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AIM: Although postprandial hyperglycemia is recognized as an important target in type 2 diabetes treatment, information on the prevalence of postprandial hyperglycemia throughout the day is limited. Therefore, we assessed the prevalence of hyperglycemia throughout the day in type 2 diabetes patients and healthy controls under standardized dietary, but otherwise free-living conditions. METHODS: 60 male type 2 diabetes patients (HbA(1c) 7.5±0.1% [58±1mmol/mol]) and 24 age- and BMI-matched normal glucose tolerant controls were recruited to participate in a comparative study of daily glycemic control. During a 3-day experimental period, blood glucose concentrations throughout the day were assessed by continuous glucose monitoring. RESULTS: Type 2 diabetes patients experienced hyperglycemia (glucose concentrations >10mmol/L) 38±4% of the day. Even diabetes patients with an HbA(1c) level below 7.0% (53mmol/mol) experienced hyperglycemia for as much as 24±5% throughout the day. Hyperglycemia was negligible in the control group (3±1%). CONCLUSION: Hyperglycemia is highly prevalent throughout the day in type 2 diabetes patients, even in those patients with a HbA(1c) level well below 7.0% (53mmol/mol). Standard medical care with prescription of oral blood glucose lowering medication does not provide ample protection against postprandial hyperglycemia. [ABSTRACT FROM AUTHOR]

Muscle weakness and exercise intolerance negatively affect the quality of life of patients with mitochondrial myopathy. Short-term dietary nitrate supplementation has been shown to improve exercise performance and reduce oxygen cost of exercise in healthy humans and trained athletes. We investigated whether 1 wk of dietary inorganic nitrate supplementation decreases the oxygen cost of exercise and improves mitochondrial function in patients with mitochondrial myopathy. Ten patients with mitochondrial myopathy (40 ± 5 yr, maximal whole body oxygen uptake = 21.2 ± 3.2 ml·min -1 ·kg body wt -1 , maximal work load = 122 ± 26 W) received 8.5 mg·kg body wt -1 ·day -1 inorganic nitrate (~7 mmol) for 8 days. Whole body oxygen consumption at 50% of the maximal work load, in vivo skeletal muscle oxidative capacity (evaluated from postexercise phosphocreatine recovery using 31 P-magnetic resonance spectroscopy), and ex vivo mitochondrial oxidative capacity in permeabilized skinned muscle fibers (measured with high-resolution respirometry) were determined before and after nitrate supplementation. Despite a sixfold increase in plasma nitrate levels, nitrate supplementation did not affect whole body oxygen cost during submaximal exercise. Additionally, no beneficial effects of nitrate were found on in vivo or ex vivo muscle mitochondrial oxidative capacity. This is the first time that the therapeutic potential of dietary nitrate for patients with mitochondrial myopathy was evaluated. We conclude that 1 wk of dietary nitrate supplementation does not reduce oxygen cost of exercise or improve mitochondrial function in the group of patients tested., (Copyright © 2017 the American Physiological Society.)

Patients with aneurysmal subarachnoid hemorrhage (a-SAH) show long-term fatigue and face difficulties in resuming daily physical activities. Impaired muscle strength, especially of the lower extremity, impacts the performance of daily activities and may trigger the onset of fatigue complaints. The present study evaluated knee muscle strength and fatigue in patients with a-SAH. This study included 33 patients, 6 months after a-SAH, and 33 sex-matched and age-matched healthy controls. Isokinetic muscle strength of the knee extensors and flexors was measured at 60 and 180°/s. Maximal voluntary muscle strength was defined as peak torque and measured in Newton-meter. Fatigue was examined using the Fatigue Severity Scale. In patients with a-SAH, the maximal knee extension was 22% (60°/s) and 25% (180°/s) lower and maximal knee flexion was 33% (60°/s) and 36% (180°/s) lower compared with that of matched controls (P≤0.001). The Fatigue Severity Scale score was related to maximal knee extension (60°/s: r=-0.426, P=0.015; 180°/s: r=-0.376, P=0.034) and flexion (60°/s: r=-0.482, P=0.005; 180°/s: r=-0.344, P=0.083). The knee muscle strength was 28-47% lower in fatigued (n=13) and 11-32% lower in nonfatigued (n=20) patients; deficits were larger in fatigued patients (P<0.05), particularly when the muscle strength (peak torque) was measured at 60°/s. The present results indicate that patients with a-SAH have considerably impaired knee muscle strength, which is related to more severe fatigue. The present findings are exploratory, but showed that knee muscle strength may play a role in the severity of fatigue complaints, or vice versa. Interventions targeting fatigue after a-SAH seem necessary and may consider strengthening exercise training in order to treat a debilitating condition.

Mankowski, RT, Michael, S, Rozenberg, R, Stokla, S, Stam, HJ, and Praet, SFE. Heart-rate variability threshold as an alternative for spiro-ergometry testing: a validation study. J Strength Cond Res 31(2): 474-479, 2017-Although spiro-ergometry is the established "gold standard" for determination of the second ventilatory threshold (VT2), it is a costly and rather time-consuming method. Previous studies suggest that assessing the second anaerobic threshold (AT2) on the basis of heart rate variability (HRV) during exercise may be a more cost-effective and noninvasive manner. However, appropriate validation studies, are still lacking. Eleven healthy, moderately trained subjects underwent 3 incremental exercise tests. Ventilation, oxygen uptake (V[Combining Dot Above]O2), CO2 production (V[Combining Dot Above]CO2), and HRV were measured continuously. Exercise testing was performed in 3 oxygen (FiO2) conditions of inspired air (14, 21, and 35% of oxygen). Participants and assessors were blinded to the FiO2 conditions. Two research teams assessed VT2s and HRVT2s independently from each other. Mean workloads corresponding to VT2 and HRVT2 in hypoxia were, respectively, 19 ± 17% (p = 0.01) and 15 ± 15% (p = 0.1) lower in comparison with hyperoxic conditions. Bland-Altman analysis showed low estimation bias (2.2%) and acceptably precise 95% limits of agreement for workload -15.7% to 20.1% for all FiO2 conditions. Bias was the lowest under normoxic conditions (1.1%) in comparison with hypoxia (3.7%) and hyperoxia (4.7%). Heart rate variability-based AT2 assessment had a most acceptable agreement with VT2 under normoxic conditions. This simple HRVT2 assessment may have potential applications for exercise monitoring in commercial fitness settings.

In this report we describe a female Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) patient who suffered from severe exercise intolerance. At age 34, the patient became pregnant for the first time. After an uneventful first 32 weeks of pregnancy she developed sinus tachycardia (resting heart rate 120-134 bpm) and lactate and creatinine kinase levels increased (3.3 mmol/L and 264 U/L, respectively). Increasing MCT supplementation (dose and frequency of administration) lowered heart rate and improved biochemical parameters. At 34 weeks the heart rate rose again and it was decided to deliver the child by caesarean section. Postpartum both mother and child did well.Prior to pregnancy, she performed exercise tests with different doses of medium chain triglycerides (MCTs) to establish a safe and effective exercise program (baseline test, second test with 10 g MCTs and third test with 20 g of MCTs). In the MCT supplemented tests the maximal power output was 23% (second test) and 26% (third test) higher, while cardiac output at maximal power output was the same in all three tests (~15.8 L/min).In conclusion, this is the first report of pregnancy in an LCHADD patient, with favourable outcome for both mother and child. Moreover, in the same patient, MCT supplementation improved cardiac performance and metabolic parameters during high intensity exercise. Using impedance cardiography, we got a clear indication that this benefit was due to improved muscle energy generation at high intensity exercise, since at the same cardiac output a higher power output could be generated.

Objective: The study investigated the feasibility and potential outcome measures during acute hyperoxia in type 2 diabetes patients (DM2)., Methods: Eleven DM2 patients (7 men and 4 women) were included in the study. The patients cycled (30 min at 20% Wmax) whilst breathing three different supplemental oxygen flows (SOF, 5, 10, 15 L min(-1)). During hyperoxic exercise, arterial blood gases and intra-arterial blood pressure measurements were obtained., Results: Arterial pO2 levels increased significantly (ANOVA, p < 0.05) with SOF: 13.9 ± 1.2 (0 L min(-1)); 18.5 ± 1.5 (5 L min(-1)); 21.7 ± 1.7 (10 L min(-1)); 24.0 ± 2.3 (15 L min(-1)). Heart rate (HR) and pH increased significantly after terminating administration of hyperoxic air., Conclusions: An SOF of 15 L min(-1) appears to be more effective than 5 or 10 L min(-1). Moreover, HR, blood pressure, blood lactate and pH are not recommended as primary outcome measures.

A short maximal steep ramp test (SRT, 25 W/10 s) has been proposed to guide exercise interventions in type 2 diabetes, but requires validation. This study aims to (a) determine the relationship between Wmax and V˙O2peak reached during SRT and the standard ramp test (RT); (b) obtain test-retest reliability; and (c) document electrocardiogram (ECG) abnormalities during SRT. Type 2 diabetes patients (35 men, 26 women) performed a cycle ergometer-based RT (women 1.2; men 1.8 W/6 s) and SRT on separate days. A random subgroup (n = 42) repeated the SRT. ECG, heart rate, and V˙O2 were monitored. Wmax during RT: 193 ± 63 (men) and 106 ± 33 W (women). Wmax during SRT: 193 ± 63 (men) and 188 ± 55 W (women). The relationship between RT and SRT was described by men RT V˙O2peak (mL/min) = 152 + 7.67 × Wmax SRT1 (r: 0.859); women RT V ˙ O 2 p e a k (mL/min) = 603 + 4.75 × Wmax SRT1 (r: 0.771); intraclass correlation coefficients between first (SRT1) and second SRT Wmax (SRT2) were men 0.951 [95% confidence interval (CI) 0.899-0.977] and women 0.908 (95% CI 0.727-0.971). No adverse events were noted during any of the exercise tests. This validation study indicates that the SRT is a low-risk, accurate, and reliable test to estimate maximal aerobic capacity during the RT to design exercise interventions in type 2 diabetes patients., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Musculotendinous overuse injuries are prevalent in people with type 2 diabetes. Non-enzymatic glycosylation of collagen resulting in tendon stiffening may play a role. In this case-control study we determined whether patients with diabetes had poorer ultrasonographic structure in their Achilles tendons compared to age-matched controls., Methods: People with type 1 diabetes or type 2 diabetes, and age-matched controls, had computerised ultrasound tissue characterisation of both Achilles tendons. In contiguous ultrasonographic images of the tendon, echopatterns were quantified and categorised into four echo-types. Tendon abnormality was quantified as sum of echo-types III+IV. Furthermore, skin autofluorescence (AF) of the forearm (AF-value) was gathered., Results: Twenty four type 2 diabetes patients, 24 controls, 24 type 1 diabetes patients and 20 controls were included. AF-value was higher in type 1 diabetes (1.55±0.17) than in their controls (1.39±0.18, p<0.001) and in type 2 diabetes (2.28±0.38) compared to their controls (1.84±0.32, p<0.001) Achilles tendons of type 2 diabetes patients contained more echo-types III+IV (14.1±7.9%) than matched controls (8.0±5.4%, p<0.001). There was a trend towards a difference in echo-types III+IV between type 1 diabetes patients (9.5±5.3%) and their controls (6.5±3.7%, p=0.055). In a stepwise linear regression analysis, body mass index (BMI) was moderately associated with tendon abnormality in patients with diabetes and controls (β=0.393, p<0.001)., Conclusions: Type 2, and possibly type 1, diabetes patients showed poorer ultrasonographic Achilles tendon structure that may be a risk factor for tendinopathy. Although markers for accumulation of advanced glycation end products were elevated in both diabetes populations, only BMI was associated with these abnormalities., Trial Registration Number: NTR2209., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Pompe disease is a proximal myopathy. We investigated whether exercise training is a safe and useful adjuvant therapy for adult Pompe patients, receiving enzyme replacement therapy., Methods: Training comprised 36 sessions of standardized aerobic, resistance and core stability exercises over 12 weeks. Before and after, the primary outcome measures safety, endurance (aerobic exercise capacity and distance walked on the 6 min walk test) and muscle strength, and secondary outcome measures core stability, muscle function and body composition, were evaluated., Results: Of 25 patients enrolled, 23 successfully completed the training. Improvements in endurance were shown by increases in maximum workload capacity (110 W before to 122 W after training, [95 % CI of the difference 6 · 0 to 19 · 7]), maximal oxygen uptake capacity (69 · 4 % and 75 · 9 % of normal, [2 · 5 to 10 · 4]), and maximum walking distance (6 min walk test: 492 meters and 508, [-4 · 4 to 27 · 7] ). There were increases in muscle strength of the hip flexors (156 · 4 N to 180 · 7 N [1 · 6 to 13 · 6) and shoulder abductors (143 · 1 N to 150 · 7 N [13 · 2 to 35 · 2]). As an important finding in secondary outcome measures the number of patients who were able to perform the core stability exercises rose, as did the core stability balancing time (p < 0.05, for all four exercises). Functional tests showed small reductions in the time needed to climb four steps (2 · 4 sec to 2 · 1, [- 0 · 54 to -0 · 04 ]) and rise to standing position (5 · 8 sec to 4 · 8, [-2 · 0 to 0 · 0]), while time to run, the quick motor function test results and body composition remained unchanged., Conclusions: Our study shows that a combination of aerobic, strength and core stability exercises is feasible, safe and beneficial to adults with Pompe disease.

Objective: To assess if a 12-week exercise intervention to improve aerobic fitness, muscle strength, and core stability also had an impact on fatigue, pain, activity, and participation in adults with Pompe disease, an inherited neuromuscular disorder., Design: Open-label trial. Change was assessed by the chi-square test and Wilcoxon signed-rank test., Setting: Physiotherapy practices., Participants: Mildly affected adult patients with Pompe disease who were not dependent on ventilators and/or walking devices and were receiving enzyme replacement therapy., Intervention: Patients participated in a 12-week exercise program, which included 36 sessions of standardized aerobic, resistance, and core stability exercises., Main Outcome Measures: Before and after the training program we evaluated fatigue (Fatigue Severity Scale), pain (yes/no), motor function (Quantitative Muscle Function Test, Rasch-built Pompe-specific Activity Scale), amount of physical activity (activity monitor), and health status (Medical Outcomes Study 36-Item Short-Form Health Survey)., Results: Of the 25 patients enrolled, 23 completed the program. At the end of the program, levels of fatigue (median, 5.33 to 4.78, P=.01) and pain (56.5% to 21.7%, P=.04) improved. The quality of motor function and the amount of physical activity patients engaged in did not change. Changes in pain and fatigue were not related to improvements in aerobic fitness or muscle strength., Conclusions: This study in mildly affected adult patients with Pompe disease suggests that a combined training program aiming to increase aerobic fitness, muscle strength, and core stability also leads to improvements in fatigue and pain., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine patient independency, health-related and disease-specific quality of life (QOL), gait pattern, and muscle strength in patients after salvage arthroplasty for failed internal fixation of a femoral neck fracture., Design: Secondary cohort study to a randomized controlled trial., Setting: Multicenter trial in the Netherlands, including 14 academic and nonacademic hospitals., Patients: Patients after salvage arthroplasty for failed internal fixation of a femoral neck fracture were studied. A comparison was made with patients who healed uneventfully after internal fixation., Intervention: None (observatory study)., Main Outcome Measurements: Patient characteristics, SF-12, and Western Ontario McMaster osteoarthritis index scores were collected. Gait parameters were measured using plantar pressure measurement. Maximum isometric forces of the hip muscles were measured using a handheld dynamometer. Differences between the fractured and contralateral leg were calculated. Groups were compared using univariate analysis., Results: Of 248 internal fixation patients (median age, 72 years), salvage arthroplasty was performed in 68 patients (27%). Salvage arthroplasty patients had a significantly lower Western Ontario McMaster osteoarthritis index score (median, 73 vs. 90; P = 0.016) than patients who healed uneventfully after internal fixation. Health-related QOL (SF-12) and patient independency did not differ significantly between the groups. Gait analysis showed a significantly impaired progression of the center of pressure in the salvage surgery patients (median ratio, -8.9 vs. 0.4, P = 0.013) and a significant greater loss of abduction strength (median, -25.4 vs. -20.4 N, P = 0.025)., Conclusions: Despite a similar level of dependency and QOL, salvage arthroplasty patients have inferior functional outcome than patients who heal after internal fixation of a femoral neck fracture., Level of Evidence: Therapeutic level III.

Tendon pathology is related to metabolic disease and mechanical overloading, but the effect of metabolic disease on tendon mechanics is unknown. This study investigated the effect of diet and apolipoprotein E deficiency (ApoE(-/-)) on mechanical properties and advanced glycation end product (AGE) cross-linking of non-weight-bearing mouse tail tendons. Twenty ApoE(-/-) male mice were used as a model for hypercholesterolemia along with 26 wild-type (WT) mice. One-half of the mice from each group was fed a normal diet (ND) and the other half was fed a high-fat diet (HFD) to induce obesity. All were killed at 40 wk, and tail tendon fascicles were mechanically tested to failure and analyzed for AGEs. Diets were also analyzed for AGEs. ApoE(-/-) mice displayed a 14% increase in plateau modulus compared with WT mice (P < 0.05), whereas HFD mice displayed a 13% decrease in plateau modulus (P < 0.05) and a 12% decrease in total modulus (P < 0.05) compared with ND mice. Tail tendons of HFD mice had significantly lower concentrations of AGEs [carboxymethyllysine (CML): 26%, P < 0.0001; methylglyoxal-derived hydroimidazolone 1 (MG-H1): 15%, P < 0.005; pentosidine: 13%, P < 0.0005]. The HFD had ∼44-fold lower content of CML (P < 0.01), ∼29-fold lower content of carboxyethyllysine (P < 0.005), and ∼16-fold lower content of MG-H1 (P < 0.05) compared with ND. ApoE(-/-) increased, whereas HFD decreased mouse tail tendon stiffness. Dietary AGE content may be a crucial determinant for accumulation of AGE cross-links in tendons and for tissue compliance. The results demonstrate how systemic metabolic factors may influence tendon health., (Copyright © 2014 the American Physiological Society.)

Background: Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise., Methods: 105 healthy individuals (18-35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 (STXBP5, rs1039084 and rs9399599), Syntaxin-2 (STX2, rs7978987) and VWF (promoter, rs7965413) were determined., Results: The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8-1.1] and increased with 47% [IQR 25-73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1-1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase., Conclusions: VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter.

Life-long regular endurance exercise is known to counteract the deterioration of cardiovascular and metabolic function and overall mortality. Yet it remains unknown if life-long regular endurance exercise can influence the connective tissue accumulation of advanced glycation endproducts (AGEs) that is associated with aging and lifestyle-related diseases. We therefore examined two groups of healthy elderly men: 15 master athletes (64 ± 4 years) who had been engaged in life-long endurance running and 12 old untrained (66 ± 4 years) together with two groups of healthy young men; ten young athletes matched for running distance (26 ± 4 years), and 12 young untrained (24 ± 3 years). AGE cross-links (pentosidine) of the patellar tendon were measured biochemically, and in the skin, it was assessed by a fluorometric method. In addition, we determined mechanical properties and microstructure of the patellar tendon. Life-long regular endurance runners (master athletes) had a 21 % lower AGE cross-link density compared to old untrained. Furthermore, both master athletes and young athletes displayed a thicker patellar tendon. These cross-sectional data suggest that life-long regular endurance running can partly counteract the aging process in connective tissue by reducing age-related accumulation of AGEs. This may not only benefit skin and tendon but also other long-lived protein tissues in the body. Furthermore, it appears that endurance running yields tendon tissue hypertrophy that may serve to lower the stress on the tendon and thereby reduce the risk of injury.

This study assesses femoral neck shortening and its effect on gait pattern and muscle strength in patients with femoral neck fractures treated with internal fixation. Seventy-six patients from a multicenter randomized controlled trial participated. Patient characteristics and Short Form 12 and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were collected. Femoral neck shortening, gait parameters, and maximum isometric forces of the hip muscles were measured and differences between the fractured and contralateral leg were calculated. Variables of patients with little or no shortening, moderate shortening, and severe shortening were compared using univariate and multivariate analyses. Median femoral neck shortening was 1.1 cm. Subtle changes in gait pattern, reduced gait velocity, and reduced abductor muscle strength were observed. Age, weight, and Pauwels classification were risk factors for femoral neck shortening. Femoral neck shortening decreased gait velocity and seemed to impair gait symmetry and physical functioning. In conclusion, internal fixation of femoral neck fractures results in permanent physical limitations. The relatively young and healthy patients in our study seem capable of compensating. Attention should be paid to femoral neck shortening and proper correction with a heel lift, as inadequate correction may cause physical complaints and influence outcome., (Copyright 2013, SLACK Incorporated.)

Context: Conflicting data exist on mitochondrial function and physical activity in type 2 diabetes mellitus (T2DM) development., Objective: The aim was to assess mitochondrial function at different stages during T2DM development in combination with physical exercise in longstanding T2DM patients., Design and Methods: We performed cross-sectional analysis of skeletal muscle from 12 prediabetic 11 longstanding T2DM male subjects and 12 male controls matched by age and body mass index., Intervention: One-year intrasubject controlled supervised exercise training intervention was done in longstanding T2DM patients., Main Outcome Measurements: Extensive ex vivo analyses of mitochondrial quality, quantity, and function were collected and combined with global gene expression analysis and in vivo ATP production capacity after 1 yr of training., Results: Mitochondrial density, complex I activity, and the expression of Krebs cycle and oxidative phosphorylation system-related genes were lower in longstanding T2DM subjects but not in prediabetic subjects compared with controls. This indicated a reduced capacity to generate ATP in longstanding T2DM patients only. Gene expression analysis in prediabetic subjects suggested a switch from carbohydrate toward lipid as an energy source. One year of exercise training raised in vivo skeletal muscle ATP production capacity by 21 ± 2% with an increased trend in mitochondrial density and complex I activity. In addition, expression levels of β-oxidation, Krebs cycle, and oxidative phosphorylation system-related genes were higher after exercise training., Conclusions: Mitochondrial dysfunction is apparent only in inactive longstanding T2DM patients, which suggests that mitochondrial function and insulin resistance do not depend on each other. Prolonged exercise training can, at least partly, reverse the mitochondrial impairments associated with the longstanding diabetic state.

Lack of physical activity has been related to an increased risk of developing insulin resistance. This study aimed to assess the impact of chronic muscle deconditioning on whole body insulin sensitivity, muscle oxidative capacity, and intramyocellular lipid (IMCL) content in subjects with paraplegia. Nine subjects with paraplegia and nine able-bodied, lean controls were recruited. An oral glucose tolerance test was performed to assess whole body insulin sensitivity. IMCL content was determined both in vivo and in vitro using (1)H-magnetic resonance spectroscopy and fluorescence microscopy, respectively. Muscle biopsy samples were stained for succinate dehydrogenase (SDH) activity to measure muscle fiber oxidative capacity. Subcellular distributions of IMCL and SDH activity were determined by defining subsarcolemmal and intermyofibrillar areas on histological samples. SDH activity was 57 ± 14% lower in muscle fibers derived from subjects with paraplegia when compared with controls (P < 0.05), but IMCL content and whole body insulin sensitivity did not differ between groups. In muscle fibers taken from controls, both SDH activity and IMCL content were higher in the subsarcolemmal region than in the intermyofibrillar area. This typical subcellular SDH and IMCL distribution pattern was lost in muscle fibers collected from subjects with paraplegia and had changed toward a more uniform distribution. In conclusion, the lower metabolic demand in deconditioned muscle of subjects with paraplegia results in a significant decline in muscle fiber oxidative capacity and is accompanied by changes in the subcellular distribution patterns of SDH activity and IMCL. However, loss of muscle activity due to paraplegia is not associated with substantial lipid accumulation in skeletal muscle tissue.

Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity.

Objective: Evaluate the efficacy of protein hydrolysate co-ingestion as a dietary strategy to improve blood glucose homeostasis under free-living conditions in long-standing type 2 diabetes patients., Methods: A total of 13 type 2 diabetes patients were enrolled in a randomized, double-blind cross-over design and studied on two occasions for 40 h under strict dietary standardization but otherwise normal, free-living conditions. In one trial, subjects ingested a protein hydrolysate (0.4 g kg(-1) bw casein hydrolysate, PRO) with every main meal. In the other trial, a placebo was ingested (PLA). Blood glucose concentrations were assessed by continuous glucose monitoring., Results: Average 24 h glucose concentrations were similar between the PLA and the PRO trials (8.9 +/- 0.8 vs 9.2 +/- 0.7 mmol l(-1), respectively). Hyperglycemia (glucose concentrations >10 mmol l(-1)) was experienced 34 +/- 9% of the time (8 +/- 2 h per 24 h) in the PLA trial. Protein hydrolysate co-ingestion with each main meal (PRO) did not reduce the prevalence of hyperglycemia (39 +/- 10%, 9 +/- 2 h per 24 h; P=0.2)., Conclusion: Co-ingestion of a protein hydrolysate with each main meal does not improve glucose homeostasis over a 24 h period in long-standing type 2 diabetes patients.

Aims/hypothesis: The 5'-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients., Methods: Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg(-1) min(-1)) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 +/- 2 years; BMI 28 +/- 1 kg/m(2))., Results: Plasma glucose rate of appearance (R (a)) was reduced following AICAR administration, while plasma glucose rate of disappearance (R (d)) was similar in the AICAR and control test. Consequently, blood glucose disposal (R (d) expressed as a percentage of R (a)) was increased following AICAR infusion (p < 0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p < 0.001). Plasma NEFA R (a) and R (d) were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p < 0.001)., Conclusions/interpretation: The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.

Aims/hypothesis: Structured exercise is considered a cornerstone in type 2 diabetes treatment. However, adherence to combined resistance and endurance type exercise or medical fitness intervention programmes is generally poor. Group-based brisk walking may represent an attractive alternative, but its long-term efficacy as compared with an individualised approach such as medical fitness intervention programmes is unknown. We compared the clinical benefits of a 12-month exercise intervention programme consisting of either brisk walking or a medical fitness programme in type 2 diabetes patients., Methods: We randomised 92 type 2 diabetes patients (60 +/- 9 years old) to either three times a week of 60 min brisk walking (n = 49) or medical fitness programme (n = 43). Primary outcome was the difference in changes in HbA1c values at 12 months. Secondary outcomes were differences in changes in blood pressure, plasma lipid concentrations, insulin sensitivity, body composition, physical fitness, programme adherence rate and health-related quality of life., Results: After 12 months, 18 brisk walking and 19 medical fitness participants were still actively participating. In both programmes, 50 and 25% of the dropout was attributed to overuse injuries and lack of motivation, respectively. Intention-to-treat analyses showed no important differences between brisk walking and medical fitness programme in primary or secondary outcome variables., Conclusions/interpretation: The prescription of group-based brisk walking represents an equally effective intervention to modulate glycaemic control and cardiovascular risk profile in type 2 diabetes patients when compared with more individualised medical fitness programmes. Future exercise intervention programmes should anticipate the high attrition rate due to overuse injuries and motivation problems.

Objective: Several lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes., Methods: Ten long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using (31)P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel (1)H MRS., Results: IMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The(31)P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups., Conclusions: The finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes.

Regular exercise has been recommended for diabetes patients for many years; however, it is not widely used clinically. This may be because of high costs, lack of reimbursement, low compliance and/or absence of proper infrastructure. Alternatively, structured exercise therapy may be underutilised because current guidelines do not include detailed information on the preferred type and intensity of exercise that should be applied to maximise the benefits of exercise for different subgroups of patients with type 2 diabetes. Based on available evidence and our own clinical research experience this article proposes that exercise therapy in type 2 diabetes might be more effective if (1) cardiac rehabilitation programmes served as a model for 'pre-cardiac diabetes rehabilitation'; (2) resistance exercise were prescribed for sarcopenic or severely deconditioned type 2 diabetes patients; and (3) a multidisciplinary approach and continued exercise training under personal supervision became standard therapy. Nevertheless, more clinical research is warranted to establish the efficacy of an approach that takes into account type 2 diabetes subpopulations at different stages of the disease and with different levels of comorbidity.

Objective: To determine the feasibility and the benefits of combined resistance and interval exercise training on phenotype characteristics and skeletal muscle function in deconditioned, type 2 diabetes (T2D) patients with polyneuropathy., Design: Short-term, single-arm intervention trial., Methods: Eleven male T2D patients (age: 59.1+/-7.5 years; body mass index: 32.2+/-4.0 kg/m2) performed progressive resistance and interval exercise training thrice a week for 10 weeks. Besides primary diabetes outcome measures, muscle strength (MUST), maximal workload capacity (Wmax), whole-body peak oxygen uptake (VO2peak) and muscle oxidative capacity (MUOX), intramyocellular lipid (IMCL) and glycogen (IMCG) storage, and systemic inflammation markers were determined before and after training. Daily exogenous insulin requirements (EIR) and historic individualized EIR were gathered and analysed., Results: MUST and Wmax increased with 17% (90% confidence intervals 9-24%) and 14% (6-21) respectively. Furthermore, mean arterial blood pressure declined with 5.5 mmHg (-9.7 to -1.4). EIR dropped with 5.0 IU/d (-11.5 to 1.5) compared with baseline. A decline of respectively -0.7 mmol/l (-2.9 to 1.5) and -147 micromol/l (-296 to 2) in fasting plasma glucose and non-esterified fatty acids concentrations were observed following the intervention, but these were not accompanied by changes in VO2peak, MUOX, IMCL or IMCG, and blood glycolysated haemoglobin, adiponectin, tumor necrosis factor-alpha and/or cholesterol concentrations., Conclusion: Short-term resistance and interval exercise training is feasible in deconditioned T2D patients with polyneuropathy and accompanied by moderate improvements in muscle function and blood pressure. Such a specific exercise regimen may provide a better framework for future exercise intervention programmes in the treatment of deconditioned T2D patients.

Other than diet and medication, exercise is considered one of the three cornerstones of good diabetes treatment. Nevertheless, current clinical guidelines on Type 2 diabetes provide no detailed information on the modalities of effective exercise intervention in the treatment of Type 2 diabetes. Based on a review of currently available literature, exercise modalities are being identified to maximize the benefits of exercise intervention in the treatment of different Type 2 diabetes subpopulations. Both endurance and resistance types of exercise have equal therapeutic strength to improve metabolic control in patients with Type 2 diabetes. When applying endurance-type exercise, energy expenditure should be equivalent to approximately 1.7-2.1 MJ/exercise bout on 3 but preferably 5 days/wk. In sarcopenic or severely deconditioned patients with Type 2 diabetes, focus should lie on the implementation of resistance-type exercise to attenuate and/or reverse the decline in skeletal muscle mass and strength. Before choosing the most appropriate exercise modalities, the patient's disease stage should be well characterized, and an ECG-stress test should be considered. Based on baseline aerobic fitness, level of co-morbidities, body composition, and muscle strength, patients should be provided with an individually tailored exercise intervention program to optimize therapeutic value. A multidisciplinary individualized approach and continued exercise training under personal supervision is essential to enhance compliance and allow long-term health benefits of an exercise intervention program.

Introduction: The impact of exercise on blood glucose homeostasis has not been assessed in long-standing type 2 diabetes patients receiving exogenous insulin treatment., Purpose: To study the effects of an acute bout of exercise on the subsequent 24-h blood glucose excursions under free-living conditions in insulin-treated type 2 diabetes patients., Methods: Eleven male type 2 diabetes patients (59 +/- 2 yr) performed an acute bout of exercise. One day before the exercise bout, a continuous glucose monitoring system (GlucoDay, A. Menarini Diagnostics) was inserted subcutaneously in the periumbilical region. The glucose sensor continuously measured glucose concentrations in the dialysate during a 48-h period., Results: The prevalence of hyperglycemic glucose excursions was reduced by 39% during a 24-h period (equivalent to 3 h) after an acute bout of exercise (P < 0.05). Average glucose concentrations 24 h before and after the exercise bout did not differ (NS). Mean dialysate glucose concentrations and the prevalence of hyperglycemic periods correlated strongly with baseline blood HbA1c concentrations (Pearson's R = 0.69, P < 0.05)., Conclusion: An acute bout of exercise effectively reduces the prevalence of hyperglycemia during a 24-h period under free-living conditions in long-standing type 2 diabetes patients on exogenous insulin therapy.

Background: Skeletal muscle mitochondrial function in type 2 diabetes (T2D) is currently being studied intensively. In vivo (31)P magnetic resonance spectroscopy ((31)P MRS) is a noninvasive tool used to measure mitochondrial respiratory function (MIFU) in skeletal muscle tissue. However, microvascular co-morbidity in long-standing T2D can interfere with the (31)P MRS methodology., Aim: To compare (31)P MRS-derived parameters describing in vivo MIFU with an in vitro assessment of muscle respiratory capacity and muscle fiber-type composition in T2D patients., Methods: (31)P MRS was applied in long-standing, insulin-treated T2D patients. (31)P MRS markers of MIFU were measured in the M. vastus lateralis. Muscle biopsy samples were collected from the same muscle and analyzed for succinate dehydrogenase activity (SDH) and fiber-type distribution., Results: Several (31)P MRS parameters of MIFU showed moderate to good correlations with the percentage of type I fibers and type I fiber-specific SDH activity (Pearson's R between 0.70 and 0.75). In vivo and in vitro parameters of local mitochondrial respiration also correlated well with whole-body fitness levels (VO (2peak)) in these patients (Pearson's R between 0.62 and 0.90)., Conclusion: Good correlations exist between in vivo and in vitro measurements of MIFU in long-standing insulin-treated T2D subjects, which are qualitatively and quantitatively consistent with previous results measured in healthy subjects. This justifies the use of (31)P MRS to measure MIFU in relation to T2D.

The aim of the present study was to assess the level of glycaemic control by the measurement of 24 h blood glucose profiles and standard blood analyses under identical nutritional and physical activity conditions in patients with Type II diabetes and healthy normoglycaemic controls. A total of 11 male patients with Type II diabetes and 11 healthy matched controls participated in a 24 h CGMS (continuous subcutaneous glucose-monitoring system) assessment trial under strictly standardized dietary and physical activity conditions. In addition, fasting plasma glucose, insulin and HbA(1c) (glycated haemoglobin) concentrations were measured, and an OGTT (oral glucose tolerance test) was performed to calculate indices of whole-body insulin sensitivity, oral glucose tolerance and/or glycaemic control. In the healthy control group, hyperglycaemia (blood glucose concentration >10 mmol/l) was hardly present (2+/-1% or 0.4+/-0.2/24 h). However, in the patients with Type II diabetes, hyperglycaemia was experienced for as much as 55+/-7% of the time (13+/-2 h over 24 h) while using the same standardized diet. Breakfast-related hyperglycaemia contributed most (46+/-7%; P<0.01 as determined by ANOVA) to the total amount of hyperglycaemia and postprandial glycaemic instability. In the diabetes patients, blood HbA(1c) content correlated well with the duration of hyperglycaemia and the postprandial glucose responses (P<0.05). In conclusion, CGMS determinations show that standard measurements of glycaemic control underestimate the amount of hyperglycaemia prevalent during real-life conditions in Type II diabetes. Given the macro- and micro-vascular damage caused by postprandial hyperglycaemia, CGMS provides an excellent tool to evaluate alternative therapeutic strategies to reduce hyperglycaemic blood glucose excursions.

Objective: The aim of this study was to investigate the effect of shoe design on the plantar pressure dynamics of patients with diabetic neuropathy during walking., Research Design and Methods: Three shoe design categories were tested. Total contact area and biomechanical variables in multiple areas under the foot were measured., Results: Shoes with a rocker bottom principle reduced pressure 35-65% underneath the heel and the central metatarsal heads. Increased contact area did not result in significant pressure reductions underneath the forefoot. Pressure dynamics underneath the heel and medial forefoot (first metatarsal head and hallux) on average showed no significant differences among the different shoes with a cushioning insole., Conclusions: The most effective way to offload the forefoot of patients with neuropathic feet is through the use of the rocker sole principle. In general, the effect of an insole depends on the design characteristics of a shoe. Predicting the effect of therapeutic footwear on an individual scale, however, remains difficult. Therefore, in-shoe pressure measurements seem to be necessary to evaluate a therapeutic shoe prescription in certain individual cases.

The control of the ground reaction force vector relative to the center of gravity (CoG) was examined while subjects performed a back-lifting task. Six male subjects (aged 24.0 +/- 2.5 years) repeatedly lifted a barbell. A biomechanical analysis that used a linked segment model revealed that the summed rotations of body segments during lifting yielded a specific rate of change of the angular momentum of the entire body. This equaled the external moment provided by Fsubg; relative to CoG. This implies that multisegment movements involve control of the angular momentum of the entire body through an appropriately directed Fsubg;. Thus, in dynamic tasks Fsubg; is pointed away from rather than lined up with the CoG, as is the case in static tasks.