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1.  The effect of endurance exercise on intestinal integrity in well‐trained healthy men 
Physiological Reports  2016;4(20):e12994.
Abstract
Exercise is one of the external factors associated with impairment of intestinal integrity, possibly leading to increased permeability and altered absorption. Here, we aimed to examine to what extent endurance exercise in the glycogen‐depleted state can affect intestinal permeability toward small molecules and protein‐derived peptides in relation to markers of intestinal function. Eleven well‐trained male volunteers (27 ± 4 years) ingested 40 g of casein protein and a lactulose/rhamnose (L/R) solution after an overnight fast in resting conditions (control) and after completing a dual – glycogen depletion and endurance – exercise protocol (first protocol execution). The entire procedure was repeated 1 week later (second protocol execution). Intestinal permeability was measured as L/R ratio in 5 h urine and 1 h plasma. Five‐hour urine excretion of betacasomorphin‐7 (BCM7), postprandial plasma amino acid levels, plasma fatty acid binding protein 2 (FABP‐2), serum pre‐haptoglobin 2 (preHP2), plasma glucagon‐like peptide 2 (GLP2), serum calprotectin, and dipeptidylpeptidase‐4 (DPP4) activity were studied as markers for excretion, intestinal functioning and recovery, inflammation, and BCM7 breakdown activity, respectively. BCM7 levels in urine were increased following the dual exercise protocol, in the first as well as the second protocol execution, whereas 1 h‐plasma L/R ratio was increased only following the first exercise protocol execution. FABP2, preHP2, and GLP2 were not changed after exercise, whereas calprotectin increased. Plasma citrulline levels following casein ingestion (iAUC) did not increase after exercise, as opposed to resting conditions. Endurance exercise in the glycogen depleted state resulted in a clear increase of BCM7 accumulation in urine, independent of DPP4 activity and intestinal permeability. Therefore, strenuous exercise could have an effect on the amount of food‐derived bioactive peptides crossing the epithelial barrier. The health consequence of increased passage needs more in depth studies.
doi:10.14814/phy2.12994
PMCID: PMC5099959  PMID: 27798350
Amino acids; betacasomorphin‐7; citrulline; dipeptidylpeptidase‐4; exercise; intestinal permeability
2.  Associations between plasma branched-chain amino acids, β-aminoisobutyric acid and body composition 
Plasma branched-chain amino acids (BCAA) are elevated in obesity and associated with increased cardiometabolic risk. β-Aminoisobutyric acid (B-AIBA), a recently identified small molecule metabolite, is associated with decreased cardiometabolic risk. Therefore, we investigated the association of BCAA and B-AIBA with each other and with detailed body composition parameters, including abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). A cross-sectional study was carried out with lean (n 15) and obese (n 33) men and women. Detailed metabolic evaluations, including measures of body composition, insulin sensitivity and plasma metabolomics were completed. Plasma BCAA were higher (1·6 (se 0·08) (×107) v. 1·3 (se 0·06) (×107) arbitrary units; P = 0·005) in obese v. lean subjects. BCAA were positively associated with VAT (R 0·49; P = 0·0006) and trended to an association with SAT (R 0·29; P = 0·052). The association between BCAA and VAT, but not SAT, remained significant after controlling for age, sex and race on multivariate modelling (P < 0·05). BCAA were also associated with parameters of insulin sensitivity (Matsuda index: R −0·50, P = 0·0004; glucose AUC: R 0·53, P < 0·001). BCAA were not associated with B-AIBA (R −0·04; P = 0·79). B-AIBA was negatively associated with SAT (R −0·37; P = 0·01) but only trended to an association with VAT (R 0·27; P = 0·07). However, neither relationship remained significant after multivariate modelling (P > 0·05). Plasma B-AIBA was associated with parameters of insulin sensitivity (Matsuda index R 0·36, P = 0·01; glucose AUC: R −0·30, P = 0·04). Plasma BCAA levels were positively correlated with VAT and markers of insulin resistance. The results suggest a possible complex role of adipose tissue in BCAA homeostasis and insulin resistance.
doi:10.1017/jns.2015.37
PMCID: PMC4791517  PMID: 27313851
Branched-chain amino acids; Visceral adiposity; β-Aminoisobutyric acid; Subcutaneous adipose tissue; Lean body mass; Metabolomics; AU, arbitrary units; B-AIBA, β-aminoisobutyric acid; BCAA, branched-chain amino acid; BCAT, branched-chain amino acid aminotransferase; BCKD, branched-chain α-ketoacid dehydrogenase; DXA, dual-energy X-ray absorptiometry; HOMA-IR, homeostasis model assessment for insulin resistance; OGTT, oral glucose tolerance test; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue
3.  Associations between plasma branched-chain amino acids, β-aminoisobutyric acid and body composition 
Plasma branched-chain amino acids (BCAA) are elevated in obesity and associated with increased cardiometabolic risk. β-Aminoisobutyric acid (B-AIBA), a recently identified small molecule metabolite, is associated with decreased cardiometabolic risk. Therefore, we investigated the association of BCAA and B-AIBA with each other and with detailed body composition parameters, including abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). A cross-sectional study was carried out with lean (n 15) and obese (n 33) men and women. Detailed metabolic evaluations, including measures of body composition, insulin sensitivity and plasma metabolomics were completed. Plasma BCAA were higher (1·6 (se 0·08) (×107) v. 1·3 (se 0·06) (×107) arbitrary units; P = 0·005) in obese v. lean subjects. BCAA were positively associated with VAT (R 0·49; P = 0·0006) and trended to an association with SAT (R 0·29; P = 0·052). The association between BCAA and VAT, but not SAT, remained significant after controlling for age, sex and race on multivariate modelling (P < 0·05). BCAA were also associated with parameters of insulin sensitivity (Matsuda index: R −0·50, P = 0·0004; glucose AUC: R 0·53, P < 0·001). BCAA were not associated with B-AIBA (R −0·04; P = 0·79). B-AIBA was negatively associated with SAT (R −0·37; P = 0·01) but only trended to an association with VAT (R 0·27; P = 0·07). However, neither relationship remained significant after multivariate modelling (P > 0·05). Plasma B-AIBA was associated with parameters of insulin sensitivity (Matsuda index R 0·36, P = 0·01; glucose AUC: R −0·30, P = 0·04). Plasma BCAA levels were positively correlated with VAT and markers of insulin resistance. The results suggest a possible complex role of adipose tissue in BCAA homeostasis and insulin resistance.
doi:10.1017/jns.2015.37
PMCID: PMC4791517  PMID: 27313851
Branched-chain amino acids; Visceral adiposity; β-Aminoisobutyric acid; Subcutaneous adipose tissue; Lean body mass; Metabolomics; AU, arbitrary units; B-AIBA, β-aminoisobutyric acid; BCAA, branched-chain amino acid; BCAT, branched-chain amino acid aminotransferase; BCKD, branched-chain α-ketoacid dehydrogenase; DXA, dual-energy X-ray absorptiometry; HOMA-IR, homeostasis model assessment for insulin resistance; OGTT, oral glucose tolerance test; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue
4.  Post-Exercise Rehydration: Effect of Consumption of Beer with Varying Alcohol Content on Fluid Balance after Mild Dehydration 
Purpose
The effects of moderate beer consumption after physical activity on rehydration and fluid balance are not completely clear. Therefore, in this study, we investigated the effect of beer consumption, with varying alcohol content, on fluid balance after exercise-induced dehydration.
Methods
Eleven healthy males were included in this cross over study (age 24.5 ± 4.7 years, body weight 75.4 ± 3.3 kg, VO2max 58.3 ± 6.4 mL kg min−1). Subjects exercised on a cycle ergometer for 45 min at 60% of their maximal power output (Wmax) until mild dehydration (1% body mass loss). Thereafter, in random order, one of five experimental beverages was consumed, in an amount equal to 100% of their sweat loss: non-alcoholic beer (0.0%), low-alcohol beer (2.0%), full-strength beer (5.0%), an isotonic sports drink, and water. Fluid balance was assessed up till 5 h after rehydration.
Results
After 1 h, urine production was significantly higher for 5% beer compared to the isotonic sports drink (299 ± 143 vs. 105 ± 67 mL; p < 0.01). At the end of the 5-h observation period, net fluid balance (NFB) was negative for all conditions (p = 0.681), with the poorest fluid retention percentage for 5% beer (21% fluid retention) and the best percentage for the isotonic sports drink (42%). Non-alcoholic beer, low-alcoholic beer, and water resulted in fluid retention of 36, 36, and 34%, respectively (p = 0.460).
Conclusion
There was no difference in NFB between the different beverages. Only a short-lived difference between full-strength beer and the isotonic sports drink in urine output and NFB was observed after mild exercise-induced dehydration. Fluid replacement – either in the form of non-alcoholic beer, low-alcoholic beer, full-strength beer, water, or an isotonic sports drink of 100% of body mass loss was not sufficient to achieve full rehydration. The combination of a moderate amount of beer, with varying alcohol content, enough water or electrolyte- and carbohydrate beverages, and salty foods might improve rehydration, but more research is needed.
doi:10.3389/fnut.2016.00045
PMCID: PMC5066341  PMID: 27800480
rehydration; exercise; alcohol; beer; urine output; fluid balance
5.  Glycogen availability and skeletal muscle adaptations with endurance and resistance exercise 
It is well established that glycogen depletion affects endurance exercise performance negatively. Moreover, numerous studies have demonstrated that post-exercise carbohydrate ingestion improves exercise recovery by increasing glycogen resynthesis. However, recent research into the effects of glycogen availability sheds new light on the role of the widely accepted energy source for adenosine triphosphate (ATP) resynthesis during endurance exercise. Indeed, several studies showed that endurance training with low glycogen availability leads to similar and sometimes even better adaptations and performance compared to performing endurance training sessions with replenished glycogen stores. In the case of resistance exercise, a few studies have been performed on the role of glycogen availability on the early post-exercise anabolic response. However, the effects of low glycogen availability on phenotypic adaptations and performance following prolonged resistance exercise remains unclear to date. This review summarizes the current knowledge about the effects of glycogen availability on skeletal muscle adaptations for both endurance and resistance exercise. Furthermore, it describes the role of glycogen availability when both exercise modes are performed concurrently.
doi:10.1186/s12986-015-0055-9
PMCID: PMC4687103  PMID: 26697098
Glycogen availability; Skeletal muscle; Adaptation; Endurance exercise; Resistance exercise
6.  Pronounced Effects of Acute Endurance Exercise on Gene Expression in Resting and Exercising Human Skeletal Muscle 
PLoS ONE  2012;7(11):e51066.
Regular physical activity positively influences whole body energy metabolism and substrate handling in exercising muscle. While it is recognized that the effects of exercise extend beyond exercising muscle, it is unclear to what extent exercise impacts non-exercising muscles. Here we investigated the effects of an acute endurance exercise bouts on gene expression in exercising and non-exercising human muscle. To that end, 12 male subjects aged 44–56 performed one hour of one-legged cycling at 50% Wmax. Muscle biopsies were taken from the exercising and non-exercising leg before and immediately after exercise and analyzed by microarray. One-legged cycling raised plasma lactate, free fatty acids, cortisol, noradrenalin, and adrenalin levels. Surprisingly, acute endurance exercise not only caused pronounced gene expression changes in exercising muscle but also in non-exercising muscle. In the exercising leg the three most highly induced genes were all part of the NR4A family. Remarkably, many genes induced in non-exercising muscle were PPAR targets or related to PPAR signalling, including PDK4, ANGPTL4 and SLC22A5. Pathway analysis confirmed this finding. In conclusion, our data indicate that acute endurance exercise elicits pronounced changes in gene expression in non-exercising muscle, which are likely mediated by changes in circulating factors such as free fatty acids. The study points to a major influence of exercise beyond the contracting muscle.
doi:10.1371/journal.pone.0051066
PMCID: PMC3511348  PMID: 23226462
7.  Prolonged Fasting Identifies Skeletal Muscle Mitochondrial Dysfunction as Consequence Rather Than Cause of Human Insulin Resistance 
Diabetes  2010;59(9):2117-2125.
OBJECTIVE
Type 2 diabetes and insulin resistance have been associated with mitochondrial dysfunction, but it is debated whether this is a primary factor in the pathogenesis of the disease. To test the concept that mitochondrial dysfunction is secondary to the development of insulin resistance, we employed the unique model of prolonged fasting in humans. Prolonged fasting is a physiologic condition in which muscular insulin resistance develops in the presence of increased free fatty acid (FFA) levels, increased fat oxidation and low glucose and insulin levels. It is therefore anticipated that skeletal muscle mitochondrial function is maintained to accommodate increased fat oxidation unless factors secondary to insulin resistance exert negative effects on mitochondrial function.
RESEARCH DESIGN AND METHODS
While in a respiration chamber, twelve healthy males were subjected to a 60 h fast and a 60 h normal fed condition in a randomized crossover design. Afterward, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, and mitochondrial function was quantified ex vivo in permeabilized muscle fibers using high-resolution respirometry.
RESULTS
Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity. Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density.
CONCLUSIONS
These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function. Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action per se can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible causes for the observed reduction in mitochondrial capacity.
doi:10.2337/db10-0519
PMCID: PMC2927932  PMID: 20573749
8.  Restoration of Muscle Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes by Exercise Training Is Paralleled by Increased Myocellular Fat Storage and Improved Insulin Sensitivity 
Diabetes  2009;59(3):572-579.
OBJECTIVE
Mitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid [IMCL]) have been linked to development of type 2 diabetes. We examined whether exercise training could restore mitochondrial function and insulin sensitivity in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
Eighteen male type 2 diabetic and 20 healthy male control subjects of comparable body weight, BMI, age, and Vo2max participated in a 12-week combined progressive training program (three times per week and 45 min per session). In vivo mitochondrial function (assessed via magnetic resonance spectroscopy), insulin sensitivity (clamp), metabolic flexibility (indirect calorimetry), and IMCL content (histochemically) were measured before and after training.
RESULTS
Mitochondrial function was lower in type 2 diabetic compared with control subjects (P = 0.03), improved by training in control subjects (28% increase; P = 0.02), and restored to control values in type 2 diabetic subjects (48% increase; P < 0.01). Insulin sensitivity tended to improve in control subjects (delta Rd 8% increase; P = 0.08) and improved significantly in type 2 diabetic subjects (delta Rd 63% increase; P < 0.01). Suppression of insulin-stimulated endogenous glucose production improved in both groups (−64%; P < 0.01 in control subjects and −52% in diabetic subjects; P < 0.01). After training, metabolic flexibility in type 2 diabetic subjects was restored (delta respiratory exchange ratio 63% increase; P = 0.01) but was unchanged in control subjects (delta respiratory exchange ratio 7% increase; P = 0.22). Starting with comparable pretraining IMCL levels, training tended to increase IMCL content in type 2 diabetic subjects (27% increase; P = 0.10), especially in type 2 muscle fibers.
CONCLUSIONS
Exercise training restored in vivo mitochondrial function in type 2 diabetic subjects. Insulin-mediated glucose disposal and metabolic flexibility improved in type 2 diabetic subjects in the face of near–significantly increased IMCL content. This indicates that increased capacity to store IMCL and restoration of improved mitochondrial function contribute to improved muscle insulin sensitivity.
doi:10.2337/db09-1322
PMCID: PMC2828651  PMID: 20028948
9.  Lower Intrinsic ADP-Stimulated Mitochondrial Respiration Underlies In Vivo Mitochondrial Dysfunction in Muscle of Male Type 2 Diabetic Patients 
Diabetes  2008;57(11):2943-2949.
OBJECTIVE—A lower in vivo mitochondrial function has been reported in both type 2 diabetic patients and first-degree relatives of type 2 diabetic patients. The nature of this reduction is unknown. Here, we tested the hypothesis that a lower intrinsic mitochondrial respiratory capacity may underlie lower in vivo mitochondrial function observed in diabetic patients.
RESEARCH DESIGN AND METHODS—Ten overweight diabetic patients, 12 first-degree relatives, and 16 control subjects, all men, matched for age and BMI, participated in this study. Insulin sensitivity was measured with a hyperinsulinemic-euglycemic clamp. Ex vivo intrinsic mitochondrial respiratory capacity was determined in permeabilized skinned muscle fibers using high-resolution respirometry and normalized for mitochondrial content. In vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time after exercise using 31P-magnetic resonance spectroscopy.
RESULTS—Insulin-stimulated glucose disposal was lower in diabetic patients compared with control subjects (11.2 ± 2.8 vs. 28.9 ± 3.7 μmol · kg−1 fat-free mass · min−1, respectively; P = 0.003), with intermediate values for first-degree relatives (22.1 ± 3.4 μmol · kg−1 fat-free mass · min−1). In vivo mitochondrial function was 25% lower in diabetic patients (P = 0.034) and 23% lower in first-degree relatives, but the latter did not reach statistical significance (P = 0.08). Interestingly, ADP-stimulated basal respiration was 35% lower in diabetic patients (P = 0.031), and fluoro-carbonyl cyanide phenylhydrazone–driven maximal mitochondrial respiratory capacity was 31% lower in diabetic patients (P = 0.05) compared with control subjects with intermediate values for first-degree relatives.
CONCLUSIONS—A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial function, independent of mitochondrial content. A reduced capacity at both the level of the electron transport chain and phosphorylation system underlies this impaired mitochondrial capacity.
doi:10.2337/db08-0391
PMCID: PMC2570390  PMID: 18678616
10.  Adipose triglyceride lipase (ATGL) expression in human skeletal muscle is type I (oxidative) fiber specific 
Histochemistry and Cell Biology  2008;129(4):535-538.
Accumulation of triacylglycerol (TAG) and lipid intermediates in skeletal muscle plays an important role in the etiology of insulin resistance and type 2 diabetes mellitus. Disturbances in skeletal muscle lipid turnover and lipolysis may contribute significantly to this. So far, knowledge on the regulation of muscle lipolysis is limited. Recently the identification of a new lipase was reported: adipose triglyceride lipase (ATGL). ATGL deficient animals show significant lipid accumulation in skeletal muscle, which may indicate that ATGL plays a pivotal role in skeletal muscle lipolysis. However, until now, it is still unknown whether ATGL protein is expressed in human skeletal muscle. Therefore, the aim of the present study was to investigate whether ATGL is expressed at the protein level in human skeletal muscle, and to examine whether its expression is fiber-type specific. To accomplish this, we established an imunohistochemical and immunofluorescent staining procedure to study ATGL protein expression in relation to fiber type in human vastus lateralis muscle of eight male subjects (BMI range: 21.0–34.5 kg/m2 and age: 38–59 years). In the present paper we report for the first time that ATGL protein is indeed expressed in human skeletal muscle. Moreover, ATGL is exclusively expressed in type I (oxidative) muscle fibers, suggesting a pivotal role for ATGL in intramuscular fatty acid handling, lipid storage and breakdown.
doi:10.1007/s00418-008-0386-y
PMCID: PMC2668625  PMID: 18224330
ATGL;  Skeletal muscle; Fiber type; Obesity; Protein
11.  Anti-inflammatory effect of rosiglitazone is not reflected in expression of NFκB-related genes in peripheral blood mononuclear cells of patients with type 2 diabetes mellitus 
Background
Rosiglitazone not only improves insulin-sensitivity, but also exerts anti-inflammatory effects. We have now examined in type 2 diabetic patients if these effects are reflected by changes in mRNA expression in peripheral blood mononuclear cells (PBMCs) to see if these cells can be used to study these anti-inflammatory effects at the molecular level in vivo.
Method
Eleven obese type 2 diabetic patients received rosiglitazone (2 × 4 mg/d) for 8 weeks. Fasting blood samples were obtained before and after treatment. Ten obese control subjects served as reference group. The expression of NFκB-related genes and PPARγ target genes in PBMCs, plasma TNFα, IL6, MCP1 and hsCRP concentrations were measured. In addition, blood samples were obtained after a hyperinsulinemic-euglycemic clamp.
Results
Rosiglitazone reduced plasma MCP1 and hsCRP concentrations in diabetic patients (-9.5 ± 5.3 pg/mL, p = 0.043 and -1.1 ± 0.3 mg/L p = 0.003), respectively). For hsCRP, the concentration became comparable with the non-diabetic reference group. However, of the 84 NFκB-related genes that were measured in PBMCs from type 2 diabetic subjects, only RELA, SLC20A1, INFγ and IL1R1 changed significantly (p < 0.05). In addition, PPARγ and its target genes (CD36 and LPL) did not change. During the clamp, insulin reduced plasma MCP1 concentration in the diabetic and reference groups (-9.1 ± 1.8%, p = 0.001 and -11.1 ± 4.1%, p = 0.023, respectively) and increased IL6 concentration in the reference group only (23.5 ± 9.0%, p = 0.028).
Conclusion
In type 2 diabetic patients, the anti-inflammatory effect of rosiglitazone is not reflected by changes in NFκB and PPARγ target genes in PBMCs in vivo. Furthermore, our results do not support that high insulin concentrations contribute to the pro-inflammatory profile in type 2 diabetic patients.
doi:10.1186/1472-6823-9-8
PMCID: PMC2653037  PMID: 19243600

Results 1-11 (11)