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Item does not contain fulltext Treatment with tyrosine kinase inhibitors (TKIs), especially nilotinib, often results in hyperglycemia, which may further increase cardiovascular disease risk in patients with chronic myeloid leukemia (CML). The mechanism underlying the TKI-induced glucose dysregulation is not clear. TKIs are suggested to affect insulin secretion but also insulin sensitivity of peripheral tissue has been proposed to play a role in the pathogenesis of TKI-induced hyperglycemia. Here, we aimed to assess whether skeletal muscle glucose uptake and insulin responses are altered in nondiabetic patients with CML receiving TKI treatment. After a glycogen-depleted exercise bout, an intravenous glucose bolus (0.3 g/kg body weight) was administered to monitor 2-h glucose tolerance and insulin response in 14 patients with CML receiving nilotinib, 14 patients with CML receiving imatinib, and 14 non-CML age- and gender-matched controls. A dynamic [(18)F]-FDG PET scan during a hyperinsulinemic-euglycemic clamp was performed in a subgroup of 12 male patients with CML to assess m. quadriceps glucose uptake. We showed that patients with CML treated with nilotinib have an increased insulin response to intravenous glucose administration after muscle glycogen-depleted exercise. Despite the increased insulin response to glucose administration in patients with CML receiving nilotinib, glucose disappearance rates were significantly slower in nilotinib-treated patients when compared with controls in the first 15 min after glucose administration. Although [(18)F]-FDG uptake in m. quadriceps was not different, patients receiving nilotinib showed a trend toward decreased glucose infusion rates during euglycemic clamping when compared with patients receiving imatinib. Together, these findings indicate disturbed skeletal muscle glucose handling in patients with CML receiving nilotinib therapy.NEW & NOTEWORTHY In this study, we have shown that non-diabetic patients with CML receiving nilotinib therapy show early signs of disturbed skeletal muscle glucose handling, which was not observed in imatinib-treated patients. These observations in nilotinib users may reflect decreased muscle insulin sensitivity, which could serve as a potential target to counteract glycemic dysregulation, and is of clinical importance since these patients have an increased cardiovascular disease risk.

Item does not contain fulltext BACKGROUND: Statin use may exacerbate exercise-induced skeletal muscle injury caused by reduced coenzyme Q10 (CoQ10) levels, which are postulated to produce mitochondrial dysfunction. OBJECTIVES: We determined the effect of prolonged moderate-intensity exercise on markers of muscle injury in statin users with and without statin-associated muscle symptoms. We also examined the association between leukocyte CoQ10 levels and muscle markers, muscle performance, and reported muscle symptoms. METHODS: Symptomatic (n = 35; age 62 ± 7 years) and asymptomatic statin users (n = 34; age 66 ± 7 years) and control subjects (n = 31; age 66 ± 5 years) walked 30, 40, or 50 km/d for 4 consecutive days. Muscle injury markers (lactate dehydrogenase, creatine kinase, myoglobin, cardiac troponin I, and N-terminal pro-brain natriuretic peptide), muscle performance, and reported muscle symptoms were assessed at baseline and after exercise. Leukocyte CoQ10 was measured at baseline. RESULTS: All muscle injury markers were comparable at baseline (P > 0.05) and increased following exercise (P 0.05). Muscle pain scores were higher at baseline in symptomatic statin users (P < 0.001) and increased similarly in all groups following exercise (P < 0.001). Muscle relaxation time increased more in symptomatic statin users than in control subjects following exercise (P = 0.035). CoQ10 levels did not differ among symptomatic (2.3 nmol/U; IQR: 1.8-2.9 nmol/U), asymptomatic statin users (2.1 nmol/U; IQR: 1.8-2.5 nmol/U), and control subjects (2.1 nmol/U; IQR: 1.8-2.3 nmol/U; P = 0.20), and did not relate to muscle injury markers, fatigue resistance, or reported muscle symptoms. CONCLUSIONS: Statin use and the presence of statin-associated muscle symptoms does not exacerbate exercise-induced muscle injury after moderate exercise. Muscle injury markers were not related to leukocyte CoQ10 levels. (Exercise-induced Muscle Damage in Statin Users; NCT05011643).

BACKGROUND The combination of statin therapy and physical activity reduces cardiovascular disease risk in patients with hyperlipidemia more than either treatment alone. However, mitochondrial dysfunction associated with statin treatment could attenuate training adaptations. OBJECTIVES This study determined whether moderate intensity exercise training improved muscle and exercise performance, muscle mitochondrial function, and fiber capillarization in symptomatic and asymptomatic statin users. METHODS Symptomatic (n = 16; age 64 +/- 4 years) and asymptomatic statin users (n = 16; age 64 +/- 4 years) and nonstatin using control subjects (n = 20; age 63 +/- 5 years) completed a 12-week endurance and resistance exercise training program. Maximal exercise performance (peak oxygen consumption), muscle performance and muscle symptoms were determined before and after training. Muscle biopsies were collected to assess citrate synthase activity, adenosine triphosphate (ATP) production capacity, muscle fiber type distribution, fiber size, and capillarization. RESULTS Type I muscle fibers were less prevalent in symptomatic statin users than control subjects at baseline (P = 0.06). Exercise training improved muscle strength (P < 0.001), resistance to fatigue (P = 0.01), and muscle fiber capillarization (P < 0.01), with no differences between groups. Exercise training improved citrate synthase activity in the total group (P < 0.01), with asymptomatic statin users showing less improvement than control subjects (P = 0.02). Peak oxygen consumption, ATP production capacity, fiber size, and muscle symptoms remained unchanged in all groups following training. Quality-of-life scores improved only in symptomatic statin users following exercise training (P < 0.01). CONCLUSIONS A moderate intensity endurance and resistance exercise training program improves muscle performance, capillarization, and mitochondrial content in both asymptomatic and symptomatic statin users without exacerbating muscle complaints. Exercise training may even increase quality of life in symptomatic statin users. (The Effects of Cholesterol-Lowering Medication on Exercise Performance [STATEX]; NL5972/NTR6346) (J Am Coll Cardiol 2021;78:2023-2037) (c) 2021 by the American College of Cardiology Foundation.

In non‐athletes, insulin sensitivity correlates negatively with intramyocellular lipid (IMCL) content. In athletes, however, a pattern of benign IMCL storage exists, which is characterized by lipid storage in type I muscle fibres, in small and numerous lipid droplets (LDs) preferable coated with PLIN5, without affecting insulin sensitivity. Administration of resveratrol has been promoted for its beneficial effects on glucose homeostasis. We observed that 30 days of oral resveratrol administration (150 mg/day) in metabolically compromised individuals showed a 33% increase in IMCL (placebo vs. resveratrol; 0.86 ± 0.090 AU vs. 1.14 ± 0.11 AU, p = 0.003) without impeding insulin sensitivity. Thus, the aim of the present study was to examine if a resveratrol‐mediated increase in IMCL content, in metabolically compromised individuals, changes the LD phenotype towards the phenotype we previously observed in athletes. For this, we studied IMCL, LD number, LD size, subcellular distribution and PLIN5 coating in different fibre types using high‐resolution confocal microscopy. As proof of concept, we observed a 2.3‐fold increase (p = 0.038) in lipid accumulation after 48 h of resveratrol incubation in cultured human primary muscle cells. In vivo analysis showed that resveratrol‐induced increase in IMCL is predominantly in type I muscle fibres (placebo vs. resveratrol; 0.97 ± 0.16% vs. 1.26 ± 0.09%; p = 0.030) in both the subsarcolemmal (p = 0.016) and intermyofibrillar region (p = 0.026) and particularly in PLIN5‐coated LDs (p = 0.024). These data indicate that administration of resveratrol augments IMCL content in metabolically compromised individuals towards a LD phenotype that mimics an ‘athlete like phenotype’., Resveratrol increases IMCL in type I muscle fibers originating primarily from an increase in number of lipid droplets rather than size.

High-fitness individuals have been suggested to be at risk of a poor vitamin B2 (riboflavin) status due to a potentially higher vitamin B2 demand, as measured by the erythrocyte glutathione reductase (EGR) activation coefficient (EGRAC). Longer-term exercise interventions have been shown to result in a lower vitamin B2 status, but studies are contradictory. Short-term exercise effects potentially contribute to discrepancies between studies but have only been tested in limited study populations. This study investigated if vitamin B2 status, measured by EGRAC, is affected by a single exercise bout in females who differ in fitness levels, and that represents long-term physical activity. At baseline and overnight after a 60-min cycling bout at 70% V·O2peak, EGR activity and EGRAC were measured in 31 young female adults, divided into a high-fit (V·O2peak ≥ 47 mL/kg/min, N = 15) and low-fit (V·O2peak ≤ 37 mL/kg/min, N = 16) group. A single exercise bout significantly increased EGR activity in high-fit and low-fit females (Ptime = 0.006). This response was not affected by fitness level (Ptime*group = 0.256). The effect of exercise on EGRAC was not significant (Ptime = 0.079) and not influenced by EGR activity. The exercise response of EGRAC was not significantly different between high-fit and low-fit females (Ptime*group = 0.141). Thus, a single exercise bout increased EGR activity, but did not affect EGRAC, indicating that vitamin B2 status was not affected. The exercise response on EGRAC and EGR did not differ between high-fit and low-fit females.

Contains fulltext : 203382.pdf (Publisher’s version ) (Open Access) BACKGROUND: An inadequate protein intake may offset the muscle protein synthetic response after physical activity, reducing the possible benefits of an active lifestyle for muscle mass. We examined the effects of 12 weeks of daily protein supplementation on lean body mass, muscle strength, and physical performance in physically active older adults with a low habitual protein intake (

Purpose: Vitamin D deficiencies are common in elderly, which increases the risk for, e.g., bone fractures. Identification of determinants of vitamin D status may provide leads for specific deficiency prevention strategies. Although determinants of vitamin D status have been studied in various populations, this has not been examined in elderly that have a physically active lifestyle. Methods: Vitamin D status of 450 physically active elderly who do not use vitamin D supplements was determined and information on possible determinants (demographic, dietary intake and physical activity) was collected around a prolonged four day walking event in July and analyzed in linear regression models. Results: The average summertime serum 25(OH)D concentration was 88.8 ± 22.4 nmol/L. Only 2% of the participants had a 25(OH)D concentration below 50 nmol/L. Dietary intake of vitamin D was 4.0 ± 1.9 µg/day, and the participants spent 12.4 ± 8.6 h/week on outdoor activities. In the multivariate model, lower age (= − 0.48, 95% CI − 0.80 to − 0.16), lower BMI (= − 0.86, 95% CI − 1.62 to − 0.10), being a moderate to high drinker versus a non-drinker (= 7.97, 95% CI 0.43–15.51) and more outdoor physical activity (= 0.25, 95% CI 0.01–0.50) were significantly associated with higher 25(OH)D concentrations. Conclusions: In physically active elderly, vitamin D status was very high in summertime, with few deficiencies, suggesting that elderly with a physical active lifestyle might not necessarily need supplements during the summer period. Lower age, lower BMI, higher alcohol intake and more outdoor physical activity had a significant association with vitamin D status.

Item does not contain fulltext Ischemic preconditioning (IPC) may enhance exercise performance. Cardioprotective effects of IPC are known to re-occur 24h after the stimulus. Whether the delayed effect of IPC has similar effects as IPC on exercise performance is unknown. OBJECTIVES: Examine whether IPC applied 24h (24-IPC) before exercise is equally effective as IPC in improving exercise performance. DESIGN: Randomized, cross-over study METHODS: 12 healthy participants were randomly exposed to SHAM-session, IPC or 24-IPC before a self-paced 5km running trial on a treadmill. Subjects were blinded for time, speed and heart rate. Furthermore, heart rate, BORG, and the local tissue saturation index were measured during exercise, while lactate levels were determined after running. Using a regression model, we explored whether these parameters predicted the change in running time after IPC and 24-IPC. RESULTS: We found no differences in finish time after IPC (SHAM: 1400+/-105s, IPC: 1381+/-112s, 24-IPC: 1385+/-113s; p=0.30). However, we observed a significant positive relation between the change in finish time after IPC and 24-IPC (p=0.016; r=0.677). Using stepwise linear regression, a lower post-exercise blood lactate level after IPC or 24-IPC was significantly related to an improvement in finish time (R2=0.47, beta=-0.687, p=0.007). CONCLUSIONS: Although no significant effect of IPC or 24-IPC on exercise performance was found, individual finish time after IPC and 24-IPC were strongly correlated. Therefore, our data suggest that, at the individual level, the effects of 24-IPC are closely related to the effects of IPC. 01 februari 2017

Contains fulltext : 225974.pdf (Publisher’s version ) (Open Access)

In this chapter we summarize the evidence for a central role of mitochondrial dysfunction in statin-associated muscle symptoms. Statin-related mitochondrial dysfunction can manifest itself in skeletal muscle by inducing a plethora of architectural and biochemical adaptations. Structural changes seen in biopsy specimens, including red ragged fibers, cytochrome oxidase-negative myofibers, and lipid-loaded vacuoles, are signs of mitochondrial respiratory chain dysfunction. Disturbances in mitochondrial energy metabolism are shown through increased lactate/pyruvate ratios, disruption of beta-oxidation, a decrease in mitochondrial DNA, and disturbances in electron transport chain complex activities. Apoptosis of myofibers may occur as a result of mitochondrial-mediated apoptosis and the formation of reactive oxygen species. Furthermore the role of coenzyme Q10 deficiency and disturbances in calcium homeostasis in relation to statin-induced mitochondrial dysfunction will be discussed.

Item does not contain fulltext Drugs are prescribed to manage or prevent symptoms and diseases, but may sometimes cause unexpected toxicity to muscles. The symptomatology and clinical manifestations of the myotoxic reaction can vary significantly between drugs and between patients on the same drug. This poses a challenge on how to recognize and prevent the occurrence of drug-induced muscle toxicity. The key to appropriate management of myotoxicity is prompt recognition that symptoms of patients may be drug related and to be aware that inter-individual differences in susceptibility to drug-induced toxicity exist. The most prevalent and well-documented drug class with unintended myotoxicity are the statins, but even today new classes of drugs with unintended myotoxicity are being discovered. This review will start off by explaining the principles of drug-induced myotoxicity and the different terminologies used to distinguish between grades of toxicity. The main part of the review will focus on the most important pathogenic mechanisms by which drugs can cause muscle toxicity, which will be exemplified by drugs with high risk of muscle toxicity. This will be done by providing information on key clinical and laboratory aspects, muscle electromyography patterns and biopsy results, and pathological mechanism and management for a specific drug from each pathogenic classification. In addition, rather new classes of drugs with unintended myotoxicity will be highlighted. Furthermore, we will explain why it is so difficult to diagnose drug-induced myotoxicity, and which tests can be used as a diagnostic aid. Lastly, a brief description will be given of how to manage and treat drug-induced myotoxicity.

Contains fulltext : 182222.pdf (Publisher’s version ) (Open Access) BACKGROUND: HMG-CoA reductase inhibitors (statins) are the first-choice therapy for primary prevention of cardiovascular disease. Some maintain that statins cause adverse musculoskeletal outcomes in highly active individuals, but few studies have examined the effects of statins on exercise-related injuries. OBJECTIVE: We sought to compare the prevalence of exercise-related injuries between runners who do or do not use statins. METHODS: Amateur runners (n = 4460) completed an extensive online questionnaire on their exercise patterns and health status. Participants replied to questions on the prevalence of exercise-related injuries in the previous year. Injuries were divided into general injuries, tendon- and ligament-related injuries, and muscle-related injuries. Participants were also queried about statin use: the type of statin, statin dose, and duration of treatment. Runners were divided into statin users, non-statin users with hypercholesterolemia, and controls for analysis. RESULTS: The crude odds ratios (ORs) for injuries, tendon- or ligament-related injuries, and muscle-related injuries in statin users compared with controls were 1.14 (95% confidence interval [CI] 0.79-1.66), 1.10 (95% CI 0.71-1.72), and 1.15 (95% CI 0.69-1.91), respectively. After adjustment for age, sex, body mass index (BMI), and metabolic equivalent of task (MET) h/week of exercise, the ORs were 1.11 (95% CI 0.76-1.62), 1.06 (95% CI 0.68-1.66), and 0.98 (95% CI 0.58-1.64), respectively. Similar effect measures were found when comparing non-statin users with hypercholesterolemia and controls. CONCLUSION: We did not find an association between statin use and the prevalence of exercise-related injuries or tendon-, ligament-, and muscle-related injuries. Runners receiving statins should continue normal physical activity without concern for increased risk of injuries.

Contains fulltext : 208380.pdf (Publisher’s version ) (Open Access)

OBJECTIVE To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of standard diabetes care. RESEARCH DESIGN AND METHODS Seventeen subjects with well-controlled type 2 diabetes (T2D) were treated with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique. RESULTS Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels (R = −0.68, P = 0.03). Intramyocellular lipid content increased in type 2 muscle fibers (P = 0.03), and systolic blood pressure tended to decrease (P = 0.09) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function (state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol (dihydroresveratrol) and the metformin dose used by the patients (R = 0.66, P = 0.005), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction. CONCLUSIONS Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes.

Contains fulltext : 153881.pdf (Publisher’s version ) (Closed access) There is an increasing need for novel preventive and therapeutic strategies to combat obesity and related metabolic disorders. In this respect, the natural polyphenol resveratrol has attracted significant interest. Animal studies indicate that resveratrol mimics the effects of calorie restriction via activation of sirtuin 1 (SIRT1). SIRT1 is an important player in the regulation of cellular energy homeostasis and mitochondrial biogenesis. Rodent studies have shown beneficial effects of resveratrol supplementation on mitochondrial function, glucose metabolism, body composition and liver fat accumulation. However, confirmation of these beneficial effects in humans by placebo-controlled clinical trials remains relatively limited. This review will give an overview of pre-clinical and clinical studies examining the effects of resveratrol on obesity-induced negative health outcomes. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. 01 juni 2015

Item does not contain fulltext Polyphenolic compounds, such as resveratrol, have recently received widespread interest because of their ability to mimic effects of calorie restriction. The objective of the present study was to gain more insight into the effects of 30 days resveratrol supplementation on adipose tissue morphology and underlying processes. Eleven healthy obese men were supplemented with placebo and resveratrol for 30 days (150 mg per day), separated by a 4-week washout period in a double-blind randomized crossover design. A postprandial abdominal subcutaneous adipose tissue biopsy was collected to assess adipose tissue morphology and gene expression using microarray analysis. Resveratrol significantly decreased adipocyte size, with a shift toward a reduction in the proportion of large and very-large adipocytes and an increase in small adipocytes. Microarray analysis revealed downregulation of Wnt and Notch signaling pathways and upregulation of pathways involved in cell cycle regulation after resveratrol supplementation, suggesting enhanced adipogenesis. Furthermore, lysosomal/phagosomal pathway and transcription factor EB were upregulated reflecting an alternative pathway of lipid breakdown by autophagy. Further research is necessary to investigate whether resveratrol improves adipose tissue function. 01 maart 2014

The number of people suffering from metabolic disorders is dramatically increasing worldwide. The need for new therapeutic strategies to combat this growing epidemic of metabolic diseases is therefore also increasing. In 2003, resveratrol was discovered to be a small molecule activator of sirtuin 1 (SIRT1), an important molecular target regulating cellular energy metabolism and mitochondrial homeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. To date, however, only limited clinical data are available that have systematically examined the health benefits of resveratrol in metabolically challenged humans. This short review will give an overview of the currently available clinical studies examining the effects of resveratrol on obesity and type 2 diabetes from a human perspective.

Context: Statin myopathy is linked to disturbances in mitochondrial function and exercise intolerance. Objectives: To determine whether differences exist in exercise performance, muscle function, and muscle mitochondrial oxidative capacity and content between symptomatic and asymptomatic statin users, and control subjects. Design: Cross-sectional study. Setting: Department of Physiology, Radboud University Medical Center. Participants: Long-term symptomatic and asymptomatic statin users, and control subjects (n = 10 per group). Interventions: Maximal incremental cycling tests, involuntary electrically stimulated isometric quadriceps-muscle contractions, and biopsy of vastus lateralis muscle. Main Outcomes Measured: Maximal exercise capacity, substrate use during exercise, muscle function, and mitochondrial energy metabolism. Results: Peak oxygen uptake, maximal work load, and ventilatory efficiency were comparable between groups, but both statin groups had a depressed anaerobic threshold compared with the control group (P = 0.01). Muscle relaxation time was prolonged in both statin groups compared with the control group and rate of maximal force rise was decreased (Ptime3group , 0.001 for both measures). Mitochondrial activity of complexes II and IV was lower in symptomatic statin users than control subjects and tended to be lower for complex (C) III (CII: P = 0.03; CIII: P = 0.05; CIV: P = 0.04). Mitochondrial content tended to be lower in both statin groups than in control subjects. Conclusion: Statin use attenuated substrate use during maximal exercise performance, induced muscle fatigue during repeated muscle contractions, and decreased muscle mitochondrial oxidative capacity. This suggests disturbances in mitochondrial oxidative capacity occur with statin use even in patients without statin-induced muscle complaints.

Background: The obese insulin-resistant state is characterized by impairments in lipid metabolism.We previously showed that 3-d supplementation of combined epigallocatechin-3-gallate and resveratrol (EGCG+RES) increased energy expenditure and improved the capacity to switch from fat toward carbohydrate oxidation with a high-fat mixed meal (HFMM) test in men. Objective: The present study aimed to investigate the longer-term effect of EGCG+RES supplementation on metabolic profile, mitochondrial capacity, fat oxidation, lipolysis, and tissue-specific insulin sensitivity. Design: In this randomized double-blind study, 38 overweight and obese subjects [18 men; aged 38 6 2 y; body mass index (kg/m2): 29.7 6 0.5] received either EGCG+RES (282 and 80 mg/d, respectively) or placebo for 12 wk. Before and after the intervention, oxidative capacity and gene expression were assessed in skeletal muscle. Fasting and postprandial (HFMM) lipid metabolism was assessed by using indirect calorimetry, blood sampling, and microdialysis. Tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with [6,6-2H2]-glucose infusion. Results: EGCG+RES supplementation did not affect the fasting plasma metabolic profile. Although whole-body fat mass was not affected, visceral adipose tissue mass tended to decrease after the intervention compared with placebo (P-time 3 treatment = 0.09). EGCG+RES supplementation significantly increased oxidative capacity in permeabilized muscle fibers (P-time 3 treatment , 0.05, P-EGCG+RES , 0.05). Moreover, EGCG+RES reduced fasting (P-time 3 treatment = 0.03) and postprandial respiratory quotient (P-time 3 treatment = 0.01) compared with placebo. Fasting and postprandial fat oxidation was not significantly affected by EGCG +RES (P-EGCG+RES = 0.46 and 0.38, respectively) but declined after placebo (P-placebo = 0.05 and 0.03, respectively). Energy expenditure was not altered (P-time 3 treatment = 0.96). Furthermore, EGCG+RES supplementation attenuated the increase in plasma triacylglycerol concentrations during the HFMM test that was observed after placebo (P-time 3 treatment = 0.04, P-placebo = 0.01). Finally, EGCG+RES had no effect on insulin-stimulated glucose disposal, suppression of endogenous glucose production, or lipolysis. Conclusion: Twelve weeks of EGCG+RES supplementation increased mitochondrial capacity and stimulated fat oxidation compared with placebo, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. This trial was registered at clinicaltrials.gov as NCT02381145. Am J Clin Nutr doi: 10.3945/ajcn.115.122937. Keywords: insulin sensitivity, mitochondrial capacity, obesity, polyphenols, resveratrol

A low fat oxidative capacity has been linked to muscle diacylglycerol (DAG) accumulation and insulin resistance. Alternatively, a low fat oxidation rate may stimulate glucose oxidation, thereby enhancing glucose disposal. Here, we investigated whether an ethyl-2-[6-(4-chlorophenoxy)hexyl]-oxirane-2-carboxylate (etomoxir)-induced inhibition of fat oxidation leads to muscle fat storage and insulin resistance. An intervention in healthy male subjects was combined with studies in human primary myotubes. Furthermore, muscle DAG and triacylglycerol (TAG), mitochondrial function, and insulin signaling were examined in etomoxir-treated C57bl6 mice. In humans, etomoxir administration increased glucose oxidation at the expense of fat oxidation. This effect was accompanied by an increased abundance of GLUT4 at the sarcolemma and a lowering of plasma glucose levels, indicative of improved glucose homeostasis. In mice, etomoxir injections resulted in accumulation of muscle TAG and DAG, yet improved insulin-stimulated GLUT4 translocation. Also in human myotubes, insulin signaling was improved by etomoxir, in the presence of increased intramyocellular lipid accumulation. These insulin-sensitizing effects in mice and human myotubes were accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK). Our results show that a reduction in fat oxidation leading to accumulation of muscle DAG does not necessarily lead to insulin resistance, as the reduction in fat oxidation may activate AMPK.

Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid (IMCL) storage exceeds intracellular needs and induces lipotoxic events, ultimately contributing to the development of insulin resistance. Lipid droplet (LD)–coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/adipose differentiation–related protein [ADRP]) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol (TAG) storage, marginally increased fatty-acid (FA) oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet–induced increase in protein content of the subunits of the oxidative phosphorylation (OXPHOS) chain. Diacylglycerol levels were unchanged, whereas ceramide levels were increased. Despite the increased IMCL accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs toward TAG storage in LDs, thereby blunting lipotoxicity-associated insulin resistance.

Failure of insulin to elicit an increase in glucose uptake and metabolism in target tissues such as skeletal muscle is a major characteristic of non-insulin dependent type 2 diabetes mellitus. A strong correlation between intramyocellular triacylglycerol concentrations and the severity of insulin resistance has been found and led to the assumption that lipid oversupply to skeletal muscle contributes to reduced insulin action. However, the molecular mechanism that links intramyocellular lipid content with the generation of muscle insulin resistance is still unclear. It appears unlikely that the neutral lipid metabolite triacylglycerol directly impairs insulin action. Hence it is believed that intermediates in fatty acid metabolism, such as fatty acyl-CoA, ceramides or diacylglycerol (DAG) link fat deposition in the muscle to compromised insulin signaling. DAG is identified as a potential mediator of lipid-induced insulin resistance, as increased DAG levels are associated with protein kinase C activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and PI3 kinase activity. As DAG is an intermediate in the synthesis of triacylglycerol from fatty acids and glycerol, its level can be lowered by either improving the oxidation of cellular fatty acids or by accelerating the incorporation of fatty acids into triacylglycerol. This review discusses the evidence that implicates DAG being central in the development of muscular insulin resistance. Furthermore, we will discuss if and how modulation of skeletal muscle DAG levels could function as a possible therapeutic target for the treatment of type 2 diabetes mellitus.

Contains fulltext : 171584.pdf (Publisher’s version ) (Open Access) Cell and animal studies have demonstrated that circadian rhythm is governed by autonomous rhythmicity of clock genes. Although disturbances in circadian rhythm have been implicated in metabolic disease development, it remains unknown whether muscle circadian rhythm is altered in human models of type 2 diabetes. Here we used human primary myotubes (HPM) to investigate if rhythmicity of clock- and metabolic gene expression is altered in donors with obesity or type 2 diabetes compared to metabolically healthy donors. HPM were obtained from skeletal muscle biopsies of four groups: type 2 diabetic patients and their BMI- and age-matched obese controls and from lean, healthy and young endurance trained athletes and their age-matched sedentary controls. HPM were differentiated for 7 days before synchronization by serum shock followed by gene expression profiling over the next 72 hours. HPM display robust circadian rhythms in clock genes, but REVERBA displayed dampened rhythmicity in type 2 diabetes. Furthermore, rhythmicity in NAMPT and SIRT1 expression was only observed in HPM from trained athletes. Rhythmicity in expression of key-regulators of carbohydrate and lipid metabolism was modest. We demonstrate that in human skeletal muscle REVERBA/B, NAMPT and SIRT1 circadian rhythms are affected in donors of sedentary life style and poor health status.

We investigated the effects of a single course of antenatal betamethasone on cognition- and anxiety-related behavior and synaptophysin and microtubule-associated protein 2 (MAP2) immunoreactivity in the adult rat hippocampus. On d 20 of gestation, pregnant rats were injected with either 1) 170 microg/kg body weight of betamethasone ("clinically equivalent dose," equivalent to 12 mg twice, 24 h apart); 2) half this dose; or 3) vehicle. Cognition- and anxiety-related behavior of the offspring was analyzed at an age of 5 mo using the Morris water maze, object recognition task, and open field test. Subsequently, synaptophysin and MAP2 immunoreactivity were measured in the hippocampus. We report no detrimental effects of antenatal betamethasone on cognition- and anxiety-related behavior and synaptophysin immunoreactivity in the adult rat. On the other hand, MAP2 immunoreactivity was decreased by betamethasone in males, suggesting a permanent impairment in the hippocampus. Interestingly, the lower dose appears to have less influence in terms of growth restriction, known to be associated with an increased risk of disease in adulthood. Further research might elucidate whether the betamethasone effect on hippocampal neurons persists later in life and could affect the aging process increasing the risk for neuropathology of the adult.

Almost 80% of postprandial glucose uptake resides in skeletal muscle (1). Hence, development of skeletal muscle insulin resistance is a hallmark of type 2 diabetes. Muscle is an ambiguous organ with respect to substrate selection. To fuel muscle contraction, both glucose and fatty acids can be oxidized. Glucose first needs to enter the muscle cells via insulin-mediated GLUT4-dependent transmembrane transport and then be converted to acetyl-CoA via the pyruvate dehydrogenase (PDH) complex. Oxidation of fatty acids, especially long-chain fatty acids, requires mitochondrial entrance via carnitine palmitoyltransferase-1 (CPT-1) prior to subsequent β-oxidation. To explain the well-known relationship between obesity and type 2 diabetes, Sir Philip Randle (2) proposed in 1963 that high uptake of fatty acids in skeletal muscle resulting from high free fatty acid levels observed in obesity would result in high fatty acid oxidation rates (Fig. 1). In turn, this would reduce glucose oxidation, thereby rendering the muscle insulin resistant. At the cellular level, high rates of fatty acid oxidation would result in accumulation of acetyl-CoA and citrate, thereby inhibiting PDH and glycolysis, ultimately resulting in reduced glucose oxidation. However, in the previous 2 decades, the concept of the Randle cycle in skeletal muscle has been challenged. Elegant studies by Shulman and colleagues (3–5) showed that in type 2 diabetes, reduced uptake of glucose due to compromised GLUT4 translocation, not a reduced glycolytic flux, is the main culprit in development of skeletal muscle insulin resistance. Moreover, fat accumulation in muscle, and particularly accumulation of muscle diacylglycerol (DAG), was suggested to impair …

Item does not contain fulltext The number of people suffering from metabolic diseases is dramatically increasing worldwide. This stresses the need for new therapeutic strategies to combat this growing epidemic of metabolic diseases. A reduced mitochondrial function is one of the characteristics of metabolic diseases and therefore a target for intervention. Here we review the evidence that mitochondrial function may act as a target to treat and prevent type 2 diabetes mellitus, and, if so, whether these effects are due to reduction in skeletal muscle fat accumulation. We describe how exercise may affect these parameters and can be beneficial for type 2 diabetes. We next focus on alternative ways to improve mitochondrial function in a non-exercise manner. Thus, in 2003, resveratrol (3,5,4'-trihydroxystilbene) was discovered to be a small molecule activator of sirtuin 1, an important molecular target regulating cellular energy metabolism and mitochondrial homoeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. Here we review data in human subjects that is available on the effects of resveratrol on metabolism and mitochondrial function and discuss how resveratrol may serve as a new therapeutic strategy to preserve metabolic health. We also discuss whether the effects of resveratrol are similar to the effects of exercise training and therefore if resveratrol can be considered as an exercise mimetic. 01 mei 2014

Item does not contain fulltext We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.

The number of people suffering from metabolic disorders is dramatically increasing worldwide. The need for new therapeutic strategies to combat this growing epidemic of metabolic diseases is therefore also increasing. In 2003, resveratrol was discovered to be a small molecule activator of sirtuin 1 (SIRT1), an important molecular target regulating cellular energy metabolism and mitochondrial homeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. To date, however, only limited clinical data are available that have systematically examined the health benefits of resveratrol in metabolically challenged humans. This short review will give an overview of the currently available clinical studies examining the effects of resveratrol on obesity and type 2 diabetes from a human perspective.

AIMS: Resveratrol, a natural polyphenolic compound produced by various plants (e.g. red grapes) and found in red wine, has glucose-lowering effects in humans and rodent models of obesity and/or diabetes. The mechanisms behind these effects have been suggested to include resveratrol-induced secretion of the gut incretin hormone glucagon-like peptide-1. We investigated postprandial incretin hormone and glucagon responses in obese human subjects before and after 30 days of resveratrol supplementation. METHODS: Postprandial plasma responses of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide and glucagon were evaluated in 10 obese men [subjects characteristics (mean +/- standard error of the mean): age 52 +/- 2 years; BMI 32 +/- 1 kg/m2 , fasting plasma glucose 5.5 +/- 0.1 mmol/l] who had been given a dietary supplement of resveratrol (Resvida(R) 150 mg/day) or placebo for 30 days in a randomized, double-blind, crossover design with a 4-week washout period. At the end of each intervention period a standardized meal test (without co-administration of resveratrol) was performed. RESULTS: Resveratrol supplementation had no impact on fasting plasma concentrations or postprandial plasma responses (area under curve values) of glucose-dependent insulinotropic polypeptide (11.2 +/- 2.1 vs. 11.8 +/- 2.2 pmol/l, P = 0.87; 17.0 +/- 2.2 vs. 14.8 +/- 1.6 min x nmol/l, P = 0.20) or glucagon-like peptide-1 (15.4 +/- 1.0 vs. 15.2 +/- 0.9 pmol/l, P = 0.84; 5.6 +/- 0.4 vs. 5.7 +/- 0.3 min x nmol/l, P = 0.73). Resveratrol supplementation significantly suppressed postprandial glucagon responses (4.4 +/- 0.4 vs. 3.9 +/- 0.4 min x nmol/l, P = 0.01) without affecting fasting glucagon levels (15.2 +/- 2.2 vs. 14.5 +/- 1.5 pmol/l, P = 0.56). CONCLUSIONS: Our data suggest that 30 days of resveratrol supplementation does not affect fasting or postprandial incretin hormone plasma levels in obese humans, but suppresses postprandial glucagon responses. This article is protected by copyright. All rights reserved.

We appreciate the interest of Mendez-del Villar et al. (1) in our experimental work with resveratrol (2). It is true that we used a relatively low dose of resveratrol (150 mg/day) in our study, and we could not agree more that indeed more human clinical trials are needed before it can be concluded whether resveratrol can be beneficial for the treatment or prevention of type 2 diabetes. In such future studies, the working mechanism of resveratrol should be further investigated as well. On the basis of a long series of preclinical and clinical studies, we examined whether resveratrol could improve glucose homeostasis via the improvement of …

The natural polyphenolic compound resveratrol was first discovered in the 1940s. In the recent years, this compound received renewed interest as several findings implicated resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction, and regulating longevity in lower organisms. Given the worldwide increase in age-related metabolic diseases the beneficial effects of resveratrol on metabolism and healthy aging in humans are currently a topic of intense investigation.

Accumulation of triacylglycerols (TAGs) and acylcarnitines in skeletal muscle upon high-fat (HF) feeding is the resultant of fatty acid uptake and oxidation and is associated with insulin resistance. As medium-chain fatty acids (MCFAs) are preferentially beta-oxidized over long-chain fatty acids, we examined the effects of medium-chain TAGs (MCTs) and long-chain TAGs (LCTs) on muscle lipid storage and whole-body glucose tolerance. Rats fed a low-fat (LF), HFLCT, or an isocaloric HFMCT diet displayed a similar body weight gain over 8 weeks of treatment. Only HFLCT increased myocellular TAG (42.3 +/- 4.9, 71.9 +/- 6.7, and 48.5 +/- 6.5 micromol/g for LF, HFLCT, and HFMCT, respectively, P < 0.05) and long-chain acylcarnitine content (P < 0.05). Neither HF diet increased myocellular diacylglycerol (DAG) content. Intraperitoneal (IP) glucose tolerance tests (1.5 g/kg) revealed a significantly decreased glucose tolerance in the HFMCT compared to the HFLCT-fed rats (802 +/- 40, 772 +/- 18, and 886 +/- 18 area under the curve for LF, HFLCT, and HFMCT, respectively, P < 0.05). Finally, no differences in myocellular insulin signaling after bolus insulin injection (10 U/kg) were observed between LF, HFLCT, or HFMCT-fed rats. These results show that accumulation of TAGs and acylcarnitines in skeletal muscle in the absence of body weight gain do not impede myocellular insulin signaling or whole-body glucose intolerance.

Objective: In conditions of continuous high-fat (HF) intake, the degree of saturation of the fatty acids (FAs) in the diet might have a crucial role in the onset of obesity and its metabolic complications. In particular, the FA composition of the diet might influence the storage form of lipids inside skeletal muscle. The aim of the present study was to examine whether the FA composition of HF diets differentially affects weight gain and accumulation of myocellular triacylglycerol (TAG) and diacylglycerol (DAG). Furthermore, we examined whether the FA composition of the diet was reflected in the composition of the myocellular lipid intermediates. Design: C57Bl6 mice were fed HF diets (45% energy) mainly containing palm oil (PO), cocoa butter (CB), olive oil (OO) or safflower oil (SO; n=6 per group) for 8 weeks. A low-fat diet (10% energy, PO) was used as control. Body weight was monitored weekly. At the end of the dietary intervention, myocellular TAG and DAG content and profiles were measured. Results: We here show that HF_CB prevented weight gain after 8 weeks of HF feeding. Furthermore, the HF diet rich in SO prevented the accumulation of both myocellular TAG and DAG. Interestingly, the FA composition of DAG and TAG in skeletal muscle was a reflection of the dietary FA composition. Conclusion: Already after a relatively short period, the dietary FA intake relates to the FA composition of the lipid metabolites in the muscle. A diet rich in polyunsaturated FAs seems to prevent myocellular lipid accumulation.