Stephan F. E. Praet

Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction

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.

Exercise therapy in Type 2 diabetes

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.

Physical Activity Is the Key Determinant of Skeletal Muscle Mitochondrial Function in Type 2 Diabetes

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.

Long-standing, insulin-treated type 2 diabetes patients with complications respond well to short-term resistance and interval exercise training

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.

Glycaemic instability is an underestimated problem in Type II diabetes

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.

Exercise: the brittle cornerstone of type 2 diabetes treatment

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.

Femoral neck shortening after internal fixation of a femoral neck fracture.

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.

Postprandial hyperglycemia is highly prevalent throughout the day in type 2 diabetes patients

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±1 mmol/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 >10 mmol/L) 38±4% of the day. Even diabetes patients with an HbA(1c) level below 7.0% (53 mmol/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% (53 mmol/mol). Standard medical care with prescription of oral blood glucose lowering medication does not provide ample protection against postprandial hyperglycemia.

31P MR spectroscopy and in vitro markers of oxidative capacity in type 2 diabetes patients.

AbstractBackground: Skeletal muscle mitochondrial function in type 2 diabetes (T2D) is currently being studied intensively. In vivo 31P magnetic resonance spectroscopy (31P 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 31P MRS methodology. Aim: To compare 31P 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: 31P MRS was applied in long-standing, insulin-treated T2D patients. 31P 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 31P 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 (VO2peak) 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 31P MRS to measure MIFU in relation to T2D.

Protein hydrolysate co-ingestion does not modulate 24 h glycemic control in long-standing type 2 diabetes patients

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.