is larger the higher the pre-treatment blood pressure level. It is unknown whether this Wilder's principle, also applies for the exercise-training blood pressure (BP) lowering effect. One hundred seventy-eight (n=178) middle-aged individuals (55±8 y) with metabolic syndrome (MetS), underwent high intensity interval training (3 days·week-1) for 16 weeks. Participants were divided into medicated (Med; n=103) or not medicated (No Med; n=75) with AHM. Office BP was evaluated before and after the exercise-training. Correlations and stepwise regression analysis were used to determine which variable better predicted the reductions in systolic BP (SBP) with training. After training, participants with hypertension lowered SBP by a similar magnitude regardless of if they were in the Med (-15 mmHg, 95% CI-12,-19; P<0.001) or No Med group (-13 mmHg, 95% CI-9,-16; P<0.001). However, SBP did not decrease among normotensive groups (P=0.847 for Med and P=0.937 for No Med). Pre-treatment SBP levels was the best predictor of exercise-training lowering effect (r=-0.650; ß=-0.642; P<0.001). For each 10 mmHg higher pre-training SBP there were a 5 mmHg deeper SBP reduction (Wilder principle). Furthermore, AHM does not interfere with exercise-training BP-lowering effect.

Effectiveness of statins vs. exercise on reducing postprandial hypertriglyceridemia in dyslipidemic population: A systematic review and network meta-analysis.

BACKGROUND: Individuals at risk of suffering cardiovascular disease (CVD) present with larger increases in blood triglyceride (TG) concentration after a high-fat meal than do healthy individuals. These postprandial hypertriglyceride levels are an independent risk factor for CVD. Prescription of statins and a bout of prolonged exercise are both effective in lowering postprandial hypertriglyceride levels. We aimed to evaluate the comparative effectiveness of statins vs. a bout of aerobic exercise in reducing fasting and postprandial TG (PPTG) concentrations in individuals at high risk of developing CVD. METHODS: Thirty-seven studies from a systematic literature search of the PubMed, EMBASE, and Cochrane databases were included in this review. The selected studies conducted trials involving statin therapy (n = 20) or a bout of aerobic exercise (n = 19) and measured their impact on PPTG levels as the outcome. Two studies analyzed both treatments and were included in duplicate. The meta-analysis was constructed using a random-effects model to calculate the mean difference (MD). The Student t test was used to compare the data sets for statins vs. exercise. RESULTS: Overall, statin and exercise interventions showed similar reductions in PPTG levels, with an MD of -0.65 mmol/L for statins (95% confidence interval (95%CI): -0.54 to -0.77; p < 0.001) and -0.46 mmol/L for exercise (95%CI: -0.21 to -0.71; p < 0.01). However, statins lowered fasting TG levels more than exercise (MD = -1.54 mmol/L, 95%CI: -2.25 to -0.83; p = 0.009). CONCLUSION: Although aerobic exercise is effective in lowering blood TG levels, statins seem to be more efficient, especially in the fasted state. A combination of exercise and statins might reveal a valuable approach to the treatment and prevention of CVD. More studies are required to determine the underlying mechanisms and the possible additive effects of these interventions.