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Zuccarelli L, De Martino M, Filippi A, Knapton A, Thackray B, Baldassarre G, Šimunič B, Pišot R, Sirago G, Monti E, Narici M, Isola M, Murray A, Lippe G, Grassi B. Mitochondrial Sensitivity to Submaximal [ADP] Following Bed Rest: A Novel Two-Phase Approach Associated With Fibre Types. J Cachexia Sarcopenia Muscle 2025; 16:e13775. [PMID: 40285367 PMCID: PMC12031883 DOI: 10.1002/jcsm.13775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/06/2025] [Accepted: 02/23/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND We recently demonstrated that following a 10-day exposure to inactivity/simulated microgravity impairments of oxidative metabolism were located 'upstream' of mitochondrial function, as evaluated by maximal ADP-stimulated mitochondrial respiration (JO2max) determined ex vivo. The aim of this study was to evaluate mitochondrial sensitivity to submaximal [ADP] by an alternative approach aimed at identifying responses associated with fibre type composition. METHODS Isolated permeabilized vastus lateralis fibres were analysed by high-resolution respirometry in 9 young males before and after a 10-day horizontal bed rest. Eleven submaximal titrations of ADP (from 12.5 to 10 000 μM) were utilized to assess complex I + II-linked ADP sensitivity. We applied to JO2 versus [ADP] data a traditional Michaelis-Menten kinetics equation, with the calculation of the apparent Km and maximal respiration (Vmax), and two 'sequential' hyperbolic equations, yielding two Km and Vmax values. The two-hyperbolic equations were solved and the [ADP] value corresponding to 50% of JO2max was calculated. Isoform expression of myosin heavy chains (MyHC) 1, 2A and 2X was also determined. Control experiments were also carried out on rat skeletal muscle samples with different percentages of MyHC isoforms. RESULTS The two hyperbolic equations provided an alternative fitting of data and identified two distinct phases of the JO2 versus [ADP] response: a first phase characterized by low Vmax (Vmax1, 28 ± 10 pmol s-1 mg-1) and apparent Km (Km1, 62 ± 54 μM) and a second phase characterized by higher Vmax (Vmax2, 61 ± 16 pmol s-1 mg-1) and Km (Km2, 1784 ± 833 μM). Data were confirmed in control experiments carried out in rat muscle samples with different percentages of MyHC isoforms. Correlation and receiver operating characteristics analyses suggest that the two phases of the response were related to the % of MyHC isoforms. CONCLUSIONS A novel mathematical approach (two sequential hyperbolic functions) for the fitting of JO2 versus [ADP] data obtained by high-resolution respirometry on permeabilized skeletal muscle fibres, obtained in humans and rats, provided an alternative fitting of the experimental data compared to the traditional Michaelis-Menten kinetics equation. This alternative model allowed the identification of two distinct phases in the responses, which were related to fibre type composition. A first phase, characterized by low apparent Km and Vmax values, was correlated with the percentage of less oxidative (Type 2A + 2X) MyHC isoforms. A second phase, characterized by high apparent Km and Vmax, was related to more oxidative (Type 1) MyHC isoforms.
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Affiliation(s)
| | | | | | - Alice E. Knapton
- Department of Physiology, Neuroscience and DevelopmentUniversity of CambridgeCambridgeUK
| | - Benjamin D. Thackray
- Department of Physiology, Neuroscience and DevelopmentUniversity of CambridgeCambridgeUK
| | | | - Boštjan Šimunič
- Institute of Kinesiology ResearchScience and Research CentreKoperSlovenia
| | - Rado Pišot
- Institute of Kinesiology ResearchScience and Research CentreKoperSlovenia
| | - Giuseppe Sirago
- Department of Biomedical SciencesUniversity of PadovaPadovaItaly
- Institute of Sport Sciences and Department of Biomedical SciencesUniversity of LausanneLausanneSwitzerland
| | - Elena Monti
- Department of Biomedical SciencesUniversity of PadovaPadovaItaly
| | - Marco Narici
- Department of Biomedical SciencesUniversity of PadovaPadovaItaly
| | - Miriam Isola
- Department of MedicineUniversity of UdineUdineItaly
| | - Andrew J. Murray
- Department of Physiology, Neuroscience and DevelopmentUniversity of CambridgeCambridgeUK
| | | | - Bruno Grassi
- Department of MedicineUniversity of UdineUdineItaly
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Møller PM, Kjøbsted R, Petersen MH, de Almeida ME, Pedersen AJT, Wojtaszewski JFP, Højlund K. Effect of acute exercise and exercise training on the ability of insulin to clear branched-chain amino acids from plasma in obesity and type 2 diabetes. Diabetologia 2025:10.1007/s00125-025-06454-y. [PMID: 40404819 DOI: 10.1007/s00125-025-06454-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/20/2025] [Indexed: 05/24/2025]
Abstract
AIMS/HYPOTHESIS Insulin resistance in obesity and type 2 diabetes is associated with elevated plasma branched-chain amino acid (BCAA) levels. Here, we examined whether the ability of insulin to clear plasma BCAAs and any influence of acute exercise or exercise training on this response are intact in obesity and type 2 diabetes. METHODS In four case-control studies of participants with type 2 diabetes matched to glucose-tolerant individuals with obesity and lean individuals, who underwent hyperinsulinaemic-euglycaemic clamps, we examined the effect of insulin on plasma BCAAs (studies I-IV), with or without prior acute exercise (60 min, 70%V ˙ O 2max ) (study II), and before and after 10 weeks of endurance exercise training (study III) or 8 weeks of high-intensity interval training (study IV). RESULTS Insulin sensitivity was reduced in individuals with type 2 diabetes compared with individuals with obesity (study I-IV) and lean individuals (studies I and IV), and in individuals with obesity vs lean individuals (study I) (all p<0.05). Exercise training (studies III and IV) increased insulin sensitivity in all groups (all p<0.01). Plasma BCAAs were elevated in individuals with type 2 diabetes compared with individuals with obesity (studies I, III and IV) and lean individuals (studies I and IV) (all p<0.05). The ability of insulin to reduce plasma BCAAs was significantly attenuated in participants with type 2 diabetes compared with both lean individuals (studies I and IV) and individuals with obesity (studies I, II and IV) (all p<0.05). Acute exercise slightly reduced plasma BCAAs in both individuals with type 2 diabetes and individuals with obesity but did not potentiate insulin's ability to reduce plasma BCAAs (study II). Exercise training had no impact on fasting BCAAs and did not affect insulin's ability to reduce plasma BCAAs in any group (studies III and IV) or rescue the attenuated insulin suppression of plasma BCAAs in participants with type 2 diabetes. CONCLUSIONS/INTERPRETATION Our results demonstrate that insulin's ability to suppress plasma BCAAs is impaired in type 2 diabetes but is intact in individuals with obesity. Although acute exercise reduces fasting BCAA levels, neither acute exercise nor exercise training affects insulin's ability to suppress plasma BCAAs in glucose-tolerant individuals with or without obesity or in individuals with type 2 diabetes.
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Affiliation(s)
- Pauline M Møller
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Rasmus Kjøbsted
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Maria H Petersen
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
| | - Martin E de Almeida
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | | | - Jørgen F P Wojtaszewski
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark.
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Vandersmissen J, Dewachter I, Cuypers K, Hansen D. The Impact of Exercise Training on the Brain and Cognition in Type 2 Diabetes, and its Physiological Mediators: A Systematic Review. SPORTS MEDICINE - OPEN 2025; 11:42. [PMID: 40274715 PMCID: PMC12022206 DOI: 10.1186/s40798-025-00836-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 03/16/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND Type 2 diabetes (T2DM) affects brain structure and function, and is associated with an increased risk of dementia and mild cognitive impairment. It is known that exercise training has a beneficial effect on cognition and brain structure and function, at least in healthy people, but the impact of exercise training on these aspects remains to be fully elucidated in patients with T2DM. OBJECTIVE To determine the impact of exercise training on cognition and brain structure and function in T2DM, and identify the involved physiological mediators. METHODS This paper systematically reviews studies that evaluate the effect of exercise training on cognition in T2DM, and aims to indicate the most beneficial exercise modality for improving or preserving cognition in this patient group. In addition, the possible physiological mediators and targets involved in these improvements are narratively described in the second part of this review. Papers published up until the 14th of January 2025 were searched by means of the electronic databases PubMed, Embase, and Web of Science. Studies directly investigating the effect of any kind of exercise training on the brain or cognition in patients with T2DM, or animal models thereof, were included, with the exception of human studies assessing cognition only at one time point, and studies combining exercise training with other interventions (e.g. dietary changes, cognitive training, etc.). Study quality was assessed by means of the TESTEX tool for human studies, and the CAMARADES tool for animal studies. RESULTS For the systematic part of the review, 22 papers were found to be eligible. 18 out of 22 papers (81.8%) showed a significant positive effect of exercise training on cognition in T2DM, of which two studies only showed significant improvements in the minority of the cognitive tests. Four papers (18.2%) could not find a significant effect of exercise on cognition in T2DM. Resistance and endurance exercise were found to be equally effective for achieving cognitive improvement. Machine-based power training is seemingly more effective than resistance training with body weight and elastic bands to reach cognitive improvement. In addition, BDNF, lactate, leptin, adiponectin, GSK3β, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway were identified as plausible mediators directly from studies investigating the effect of exercise training on brain structure and function in T2DM. Via these mediators, exercise training induces multiple beneficial brain changes, such as increased neuroplasticity, increased insulin sensitivity, and decreased inflammation. CONCLUSION Overall, exercise training beneficially affects cognition and brain structure and function in T2DM, with resistance and endurance exercise having similar effects. However, there is a need for additional studies, and more methodological consistency between different studies in order to define an exercise program optimal for improving cognition in T2DM. Furthermore, we were able to define several mediators involved in the effect of exercise training on cognition in T2DM, but further research is necessary to unravel the entire process.
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Affiliation(s)
- Jitske Vandersmissen
- Faculty of Rehabilitation Sciences, REVAL - Rehabilitation Research Center, Hasselt University, Wetenschapspark 7, 3590, Diepenbeek, Belgium.
| | - Ilse Dewachter
- Biomedical Research Institute, BIOMED, Hasselt University, 3590, Diepenbeek, Belgium
| | - Koen Cuypers
- Faculty of Rehabilitation Sciences, REVAL - Rehabilitation Research Center, Hasselt University, Wetenschapspark 7, 3590, Diepenbeek, Belgium
- Movement Control and Neuroplasticity Research Group, Department of Movement Sciences, Group Biomedical Sciences, KU Leuven, 3000, Leuven, Belgium
| | - Dominique Hansen
- Faculty of Rehabilitation Sciences, REVAL - Rehabilitation Research Center, Hasselt University, Wetenschapspark 7, 3590, Diepenbeek, Belgium
- Heart Centre Hasselt, Jessa Hospital, 3500, Hasselt, Belgium
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Bhrigu B, Sharma S, Kumar N, Banik BK. Assessment for Diabetic Neuropathy: Treatment and Neurobiological Perspective. Curr Diabetes Rev 2025; 21:12-31. [PMID: 38798207 DOI: 10.2174/0115733998290606240521113832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/01/2024] [Accepted: 04/19/2024] [Indexed: 05/29/2024]
Abstract
Diabetic neuropathy, also known as diabetic peripheral sensorimotor neuropathy (DPN), is a consequential complexity of diabetes, alongside diabetic nephropathy, diabetic cardiomyopathy, and diabetic retinopathy. It is characterized by signs and symptoms of peripheral nerve damage in diabetes patients after ruling out other causes. Approximately 20% of people with diabetes are affected by this painful and severe condition. The development of diabetic neuropathy is influenced by factors such as impaired blood flow to the peripheral nerves and metabolic issues, including increased polyol pathway activation, myo-inositol loss, and nonenzymatic glycation. The present review article provides a brief overview of the pathological changes in diabetic neuropathy and the mechanisms and types of DPN. Various diagnostic tests and biomarkers are available to assess nerve damage and its severity. Pharmacotherapy for neuropathic pain in diabetic neuropathy is complex. This review will explore current treatment options and potential future developments to improve the quality of life for patients suffering from diabetic neuropathy.
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Affiliation(s)
- Bhanupriya Bhrigu
- Department of Pharmaceutical Science, Lords University, Alwar, 301028, Rajasthan, India
| | - Shikha Sharma
- Department of Pharmaceutical Science, Lords University, Alwar, 301028, Rajasthan, India
| | - Nitin Kumar
- Department of Pharmaceutical Science, Lords University, Alwar, 301028, Rajasthan, India
| | - Bimal Krishna Banik
- Department of Mathematics and Natural Sciences, College of Sciences and Human Studies, Prince Mohammad Bin Fahd University, Al Khobar, Kingdom of Saudi Arabia
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Pham TCP, Raun SH, Havula E, Henriquez-Olguín C, Rubalcava-Gracia D, Frank E, Fritzen AM, Jannig PR, Andersen NR, Kruse R, Ali MS, Irazoki A, Halling JF, Ringholm S, Needham EJ, Hansen S, Lemminger AK, Schjerling P, Petersen MH, de Almeida ME, Jensen TE, Kiens B, Hostrup M, Larsen S, Ørtenblad N, Højlund K, Kjær M, Ruas JL, Trifunovic A, Wojtaszewski JFP, Nielsen J, Qvortrup K, Pilegaard H, Richter EA, Sylow L. The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms. Nat Commun 2024; 15:9826. [PMID: 39537626 PMCID: PMC11561311 DOI: 10.1038/s41467-024-54183-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.
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Affiliation(s)
- Tang Cam Phung Pham
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Steffen Henning Raun
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Essi Havula
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Carlos Henriquez-Olguín
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
- Exercise Science Laboratory, Faculty of Medicine, Universidad Finis Terrae, Av. Pedro de Valdivia 1509, Santiago, Chile
| | - Diana Rubalcava-Gracia
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Emma Frank
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Andreas Mæchel Fritzen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Paulo R Jannig
- Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, SE-17177, Stockholm, Sweden
| | - Nicoline Resen Andersen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Rikke Kruse
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
| | - Mona Sadek Ali
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Andrea Irazoki
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Frey Halling
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Stine Ringholm
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Elise J Needham
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia
| | - Solvejg Hansen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Anders Krogh Lemminger
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Peter Schjerling
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark
- Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Martin Eisemann de Almeida
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Thomas Elbenhardt Jensen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Bente Kiens
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Morten Hostrup
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Steen Larsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark
- Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Niels Ørtenblad
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Michael Kjær
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark
- Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jorge L Ruas
- Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, SE-17177, Stockholm, Sweden
| | - Aleksandra Trifunovic
- Institute for Mitochondrial Diseases and Aging, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
| | | | - Joachim Nielsen
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Klaus Qvortrup
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Erik Arne Richter
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Lykke Sylow
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Sabaratnam R, Kristensen JM, Pedersen AJT, Kruse R, Handberg A, Wojtaszewski JFP, Højlund K. Acute Exercise Increases GDF15 and Unfolded Protein Response/Integrated Stress Response in Muscle in Type 2 Diabetes. J Clin Endocrinol Metab 2024; 109:1754-1764. [PMID: 38242693 DOI: 10.1210/clinem/dgae032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 12/27/2023] [Accepted: 01/16/2024] [Indexed: 01/21/2024]
Abstract
CONTEXT Regular exercise is a key prevention strategy for obesity and type 2 diabetes (T2D). Exerkines secreted in response to exercise or recovery may contribute to improved systemic metabolism. Conversely, an impaired exerkine response to exercise and recovery may contribute to cardiometabolic diseases. OBJECTIVE We investigated if the exercise-induced regulation of the exerkine, growth differentiation factor 15 (GDF15) and its putative upstream regulators of the unfolded protein response (UPR)/integrated stress response (ISR) is impaired in skeletal muscle in patients with T2D compared with weight-matched glucose-tolerant men. METHODS Thirteen male patients with T2D and 14 age- and weight-matched overweight/obese glucose-tolerant men exercised at 70% of VO2max for 1 hour. Blood and skeletal muscle biopsies were sampled before, immediately after, and 3 hours into recovery. Serum and muscle transcript levels of GDF15 and key markers of UPR/ISR were determined. Additionally, protein/phosphorylation levels of key regulators in UPR/ISR were investigated. RESULTS Acute exercise increased muscle gene expression and serum GDF15 levels in both groups. In recovery, muscle expression of GDF15 decreased toward baseline, whereas serum GDF15 remained elevated. In both groups, acute exercise increased the expression of UPR/ISR markers, including ATF4, CHOP, EIF2K3 (encoding PERK), and PPP1R15A (encoding GADD34), of which only CHOP remained elevated 3 hours into recovery. Downstream molecules of the UPR/ISR including XBP1-U, XBP1-S, and EDEM1 were increased with exercise and 3 hours into recovery in both groups. The phosphorylation levels of eIF2α-Ser51, a common marker of unfolded protein response (UPR) and ISR, increased immediately after exercise in controls, but decreased 3 hours into recovery in both groups. CONCLUSION In conclusion, exercise-induced regulation of GDF15 and key markers of UPR/ISR are not compromised in patients with T2D compared with weight-matched controls.
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Affiliation(s)
- Rugivan Sabaratnam
- Department of Clinical Research & Department of Molecular Medicine, University of Southern Denmark, DK-5230 Odense M, Denmark
- Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark
| | - Jonas M Kristensen
- Department of Clinical Research & Department of Molecular Medicine, University of Southern Denmark, DK-5230 Odense M, Denmark
- Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Andreas J T Pedersen
- Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark
| | - Rikke Kruse
- Department of Clinical Research & Department of Molecular Medicine, University of Southern Denmark, DK-5230 Odense M, Denmark
- Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark
| | - Aase Handberg
- Department of Clinical Biochemistry, Aalborg University Hospital, North Denmark Region, DK-9000 Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, DK-9000 Aalborg, Denmark
| | - Jørgen F P Wojtaszewski
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Kurt Højlund
- Department of Clinical Research & Department of Molecular Medicine, University of Southern Denmark, DK-5230 Odense M, Denmark
- Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark
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Espino-Gonzalez E, Dalbram E, Mounier R, Gondin J, Farup J, Jessen N, Treebak JT. Impaired skeletal muscle regeneration in diabetes: From cellular and molecular mechanisms to novel treatments. Cell Metab 2024; 36:1204-1236. [PMID: 38490209 DOI: 10.1016/j.cmet.2024.02.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 01/10/2024] [Accepted: 02/22/2024] [Indexed: 03/17/2024]
Abstract
Diabetes represents a major public health concern with a considerable impact on human life and healthcare expenditures. It is now well established that diabetes is characterized by a severe skeletal muscle pathology that limits functional capacity and quality of life. Increasing evidence indicates that diabetes is also one of the most prevalent disorders characterized by impaired skeletal muscle regeneration, yet underlying mechanisms and therapeutic treatments remain poorly established. In this review, we describe the cellular and molecular alterations currently known to occur during skeletal muscle regeneration in people with diabetes and animal models of diabetes, including its associated comorbidities, e.g., obesity, hyperinsulinemia, and insulin resistance. We describe the role of myogenic and non-myogenic cell types on muscle regeneration in conditions with or without diabetes. Therapies for skeletal muscle regeneration and gaps in our knowledge are also discussed, while proposing future directions for the field.
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Affiliation(s)
- Ever Espino-Gonzalez
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Emilie Dalbram
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Rémi Mounier
- Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1, CNRS UMR 5261, Inserm U1315, Univ Lyon, Lyon, France
| | - Julien Gondin
- Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1, CNRS UMR 5261, Inserm U1315, Univ Lyon, Lyon, France
| | - Jean Farup
- Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus 8200, Denmark
| | - Niels Jessen
- Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus 8200, Denmark; Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus 8200, Denmark
| | - Jonas T Treebak
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
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Shen J, Wang X, Wang M, Zhang H. Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases. Front Physiol 2024; 15:1337442. [PMID: 38818523 PMCID: PMC11137309 DOI: 10.3389/fphys.2024.1337442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 04/29/2024] [Indexed: 06/01/2024] Open
Abstract
Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.
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Affiliation(s)
- Jiawen Shen
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Xianping Wang
- School of Medicine, Taizhou University, Taizhou, China
| | - Minghui Wang
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Hu Zhang
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
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9
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Soares RN, Lessard SJ. Low Response to Aerobic Training in Metabolic Disease: Role of Skeletal Muscle. Exerc Sport Sci Rev 2024; 52:47-53. [PMID: 38112622 PMCID: PMC10963145 DOI: 10.1249/jes.0000000000000331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
Aerobic exercise is established to increase cardiorespiratory fitness (CRF), which is linked to reduced morbidity and mortality. However, people with metabolic diseases such as type 1 and type 2 diabetes may be more likely to display blunted improvements in CRF with training. Here, we present evidence supporting the hypothesis that altered skeletal muscle signaling and remodeling may contribute to low CRF with metabolic disease.
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10
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Serrano QA, Le Garf S, Martin V, Colson SS, Chevalier N. Is Physical Activity an Efficient Strategy to Control the Adverse Effects of Persistent Organic Pollutants in the Context of Obesity? A Narrative Review. Int J Mol Sci 2024; 25:883. [PMID: 38255955 PMCID: PMC10815489 DOI: 10.3390/ijms25020883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/21/2023] [Accepted: 12/27/2023] [Indexed: 01/24/2024] Open
Abstract
Obesity affects nearly 660 million adults worldwide and is known for its many comorbidities. Although the phenomenon of obesity is not fully understood, science regularly reveals new determinants of this pathology. Among them, persistent organic pollutants (POPs) have been recently highlighted. Mainly lipophilic, POPs are normally stored in adipose tissue and can lead to adverse metabolic effects when released into the bloodstream. The main objective of this narrative review is to discuss the different pathways by which physical activity may counteract POPs' adverse effects. The research that we carried out seems to indicate that physical activity could positively influence several pathways negatively influenced by POPs, such as insulin resistance, inflammation, lipid accumulation, adipogenesis, and gut microbiota dysbiosis, that are associated with the development of obesity. This review also indicates how, through the controlled mobilization of POPs, physical activity could be a valuable approach to reduce the concentration of POPs in the bloodstream. These findings suggest that physical activity should be used to counteract the adverse effects of POPs. However, future studies should accurately assess its impact in specific situations such as bariatric surgery, where weight loss promotes POPs' blood release.
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Affiliation(s)
| | | | - Vincent Martin
- Université Clermont Auvergne, AME2P, F-63000 Clermont-Ferrand, France;
- Institut Universitaire de France (IUF), 75005 Paris, France
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11
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Bir A, Ghosh A, Müller WE, Ganguly A. Mitochondrial dysfunction and metabolic syndrome. METABOLIC SYNDROME 2024:157-172. [DOI: 10.1016/b978-0-323-85732-1.00043-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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12
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Tian J, Fan J, Zhang T. Mitochondria as a target for exercise-mitigated type 2 diabetes. J Mol Histol 2023; 54:543-557. [PMID: 37874501 DOI: 10.1007/s10735-023-10158-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 09/17/2023] [Indexed: 10/25/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is one of most common metabolic diseases and continues to be a leading cause of death worldwide. Although great efforts have been made to elucidate the pathogenesis of diabetes, the underlying mechanism still remains unclear. Notably, overwhelming evidence has demonstrated that mitochondria are tightly correlated with the development of T2DM, and the defects of mitochondrial function in peripheral insulin-responsive tissues, such as skeletal muscle, liver and adipose tissue, are crucial drivers of T2DM. Furthermore, exercise training is considered as an effective stimulus for improving insulin sensitivity and hence is regarded as the best strategy to prevent and treat T2DM. Although the precise mechanisms by which exercise alleviates T2DM are not fully understood, mitochondria may be critical for the beneficial effects of exercise.
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Affiliation(s)
- Jingjing Tian
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai, China
| | - Jingcheng Fan
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai, China
| | - Tan Zhang
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China.
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai, China.
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13
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Larsen JK, Kruse R, Sahebekhtiari N, Moreno-Justicia R, Gomez Jorba G, Petersen MH, de Almeida ME, Ørtenblad N, Deshmukh AS, Højlund K. High-throughput proteomics uncovers exercise training and type 2 diabetes-induced changes in human white adipose tissue. SCIENCE ADVANCES 2023; 9:eadi7548. [PMID: 38019916 PMCID: PMC10686561 DOI: 10.1126/sciadv.adi7548] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023]
Abstract
White adipose tissue (WAT) is important for metabolic homeostasis. We established the differential proteomic signatures of WAT in glucose-tolerant lean and obese individuals and patients with type 2 diabetes (T2D) and the response to 8 weeks of high-intensity interval training (HIIT). Using a high-throughput and reproducible mass spectrometry-based proteomics pipeline, we identified 3773 proteins and found that most regulated proteins displayed progression in markers of dysfunctional WAT from lean to obese to T2D individuals and were highly associated with clinical measures such as insulin sensitivity and HbA1c. We propose that these distinct markers could serve as potential clinical biomarkers. HIIT induced only minor changes in the WAT proteome. This included an increase in WAT ferritin levels independent of obesity and T2D, and WAT ferritin levels were strongly correlated with individual insulin sensitivity. Together, we report a proteomic signature of WAT related to obesity and T2D and highlight an unrecognized role of human WAT iron metabolism in exercise training adaptations.
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Affiliation(s)
- Jeppe Kjærgaard Larsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Rikke Kruse
- Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense C, Denmark
| | - Navid Sahebekhtiari
- Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense C, Denmark
| | - Roger Moreno-Justicia
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Gerard Gomez Jorba
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Maria H. Petersen
- Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark
| | - Martin E. de Almeida
- Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Niels Ørtenblad
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Atul S. Deshmukh
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense C, Denmark
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14
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Xiong L, Dorus S, Ramalingam L. Role of Fish Oil in Preventing Paternal Obesity and Improving Offspring Skeletal Muscle Health. Biomedicines 2023; 11:3120. [PMID: 38137341 PMCID: PMC10740802 DOI: 10.3390/biomedicines11123120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/14/2023] [Accepted: 11/15/2023] [Indexed: 12/24/2023] Open
Abstract
This study investigates the effects of fish oil supplementation during the periconceptional period in male mice. Specifically, it examines the impact of fish oil on intergenerational health, as determined by skeletal muscle markers. To mimic paternal obesity, thirty mice were separated into three groups with distinct dietary regimes for 10 weeks: a high-fat diet (HF), a high-fat diet supplemented with fish oil (FO), and a low-fat diet (LF). Then, these mice mated with control female mice. Dams and offspring consumed a chow diet during gestation and lactation, and the offspring continued on a chow diet. To study short-term (8 weeks) and long-term (16 weeks) effects of FO, skeletal muscle was isolated at the time of sacrifice, and gene analyses were performed. Results suggest that offspring born to FO-supplemented sires exhibited a significant, short-term upregulation of genes associated with insulin signaling, fatty acid oxidation, and skeletal muscle growth with significant downregulation of genes involved in fatty acid synthesis at 8 weeks. Prominent differences in the above markers were observed at 8 weeks compared to 16 weeks. These findings suggest the potential benefits of FO supplementation for fathers during the periconceptional period in reducing the health risks of offspring due to paternal obesity.
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Affiliation(s)
- Ligeng Xiong
- Department of Nutrition and Food Studies, Syracuse University, Syracuse, NY 13244, USA
| | - Stephen Dorus
- Department of Biology, Syracuse University, Syracuse, NY 13244, USA
| | - Latha Ramalingam
- Department of Nutrition and Food Studies, Syracuse University, Syracuse, NY 13244, USA
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15
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Li Q, Jiang X, Zhou Y, Gu Y, Ding Y, Luo J, Pang N, Sun Y, Pei L, Pan J, Gao M, Ma S, Xiao Y, Hu D, Wu F, Yang L. Improving Mitochondrial Function in Skeletal Muscle Contributes to the Amelioration of Insulin Resistance by Nicotinamide Riboside. Int J Mol Sci 2023; 24:10015. [PMID: 37373163 DOI: 10.3390/ijms241210015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/01/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
High-fat diet (HFD)-induced insulin resistance (IR) in skeletal muscle is often accompanied by mitochondrial dysfunction and oxidative stress. Boosting nicotinamide adenine dinucleotide (NAD) using nicotinamide riboside (NR) can effectively decrease oxidative stress and increase mitochondrial function. However, whether NR can ameliorate IR in skeletal muscle is still inconclusive. We fed male C57BL/6J mice with an HFD (60% fat) ± 400 mg/kg·bw NR for 24 weeks. C2C12 myotube cells were treated with 0.25 mM palmitic acid (PA) ± 0.5 mM NR for 24 h. Indicators for IR and mitochondrial dysfunction were analyzed. NR treatment alleviated IR in HFD-fed mice with regard to improved glucose tolerance and a remarkable decrease in the levels of fasting blood glucose, fasting insulin and HOMA-IR index. NR-treated HFD-fed mice also showed improved metabolic status regarding a significant reduction in body weight and lipid contents in serum and the liver. NR activated AMPK in the skeletal muscle of HFD-fed mice and PA-treated C2C12 myotube cells and upregulated the expression of mitochondria-related transcriptional factors and coactivators, thereby improving mitochondrial function and alleviating oxidative stress. Upon inhibiting AMPK using Compound C, NR lost its ability in enhancing mitochondrial function and protection against IR induced by PA. In summary, improving mitochondrial function through the activation of AMPK pathway in skeletal muscle may play an important role in the amelioration of IR using NR.
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Affiliation(s)
- Qiuyan Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Xuye Jiang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
- Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 1172 Copenhagen, Denmark
| | - Yujia Zhou
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yingying Gu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yijie Ding
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Jing Luo
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Nengzhi Pang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yan Sun
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Lei Pei
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Jie Pan
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Mengqi Gao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Sixi Ma
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Ying Xiao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - De Hu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Feilong Wu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Lili Yang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
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16
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Busa P, Kuthati Y, Huang N, Wong CS. New Advances on Pathophysiology of Diabetes Neuropathy and Pain Management: Potential Role of Melatonin and DPP-4 Inhibitors. Front Pharmacol 2022; 13:864088. [PMID: 35496279 PMCID: PMC9039240 DOI: 10.3389/fphar.2022.864088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/14/2022] [Indexed: 12/14/2022] Open
Abstract
Pre-diabetes and diabetes are growing threats to the modern world. Diabetes mellitus (DM) is associated with comorbidities such as hypertension (83.40%), obesity (90.49%), and dyslipidemia (93.43%), creating a substantial burden on patients and society. Reductive and oxidative (Redox) stress level imbalance and inflammation play an important role in DM progression. Various therapeutics have been investigated to treat these neuronal complications. Melatonin and dipeptidyl peptidase IV inhibitors (DPP-4i) are known to possess powerful antioxidant and anti-inflammatory properties and have garnered significant attention in the recent years. In this present review article, we have reviewed the recently published reports on the therapeutic efficiency of melatonin and DPP-4i in the treatment of DM. We summarized the efficacy of melatonin and DPP-4i in DM and associated complications of diabetic neuropathy (DNP) and neuropathic pain. Furthermore, we discussed the mechanisms of action and their efficacy in the alleviation of oxidative stress in DM.
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Affiliation(s)
- Prabhakar Busa
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
| | - Yaswanth Kuthati
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
| | - Niancih Huang
- Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan
- Grauate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Shung Wong
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
- Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan
- Grauate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
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17
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Mthembu SXH, Mazibuko-Mbeje SE, Ziqubu K, Nyawo TA, Obonye N, Nyambuya TM, Nkambule BB, Silvestri S, Tiano L, Muller CJF, Dludla PV. Impact of physical exercise and caloric restriction in patients with type 2 diabetes: Skeletal muscle insulin resistance and mitochondrial dysfunction as ideal therapeutic targets. Life Sci 2022; 297:120467. [PMID: 35271881 DOI: 10.1016/j.lfs.2022.120467] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/04/2022] [Accepted: 03/04/2022] [Indexed: 01/01/2023]
Abstract
Skeletal muscle insulin resistance and mitochondrial dysfunction are some of the major pathological defects implicated in the development of type 2 diabetes (T2D). Therefore, it has become necessary to understand how common interventions such as physical exercise and caloric restriction affect metabolic function, including physiological processes that implicate skeletal muscle dysfunction within a state of T2D. This review critically discusses evidence on the impact of physical exercise and caloric restriction on markers of insulin resistance and mitochondrial dysfunction within the skeletal muscle of patients with T2D or related metabolic complications. Importantly, relevant information from clinical studies was acquired through a systematic approach targeting major electronic databases and search engines such as PubMed, Google Scholar, and Cochrane library. The reported evidence suggests that interventions like physical exercise and caloric restriction, within a duration of approximately 2 to 4 months, can improve insulin sensitivity, in part by targeting the phosphoinositide 3-kinases/protein kinase B pathway in patients with T2D. Furthermore, both physical exercise and caloric restriction can effectively modulate markers related to improved mitochondrial function and dynamics. This was consistent with an improved modulation of mitochondrial oxidative capacity and reduced production of reactive oxygen species in patients with T2D or related metabolic complications. However, such conclusions are based on limited evidence, additional clinical trials are required to better understand these interventions on pathological mechanisms of T2D and related abnormalities.
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Affiliation(s)
- Sinenhlanhla X H Mthembu
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; Department of Biochemistry, North-West University, Mafikeng Campus, Mmabatho 2735, South Africa
| | | | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mafikeng Campus, Mmabatho 2735, South Africa
| | - Thembeka A Nyawo
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; Centre for Cardiometabolic Research Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa
| | - Nnini Obonye
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; Centre for Cardiometabolic Research Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa
| | - Tawanda M Nyambuya
- Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Windhoek 9000, Namibia
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu Natal, Durban 4000, South Africa
| | - Sonia Silvestri
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy
| | - Christo J F Muller
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa; Centre for Cardiometabolic Research Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa.
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18
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Malamouli M, Levinger I, McAinch AJ, Trewin AJ, Rodgers RJ, Moreno-Asso A. The mitochondrial profile in women with polycystic ovary syndrome: impact of exercise. J Mol Endocrinol 2022; 68:R11-R23. [PMID: 35060480 PMCID: PMC8942332 DOI: 10.1530/jme-21-0177] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 01/21/2022] [Indexed: 11/28/2022]
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting pre-menopausal women and involves metabolic dysregulation. Despite the high prevalence of insulin resistance, the existence of mitochondrial dysregulation and its role in the pathogenesis of PCOS is not clear. Exercise is recommended as the first-line therapy for women with PCOS. In particular, high-intensity interval training (HIIT) is known to improve metabolic health and enhance mitochondrial characteristics. In this narrative review, the existing knowledge of mitochondrial characteristics in skeletal muscle and adipose tissue of women with PCOS and the effect of exercise interventions in ameliorating metabolic and mitochondrial health in these women are discussed. Even though the evidence on mitochondrial dysfunction in PCOS is limited, some studies point to aberrant mitochondrial functions mostly in skeletal muscle, while there is very little research in adipose tissue. Although most exercise intervention studies in PCOS report improvements in metabolic health, they show diverse and inconclusive findings in relation to mitochondrial characteristics. A limitation of the current study is the lack of comprehensive mitochondrial analyses and the diversity in exercise modalities, with only one study investigating the impact of HIIT alone. Therefore, further comprehensive large-scale exercise intervention studies are required to understand the association between metabolic dysfunction and aberrant mitochondrial profile, and the molecular mechanisms underlying the exercise-induced metabolic adaptations in women with PCOS.
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Affiliation(s)
- Melpomeni Malamouli
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Western Health, Victoria University, Victoria, Australia
| | - Itamar Levinger
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Western Health, Victoria University, Victoria, Australia
| | - Andrew J McAinch
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Western Health, Victoria University, Victoria, Australia
| | - Adam J Trewin
- Institute for Physical Activity and Nutrition, Deakin University, Geelong, Victoria, Australia
| | - Raymond J Rodgers
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
- The Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Alba Moreno-Asso
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Western Health, Victoria University, Victoria, Australia
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19
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Khutami C, Sumiwi SA, Khairul Ikram NK, Muchtaridi M. The Effects of Antioxidants from Natural Products on Obesity, Dyslipidemia, Diabetes and Their Molecular Signaling Mechanism. Int J Mol Sci 2022; 23:ijms23042056. [PMID: 35216172 PMCID: PMC8875143 DOI: 10.3390/ijms23042056] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/06/2022] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
Obesity is a risk factor that leads to the development of other diseases such as dyslipidemia and diabetes. These three metabolic disorders can occur simultaneously, hence, the treatment requires many drugs. Antioxidant compounds have been reported to have activities against obesity, dyslipidemia and diabetes via several mechanisms. This review aims to discuss the antioxidant compounds that have activity against obesity, dyslipidemia and diabetes together with their molecular signaling mechanism. The literature discussed in this review was obtained from the PUBMED database. Based on the collection of literature obtained, antioxidant compounds having activity against the three disorders (obesity, dyslipidemia and diabetes) were identified. The activity is supported by various molecular signaling pathways that are influenced by these antioxidant compounds, further study of which would be useful in predicting drug targets for a more optimal effect. This review provides insights on utilizing one of these antioxidant compounds as opposed to several drugs. It is hoped that in the future, the number of drugs in treating obesity, dyslipidemia and diabetes altogether can be minimized consequently reducing the risk of side effects.
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Affiliation(s)
- Chindiana Khutami
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang KM 21, Sumedang 45363, Indonesia; (C.K.); (S.A.S.)
| | - Sri Adi Sumiwi
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang KM 21, Sumedang 45363, Indonesia; (C.K.); (S.A.S.)
| | - Nur Kusaira Khairul Ikram
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
- Centre for Research in Biotechnology for Agriculture (CEBAR), Kuala Lumpur 50603, Malaysia
| | - Muchtaridi Muchtaridi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang KM 21, Sumedang 45363, Indonesia
- Correspondence:
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20
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Sabaratnam R, Wojtaszewski JFP, Højlund K. Factors mediating exercise-induced organ crosstalk. Acta Physiol (Oxf) 2022; 234:e13766. [PMID: 34981891 DOI: 10.1111/apha.13766] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 10/11/2021] [Accepted: 01/01/2022] [Indexed: 12/21/2022]
Abstract
Exercise activates a plethora of metabolic and signalling pathways in skeletal muscle and other organs causing numerous systemic beneficial metabolic effects. Thus, regular exercise may ameliorate and prevent the development of several chronic metabolic diseases. Skeletal muscle is recognized as an important endocrine organ regulating systemic adaptations to exercise. Skeletal muscle may mediate crosstalk with other organs through the release of exercise-induced cytokines, peptides and proteins, termed myokines, into the circulation. Importantly, other tissues such as the liver and adipose tissue may also release cytokines and peptides in response to exercise. Hence, exercise-released molecules are collectively called exerkines. Moreover, extracellular vesicles (EVs), in the form of exosomes or microvesicles, may carry some of the signals involved in tissue crosstalk. This review focuses on the role of factors potentially mediating crosstalk between muscle and other tissues in response to exercise.
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Affiliation(s)
- Rugivan Sabaratnam
- Steno Diabetes Center Odense Odense University Hospital Odense C Denmark
- Section of Molecular Diabetes & Metabolism, Department of Clinical Research & Department of Molecular Medicine University of Southern Denmark Odense C Denmark
| | - Jørgen F. P. Wojtaszewski
- Section of Molecular Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Copenhagen Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense Odense University Hospital Odense C Denmark
- Section of Molecular Diabetes & Metabolism, Department of Clinical Research & Department of Molecular Medicine University of Southern Denmark Odense C Denmark
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21
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Petersen MH, de Almeida ME, Wentorf EK, Jensen K, Ørtenblad N, Højlund K. High-intensity interval training combining rowing and cycling efficiently improves insulin sensitivity, body composition and VO 2max in men with obesity and type 2 diabetes. Front Endocrinol (Lausanne) 2022; 13:1032235. [PMID: 36387850 PMCID: PMC9664080 DOI: 10.3389/fendo.2022.1032235] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/17/2022] [Indexed: 11/07/2022] Open
Abstract
AIMS Non-weight-bearing high-intensity interval training (HIIT) involving several muscle groups may efficiently improve metabolic health without compromising adherence in obesity and type 2 diabetes. In a non-randomized intervention study, we examined the effect of a novel HIIT-protocol, recruiting both lower and upper body muscles, on insulin sensitivity, measures of metabolic health and adherence in obesity and type 2 diabetes. METHODS In 15 obese men with type 2 diabetes and age-matched obese (n=15) and lean (n=18) glucose-tolerant men, the effects of 8-weeks supervised HIIT combining rowing and cycling on ergometers (3 sessions/week) were examined by DXA-scan, incremental exercise test and hyperinsulinemic-euglycemic clamp combined with indirect calorimetry. RESULTS At baseline, insulin-stimulated glucose disposal rate (GDR) was ~40% reduced in the diabetic vs the non-diabetic groups (all p<0.01). In response to HIIT, insulin-stimulated GDR increased ~30-40% in all groups (all p<0.01) entirely explained by increased glucose storage. These changes were accompanied by ~8-15% increases in VO2max, (all p<0.01), decreased total fat mass and increased lean body mass in all groups (all p<0.05). There were no correlations between these training adaptations and no group-differences in these responses. HbA1c showed a clinically relevant decrease in men with type 2 diabetes (4±2 mmol/mol; p<0.05). Importantly, adherence was high (>95%) in all groups and no injuries were reported. CONCLUSIONS A novel HIIT-protocol recruiting lower and upper body muscles efficiently improves insulin sensitivity, VO2max and body composition with intact responses in obesity and type 2 diabetes. The high adherence and lack of injuries show that non-weight-bearing HIIT involving several muscle groups is a promising mode of exercise training in obesity and type 2 diabetes.
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Affiliation(s)
| | - Martin Eisemann de Almeida
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Emil Kleis Wentorf
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Kurt Jensen
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Niels Ørtenblad
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- *Correspondence: Kurt Højlund,
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22
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Bassi-Dibai D, Santos-de-Araújo AD, Dibai-Filho AV, de Azevedo LFS, Goulart CDL, Luz GCP, Burke PR, Garcia-Araújo AS, Borghi-Silva A. Rehabilitation of Individuals With Diabetes Mellitus: Focus on Diabetic Myopathy. Front Endocrinol (Lausanne) 2022; 13:869921. [PMID: 35498435 PMCID: PMC9047902 DOI: 10.3389/fendo.2022.869921] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/21/2022] [Indexed: 12/20/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease characterized by high blood glucose levels, causing serious damage to the cardiovascular, respiratory, renal and other systems. The prevalence of type 2 diabetes mellitus (T2DM) was 6.28% in 2017, considering all age groups worldwide (prevalence rate of 6,059 cases per 100,000), and its global prevalence is projected to increase to 7,079 cases per 100,000 by 2030. Furthermore, these individuals are often affected by diabetic myopathy, which is the failure to preserve muscle mass and function in the course of DM. This happens in type 1 diabetes mellitus (T1DM) and T2DM. As skeletal muscle plays a key role in locomotion and glucose homeostasis, diabetic myopathy may contribute to additional complications of the disease. In addition, chronic hyperglycemia is associated with lung functional changes seen in patients with DM, such as reduced lung volumes and compliance, inspiratory muscle strength, and lung elastic recoil. Thus, the weakness of the inspiratory muscles, a consequence of diabetic myopathy, can influence exercise tolerance. Thus, moderate strength training in T2DM can contribute to the gain of peripheral muscle strength. Although the literature is robust on the loss of mass and consequent muscle weakness in diabetic myopathy, triggering pathophysiological factors, the impact on functional capacity, as well as the prescription of physical exercise for this condition deserves to be further explored. This review aims to explore the consequences of diabetic myopathy and its implication in rehabilitation from prescription to safety in the practice of physical exercises for these individuals.
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Affiliation(s)
| | | | | | | | - Cássia da Luz Goulart
- Postgraduate Program in Physical Therapy, Universidade Federal de São Carlos, São Carlos, Brazil
| | | | | | | | - Audrey Borghi-Silva
- Postgraduate Program in Physical Therapy, Universidade Federal de São Carlos, São Carlos, Brazil
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23
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Szczerbinski L, Taylor MA, Puchta U, Konopka P, Paszko A, Citko A, Szczerbinski K, Goscik J, Gorska M, Larsen S, Kretowski A. The Response of Mitochondrial Respiration and Quantity in Skeletal Muscle and Adipose Tissue to Exercise in Humans with Prediabetes. Cells 2021; 10:cells10113013. [PMID: 34831236 PMCID: PMC8616473 DOI: 10.3390/cells10113013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/28/2021] [Accepted: 11/03/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes, but its contribution to the early stages of dysglycemia remains poorly understood. By collecting a high-resolution stage-based spectrum of dysglycemia, our study fills this gap by evaluating derangement in both the function and quantity of mitochondria. We sampled mitochondria in skeletal muscle and subcutaneous adipose tissues of subjects with progressive advancement of dysglycemia under a three-month exercise intervention. Methods: We measured clinical metabolic parameters and gathered skeletal muscle and adipose tissue biopsies before and after the three-month exercise intervention. We then assayed the number of mitochondria via citrate synthase (CS) activity and functional parameters with high-resolution respirometry. Results: In muscle, there were no differences in mitochondrial quantity or function at baseline between normoglycemics and prediabetics. However, the intervention caused improvement in CS activity, implying an increase in mitochondrial quantity. By contrast in adipose tissue, baseline differences in CS activity were present, with the lowest CS activity coincident with impaired fasting glucose and impaired glucose tolerance (IFG + IGT). Finally, CS activity, but few of the functional metrics, improved under the intervention. Conclusions: We show that in prediabetes, no differences in the function or amount of mitochondria (measured by CS activity) in skeletal muscle are apparent, but in adipose tissue of subjects with IFG + IGT, a significantly reduced activity of CS was observed. Finally, metabolic improvements under the exercise correlate to improvements in the amount, rather than function, of mitochondria in both tissues.
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Affiliation(s)
- Lukasz Szczerbinski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (U.P.); (K.S.); (M.G.); (A.K.)
- Clinical Research Centre, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (M.A.T.); (P.K.); (A.P.); (A.C.); (J.G.); (S.L.)
- Correspondence: ; Tel.: +48-85-831-8150
| | - Mark Alan Taylor
- Clinical Research Centre, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (M.A.T.); (P.K.); (A.P.); (A.C.); (J.G.); (S.L.)
- Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, 1450 3rd St., San Francisco, CA 94158, USA
| | - Urszula Puchta
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (U.P.); (K.S.); (M.G.); (A.K.)
| | - Paulina Konopka
- Clinical Research Centre, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (M.A.T.); (P.K.); (A.P.); (A.C.); (J.G.); (S.L.)
| | - Adam Paszko
- Clinical Research Centre, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (M.A.T.); (P.K.); (A.P.); (A.C.); (J.G.); (S.L.)
| | - Anna Citko
- Clinical Research Centre, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (M.A.T.); (P.K.); (A.P.); (A.C.); (J.G.); (S.L.)
| | - Karol Szczerbinski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (U.P.); (K.S.); (M.G.); (A.K.)
| | - Joanna Goscik
- Clinical Research Centre, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (M.A.T.); (P.K.); (A.P.); (A.C.); (J.G.); (S.L.)
| | - Maria Gorska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (U.P.); (K.S.); (M.G.); (A.K.)
| | - Steen Larsen
- Clinical Research Centre, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (M.A.T.); (P.K.); (A.P.); (A.C.); (J.G.); (S.L.)
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark
| | - Adam Kretowski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (U.P.); (K.S.); (M.G.); (A.K.)
- Clinical Research Centre, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland; (M.A.T.); (P.K.); (A.P.); (A.C.); (J.G.); (S.L.)
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24
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de Meeûs d'Argenteuil C, Boshuizen B, Vidal Moreno de Vega C, Leybaert L, de Maré L, Goethals K, De Spiegelaere W, Oosterlinck M, Delesalle C. Comparison of Shifts in Skeletal Muscle Plasticity Parameters in Horses in Three Different Muscles, in Answer to 8 Weeks of Harness Training. Front Vet Sci 2021; 8:718866. [PMID: 34733900 PMCID: PMC8558477 DOI: 10.3389/fvets.2021.718866] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 09/07/2021] [Indexed: 12/02/2022] Open
Abstract
Training-induced follow-up of multiple muscle plasticity parameters in postural stability vs. locomotion muscles provides an integrative physiological view on shifts in the muscular metabolic machinery. It can be expected that not all muscle plasticity parameters show the same expression time profile across muscles. This knowledge is important to underpin results of metabolomic studies. Twelve non-competing Standardbred mares were subjected to standardized harness training. Muscle biopsies were taken on a non-training day before and after 8 weeks. Shifts in muscle fiber type composition and muscle fiber cross-sectional area (CSA) were compared in the m. pectoralis, the m. vastus lateralis, and the m. semitendinosus. In the m. vastus lateralis, which showed most pronounced training-induced plasticity, two additional muscle plasticity parameters (capillarization and mitochondrial density) were assessed. In the m. semitendinosus, additionally the mean minimum Feret's diameter was assessed. There was a significant difference in baseline profiles. The m. semitendinosus contained less type I and more type IIX fibers compatible with the most pronounced anaerobic profile. Though no baseline fiber type-specific and overall mean CSA differences could be detected, there was a clear post-training decrease in fiber type specific CSA, most pronounced for the m. vastus lateralis, and this was accompanied by a clear increase in capillary supply. No shifts in mitochondrial density were detected. The m. semitendinosus showed a decrease in fiber type specific CSA of type IIAX fibers and a decrease of type I fiber Feret's diameter as well as mean minimum Feret's diameter. The training-induced increased capillary supply in conjunction with a significant decrease in muscle fiber CSA suggests that the muscular machinery models itself toward an optimal smaller individual muscle fiber structure to receive and process fuels that can be swiftly delivered by the circulatory system. These results are interesting in view of the recently identified important fuel candidates such as branched-chain amino acids, aromatic amino acids, and gut microbiome-related xenobiotics, which need a rapid gut-muscle gateway to reach these fibers and are less challenging for the mitochondrial system. More research is needed with that respect. Results also show important differences between muscle groups with respect to baseline and training-specific modulation.
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Affiliation(s)
- Constance de Meeûs d'Argenteuil
- Department of Translational Physiology, Infectiology and Public Health, Research Group of Comparative Physiology, Faculty of Veterinary Medicine, Research Group of Comparative Physiology, Ghent University, Merelbeke, Belgium
| | - Berit Boshuizen
- Department of Translational Physiology, Infectiology and Public Health, Research Group of Comparative Physiology, Faculty of Veterinary Medicine, Research Group of Comparative Physiology, Ghent University, Merelbeke, Belgium
- Wolvega Equine Hospital, Oldeholtpade, Netherlands
| | - Carmen Vidal Moreno de Vega
- Department of Translational Physiology, Infectiology and Public Health, Research Group of Comparative Physiology, Faculty of Veterinary Medicine, Research Group of Comparative Physiology, Ghent University, Merelbeke, Belgium
| | - Luc Leybaert
- Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lorie de Maré
- Department of Translational Physiology, Infectiology and Public Health, Research Group of Comparative Physiology, Faculty of Veterinary Medicine, Research Group of Comparative Physiology, Ghent University, Merelbeke, Belgium
| | - Klara Goethals
- Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Research Group Biometrics, Ghent University, Merelbeke, Belgium
| | - Ward De Spiegelaere
- Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Maarten Oosterlinck
- Department of Large Animal Surgery, Anaesthesia and Orthopaedics, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Cathérine Delesalle
- Department of Translational Physiology, Infectiology and Public Health, Research Group of Comparative Physiology, Faculty of Veterinary Medicine, Research Group of Comparative Physiology, Ghent University, Merelbeke, Belgium
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25
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26
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Søndergård SD, Cintin I, Kuhlman AB, Morville TH, Bergmann ML, Kjær LK, Poulsen HE, Giustarini D, Rossi R, Dela F, Helge JW, Larsen S. The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: a randomized trial. Appl Physiol Nutr Metab 2021; 46:1133-1142. [PMID: 33740389 DOI: 10.1139/apnm-2020-1099] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The effect of oral glutathione (GSH) supplementation was studied in obese subjects with and without type 2 diabetes (T2DM) on measures of glucose homeostasis and markers of oxidative stress. Twenty subjects (10 patients with T2DM and 10 obese subjects) were recruited for the study, and randomized in a double-blinded placebo-controlled manner to consume either 1000 mg GSH per day or placebo for 3 weeks. Before and after the 3 weeks insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp and a muscle biopsy was obtained to measure GSH and skeletal muscle mitochondrial hydrogen peroxide (H2O2) emission rate. Whole body insulin sensitivity increased significantly in the GSH group. Skeletal muscle GSH was numerically increased (∼19%) in the GSH group; no change was seen in GSH to glutathione disulfide ratio. Skeletal muscle mitochondrial H2O2 emission rate did not change in response to the intervention and neither did the urinary excretion of the RNA oxidation product 8-oxo-7,8-dihydroguanosine or the DNA oxidation product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), although 8-oxodG decreased as a main effect of time. Oral GSH supplementation improves insulin sensitivity in obese subjects with and without T2DM, although it does not alter markers of oxidative stress. The study has been registered in clinicaltrials.gov (NCT02948673). Novelty: Reduced glutathione supplementation increases insulin sensitivity in obese subjects with and without T2DM. H2O2 emission rate from skeletal muscle mitochondria was not affected by GSH supplementation.
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Affiliation(s)
- Stine D Søndergård
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ida Cintin
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anja B Kuhlman
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas H Morville
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Marie Louise Bergmann
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Laura K Kjær
- Laboratory of Clinical Pharmacology, Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Henrik E Poulsen
- Laboratory of Clinical Pharmacology, Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Daniela Giustarini
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Ranieri Rossi
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Flemming Dela
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Geriatrics, Bispebjerg University Hospital, Copenhagen, Denmark
| | - Jørn W Helge
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Steen Larsen
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.,Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
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27
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Modaresi MS, Fathei M, Attarzadeh Hosseini SR, Ziaaldini MM, Sadeghian Shahi MR. The effects of two iso-volume endurance training protocols on mitochondrial dysfunction in type 2 diabetic male mice. J Diabetes Metab Disord 2021; 19:1097-1103. [PMID: 33520827 DOI: 10.1007/s40200-020-00611-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 07/18/2020] [Accepted: 08/07/2020] [Indexed: 11/28/2022]
Abstract
Purpose Type 2diabetes(T2D) is one of the more common diseases in the world and has been widely spread. One of the suggested mechanisms in development of T2D, is mitochondrial dysfunction. The purpose of this study is to compare the effects of two endurance training protocols with low and moderate intensity on biogenesis and mitochondrial function, in Diabetic mice induced by high fat diet and Streptozotocin(STZ). Methods 40 five week old mice divided to four groups including: health control (HC, n = 7), diabetic control (DC, n = 7), low endurance training (DLT, n = 7) and moderate endurance training (DMT, n = 7). DMT group ran at 5 m/min for an hour, 3 days a week on a treadmill, and DLT group ran at 3 m/min for an hour, 5 days a week on a treadmill for 8 weeks. Results The cytosolic content of PGC1α, Tfam and mitochondrial content of citrate synthase(Cs) and cytochrome c oxidase(Cox) in DC was significantly reduced compared to HC(P˂0.05). All of the parameters except for Cs in both DLT and DMT were increased compared to DC (P˂0.05), but there was no difference between them and the HC (P˃0.05). There was no difference in Cs enzyme between the DC and the DLT(P˃0.05), but it was significantly increased in the DMT(P˂0.05). There was a significantly difference between Cs enzyme in HC and DLT(P˂0.05), but there wasn't any significant difference between HC and DMT(P˃0.05). Conclusions The results showed that in same volume condition, both endurance training protocols improved the proteins involved in biogenesis and mitochondrial function in T2D mice and there was no significant difference between them.
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Affiliation(s)
| | - Mehrdad Fathei
- Faculty of Sport Science, Ferdowsi University of Mashhad, Azadi sq, Mashhad, Iran
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28
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Heo JW, No MH, Cho J, Choi Y, Cho EJ, Park DH, Kim TW, Kim CJ, Seo DY, Han J, Jang YC, Jung SJ, Kang JH, Kwak HB. Moderate aerobic exercise training ameliorates impairment of mitochondrial function and dynamics in skeletal muscle of high-fat diet-induced obese mice. FASEB J 2021; 35:e21340. [PMID: 33455027 DOI: 10.1096/fj.202002394r] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/10/2020] [Accepted: 12/21/2020] [Indexed: 12/31/2022]
Abstract
The purpose of this study is to determine whether moderate aerobic exercise training improves high-fat diet-induced alterations in mitochondrial function and structure in the skeletal muscle. Male 4-week-old C57BL/6 mice were randomly divided into four groups: control (CON), control plus exercise (CON + EX), high-fat diet (HFD), and high-fat diet plus exercise (HFD + EX). After obesity was induced by 20 weeks of 60% HFD, treadmill exercise training was performed at 13-16 m/min, 40-50 min/day, and 6 days/week for 12 weeks. Mitochondrial structure, function, and dynamics, and mitophagy were analyzed in the skeletal muscle fibers from the red gastrocnemius. Exercise training increased mitochondrial number and area and reduced high-fat diet-induced obesity and hyperglycemia. In addition, exercise training attenuated mitochondrial dysfunction in the permeabilized myofibers, indicating that HFD-induced decrease of mitochondrial O2 respiration and Ca2+ retention capacity and increase of mitochondrial H2 O2 emission were attenuated in the HFD + EX group compared to the HFD group. Exercise also ameliorated HFD-induced imbalance of mitochondrial fusion and fission, demonstrating that HFD-induced decrease in fusion protein levels was elevated, and increase in fission protein levels was reduced in the HFD + EX groups compared with the HFD group. Moreover, dysregulation of mitophagy induced by HFD was mitigated in the HFD + EX group, indicating a decrease in PINK1 protein level. Our findings demonstrated that moderate aerobic exercise training mitigated obesity-induced insulin resistance by improving mitochondrial function, and reversed obesity-induced mitochondrial structural damage by improving mitochondrial dynamics and mitophagy, suggesting that moderate aerobic exercise training may play a therapeutic role in protecting the skeletal muscle against mitochondrial impairments and insulin resistance induced by obesity.
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Affiliation(s)
- Jun-Won Heo
- Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea.,Institute of Sports & Arts Convergence, Inha University, Incheon, Republic of Korea
| | - Mi-Hyun No
- Department of Kinesiology, Inha University, Incheon, Republic of Korea
| | - Jinkyung Cho
- Institute of Sports & Arts Convergence, Inha University, Incheon, Republic of Korea
| | - Youngju Choi
- Institute of Sports & Arts Convergence, Inha University, Incheon, Republic of Korea
| | - Eun-Jeong Cho
- Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea.,Institute of Sports & Arts Convergence, Inha University, Incheon, Republic of Korea
| | - Dong-Ho Park
- Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea.,Institute of Sports & Arts Convergence, Inha University, Incheon, Republic of Korea.,Department of Kinesiology, Inha University, Incheon, Republic of Korea
| | - Tae-Woon Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Chang-Ju Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Dae Yun Seo
- National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea
| | - Jin Han
- National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea
| | - Young C Jang
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Su-Jeen Jung
- Department of Leisure Sports, Seoil University, Seoul, Republic of Korea
| | - Ju-Hee Kang
- Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea.,Institute of Sports & Arts Convergence, Inha University, Incheon, Republic of Korea.,Department of Pharmacology, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Hyo-Bum Kwak
- Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea.,Institute of Sports & Arts Convergence, Inha University, Incheon, Republic of Korea.,Department of Kinesiology, Inha University, Incheon, Republic of Korea
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29
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Mancilla R, Brouwers B, Schrauwen‐Hinderling VB, Hesselink MKC, Hoeks J, Schrauwen P. Exercise training elicits superior metabolic effects when performed in the afternoon compared to morning in metabolically compromised humans. Physiol Rep 2021; 8:e14669. [PMID: 33356015 PMCID: PMC7757369 DOI: 10.14814/phy2.14669] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/13/2020] [Accepted: 11/14/2020] [Indexed: 01/08/2023] Open
Abstract
The circadian clock and metabolism are tightly intertwined. Hence, the specific timing of interventions that target metabolic changes may affect their efficacy. Here we retrospectively compared the metabolic health effects of morning versus afternoon exercise training in metabolically compromised subjects enrolled in a 12-week exercise training program. Thirty-two adult males (58 ± 7 yrs) at risk for or diagnosed with type 2 diabetes performed 12 weeks of supervised exercise training either in the morning (8.00-10.00 a.m., N = 12) or in the afternoon (3.00-6.00 p.m., N = 20). Compared to participants who trained in the morning, participants who trained in the afternoon experienced superior beneficial effects of exercise training on peripheral insulin sensitivity (+5.2 ± 6.4 vs. -0.5 ± 5.4 μmol/min/kgFFM, p = .03), insulin-mediated suppression of adipose tissue lipolysis (-4.5 ± 13.7% vs. +5.9 ± 11%, p = .04), fasting plasma glucose levels (-0.3 ± 1.0 vs. +0.5 ± 0.8 mmol/l, p = .02), exercise performance (+0.40 ± 0.2 vs. +0.2 ± 0.1 W/kg, p = .05) and fat mass (-1.2 ± 1.3 vs. -0.2 ± 1.0 kg, p = .03). In addition, exercise training in the afternoon also tended to elicit superior effects on basal hepatic glucose output (p = .057). Our findings suggest that metabolically compromised subjects may reap more pronounced metabolic benefits from exercise training when this training is performed in the afternoon versus morning. CLINICALTRIALS.GOV ID: NCT01317576.
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Affiliation(s)
- Rodrigo Mancilla
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
- Department of Nutrition and Movement SciencesMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Bram Brouwers
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
- Department of Nutrition and Movement SciencesMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Vera B. Schrauwen‐Hinderling
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
- Department of RadiologyMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Matthijs K. C. Hesselink
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
- Department of Nutrition and Movement SciencesMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Joris Hoeks
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
- Department of Nutrition and Movement SciencesMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Patrick Schrauwen
- NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
- Department of Nutrition and Movement SciencesMaastricht University Medical CenterMaastrichtThe Netherlands
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Hoffmann C, Schneeweiss P, Randrianarisoa E, Schnauder G, Kappler L, Machann J, Schick F, Fritsche A, Heni M, Birkenfeld A, Niess AM, Häring HU, Weigert C, Moller A. Response of Mitochondrial Respiration in Adipose Tissue and Muscle to 8 Weeks of Endurance Exercise in Obese Subjects. J Clin Endocrinol Metab 2020; 105:5895511. [PMID: 32827042 DOI: 10.1210/clinem/dgaa571] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/19/2020] [Indexed: 01/04/2023]
Abstract
CONTEXT Exercise training improves glycemic control and increases mitochondrial content and respiration capacity in skeletal muscle. Rodent studies suggest that training increases mitochondrial respiration in adipose tissue. OBJECTIVE To assess the effects of endurance training on respiratory capacities of human skeletal muscle and abdominal subcutaneous adipose tissue and to study the correlation with improvement in insulin sensitivity. DESIGN Using high-resolution respirometry, we analyzed biopsies from 25 sedentary (VO2 peak 25.1 ± 4.0 VO2 mL/[kg*min]) subjects (16 female, 9 male; 29.8 ± 8.4 years) with obesity (body mass index [BMI] 31.5 ± 4.3 kg/m2), who did not have diabetes. They performed a supervised endurance training over 8 weeks (3 × 1 hour/week at 80% VO2 peak). RESULTS Based on change in insulin sensitivity after intervention (using the Matsuda insulin sensitivity index [ISIMats]), subjects were grouped in subgroups as responders (>15% increase in ISIMats) and low-responders. The response in ISIMats was correlated to a reduction of subcutaneous and visceral adipose tissue volume. Both groups exhibited similar increases in fitness, respiratory capacity, and abundance of mitochondrial enzymes in skeletal muscle fibers. Respiratory capacities in subcutaneous adipose tissue were not altered by the intervention. Compared with muscle fibers, adipose tissue respiration showed a preference for β-oxidation and complex II substrates. Respiratory capacities were higher in adipose tissue from female participants. CONCLUSION Our data show that the improvement of peripheral insulin sensitivity after endurance training is not directly related to an increase in mitochondrial respiratory capacities in skeletal muscle and occurs without an increase in the respiratory capacity of subcutaneous adipose tissue.
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Affiliation(s)
- Christoph Hoffmann
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Patrick Schneeweiss
- Department of Sports Medicine, University Hospital Tübingen, Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, University of Tübingen, Tübingen, Germany
| | - Elko Randrianarisoa
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
| | - Günter Schnauder
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Lisa Kappler
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
- Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Fritz Schick
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
- Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Birkenfeld
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Andreas M Niess
- Department of Sports Medicine, University Hospital Tübingen, Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, University of Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Cora Weigert
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
| | - Anja Moller
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD)
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
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31
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Genders AJ, Holloway GP, Bishop DJ. Are Alterations in Skeletal Muscle Mitochondria a Cause or Consequence of Insulin Resistance? Int J Mol Sci 2020; 21:ijms21186948. [PMID: 32971810 PMCID: PMC7554894 DOI: 10.3390/ijms21186948] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/14/2022] Open
Abstract
As a major site of glucose uptake following a meal, skeletal muscle has an important role in whole-body glucose metabolism. Evidence in humans and animal models of insulin resistance and type 2 diabetes suggests that alterations in mitochondrial characteristics accompany the development of skeletal muscle insulin resistance. However, it is unclear whether changes in mitochondrial content, respiratory function, or substrate oxidation are central to the development of insulin resistance or occur in response to insulin resistance. Thus, this review will aim to evaluate the apparent conflicting information placing mitochondria as a key organelle in the development of insulin resistance in skeletal muscle.
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Affiliation(s)
- Amanda J. Genders
- Institute for Health and Sport (iHeS), Victoria University, Melbourne 8001, Australia;
- Correspondence: ; Tel.: +61-3-9919-9556
| | - Graham P. Holloway
- Dept. Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada;
| | - David J. Bishop
- Institute for Health and Sport (iHeS), Victoria University, Melbourne 8001, Australia;
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32
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Nascimento EBM, Hangelbroek RWJ, Hooiveld GJEJ, Hoeks J, Van Marken Lichtenbelt WD, Hesselink MHC, Schrauwen P, Kersten S. Comparative transcriptome analysis of human skeletal muscle in response to cold acclimation and exercise training in human volunteers. BMC Med Genomics 2020; 13:124. [PMID: 32887608 PMCID: PMC7487556 DOI: 10.1186/s12920-020-00784-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 08/24/2020] [Indexed: 01/12/2023] Open
Abstract
Background Cold acclimation and exercise training were previously shown to increase peripheral insulin sensitivity in human volunteers with type 2 diabetes. Although cold is a potent activator of brown adipose tissue, the increase in peripheral insulin sensitivity by cold is largely mediated by events occurring in skeletal muscle and at least partly involves GLUT4 translocation, as is also observed for exercise training. Methods To investigate if cold acclimation and exercise training overlap in the molecular adaptive response in skeletal muscle, we performed transcriptomics analysis on vastus lateralis muscle collected from human subjects before and after 10 days of cold acclimation, as well as before and after a 12-week exercise training intervention. Results Cold acclimation altered the expression of 756 genes (422 up, 334 down, P < 0.01), while exercise training altered the expression of 665 genes (444 up, 221 down, P < 0.01). Principal Component Analysis, Venn diagram, similarity analysis and Rank–rank Hypergeometric Overlap all indicated significant overlap between cold acclimation and exercise training in upregulated genes, but not in downregulated genes. Overlapping gene regulation was especially evident for genes and pathways associated with extracellular matrix remodeling. Interestingly, the genes most highly induced by cold acclimation were involved in contraction and in signal transduction between nerve and muscle cells, while no significant changes were observed in genes and pathways related to insulin signaling or glucose metabolism. Conclusions Overall, our results indicate that cold acclimation and exercise training have overlapping effects on gene expression in human skeletal muscle, but strikingly these overlapping genes are designated to pathways related to tissue remodeling rather than metabolic pathways.
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Affiliation(s)
- Emmani B M Nascimento
- Department of Nutrition and Movement Sciences, Maastricht Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Roland W J Hangelbroek
- Nutrition, Metabolism and Genomics group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Guido J E J Hooiveld
- Nutrition, Metabolism and Genomics group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Joris Hoeks
- Department of Nutrition and Movement Sciences, Maastricht Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Wouter D Van Marken Lichtenbelt
- Department of Nutrition and Movement Sciences, Maastricht Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Matthijs H C Hesselink
- Department of Nutrition and Movement Sciences, Maastricht Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Patrick Schrauwen
- Department of Nutrition and Movement Sciences, Maastricht Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Sander Kersten
- Nutrition, Metabolism and Genomics group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
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33
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Baek KW, Gim JA, Park JJ. Regular moderate aerobic exercise improves high-fat diet-induced nonalcoholic fatty liver disease via monoacylglycerol O-acyltransferase 1 pathway suppression. JOURNAL OF SPORT AND HEALTH SCIENCE 2020; 9:472-478. [PMID: 32928450 PMCID: PMC7498633 DOI: 10.1016/j.jshs.2018.09.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 03/16/2018] [Accepted: 04/26/2018] [Indexed: 06/11/2023]
Abstract
PURPOSE Monoacylglycerol O-acyltransferase 1 (MGAT1) is reported to play a key role in the development of diet-induced nonalcoholic fatty liver disease (NAFLD). Thus, this study investigated the effect of exercise on suppression of the MGAT1 pathway in NAFLD tissue of high-fat diet (HFD)-induced obese rats. METHODS Male Sprague-Dawley rats were fed an HFD containing 45% fat for 6 weeks. Upon confirmation that NAFLD had been induced in the obese animals, they were divided into HFD-fed groups provided with exercise (HFD + EXE) or without exercise (HFD) and a group given dietary adjustment (DA) only, for a further 6 weeks of intervention treatment. The 6-week regular moderate aerobic exercise consisted of an accommodation phase with increasing exercise. Lipid accumulation in the liver tissue was determined by Oil Red O staining. The MGAT1 and liver lipogenic gene mRNA levels were measured by qPCR, and their protein levels by western blot assay. RESULTS Oil Red O staining showed that NAFLD was successfully induced by HFD-fed. The gene expression of MGAT1 was significantly lower in HFD + EXE than HFD. However, there was no significant difference between HFD + EXE and DA. The protein expression of MGAT1 was significantly lower in HFD + EXE than both HFD and DA. Messenger RNA and protein expression of other lipogenic genes were not different among groups. These data indicate that exercise suppresses MGAT1 pathway regardless of HFD feeding; in part, this effect could be greater than DA. CONCLUSION Our data suggest that exercise can improve NAFLD, which is probably due to suppression of MGAT1 pathway.
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Affiliation(s)
- Kyung-Wan Baek
- Division of Sport Science, Pusan National University, Busan 46241, Korea
| | - Jeong-An Gim
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Korea
| | - Jung-Jun Park
- Division of Sport Science, Pusan National University, Busan 46241, Korea.
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Kruse R, Sahebekhtiari N, Højlund K. The Mitochondrial Proteomic Signatures of Human Skeletal Muscle Linked to Insulin Resistance. Int J Mol Sci 2020; 21:ijms21155374. [PMID: 32731645 PMCID: PMC7432338 DOI: 10.3390/ijms21155374] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/20/2020] [Accepted: 07/26/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction: Mitochondria are essential in energy metabolism and cellular survival, and there is growing evidence that insulin resistance in chronic metabolic disorders, such as obesity, type 2 diabetes (T2D), and aging, is linked to mitochondrial dysfunction in skeletal muscle. Protein profiling by proteomics is a powerful tool to investigate mechanisms underlying complex disorders. However, despite significant advances in proteomics within the past two decades, the technologies have not yet been fully exploited in the field of skeletal muscle proteome. Area covered: Here, we review the currently available studies characterizing the mitochondrial proteome in human skeletal muscle in insulin-resistant conditions, such as obesity, T2D, and aging, as well as exercise-mediated changes in the mitochondrial proteome. Furthermore, we outline technical challenges and limitations and methodological aspects that should be considered when planning future large-scale proteomics studies of mitochondria from human skeletal muscle. Authors’ view: At present, most proteomic studies of skeletal muscle or isolated muscle mitochondria have demonstrated a reduced abundance of proteins in several mitochondrial biological processes in obesity, T2D, and aging, whereas the beneficial effects of exercise involve an increased content of muscle proteins involved in mitochondrial metabolism. Powerful mass-spectrometry-based proteomics now provides unprecedented opportunities to perform in-depth proteomics of muscle mitochondria, which in the near future is expected to increase our understanding of the complex molecular mechanisms underlying the link between mitochondrial dysfunction and insulin resistance in chronic metabolic disorders.
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Affiliation(s)
- Rikke Kruse
- Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark; (R.K.); (N.S.)
- Department of Clinical Research & Department of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark
| | - Navid Sahebekhtiari
- Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark; (R.K.); (N.S.)
- Department of Clinical Research & Department of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, DK-5000 Odense C, Denmark; (R.K.); (N.S.)
- Department of Clinical Research & Department of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark
- Correspondence: ; Tel.: +45-2532-06-48
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35
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Goto Y, Otsuka Y, Ashida K, Nagayama A, Hasuzawa N, Iwata S, Hara K, Tsuruta M, Wada N, Motomura S, Tajiri Y, Nomura M. Improvement of skeletal muscle insulin sensitivity by 1 week of SGLT2 inhibitor use. Endocr Connect 2020; 9:599-606. [PMID: 32580152 PMCID: PMC7354734 DOI: 10.1530/ec-20-0082] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 06/04/2020] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIMS It is currently unclear whether sodium-glucose co-transporter 2 (SGLT2) inhibitor administration can improve the insulin sensitivity as well as rapidly reduce plasma glucose concentrations in humans during the early phase of treatment initiation. This study aimed to investigate the effect of SGLT2 inhibitor on insulin sensitivity in the early phase of treatment initiation. METHODS AND RESULTS This single-center, open label, and single-arm prospective study recruited 20 patients (14 men) with type 2 diabetes mellitus (T2DM). We examined the patients' metabolic parameters before and 1 week after SGLT2 inhibitor (10 mg/day of empagliflozin) administration. The glucose infusion rate (GIR) was evaluated using the euglycemic hyperinsulinemic glucose clamp technique. Changes in laboratory and anthropometric parameters before and after SGLT2 inhibitor administration were analyzed according to the change in the GIR. The BMI, body fat amount, skeletal muscle amount, systolic blood pressure, and triglyceride level significantly decreased along with the treatment, while urinary glucose level and log GIR value significantly increased. Notably, changes in the GIR after SGLT2 inhibitor administration, which indicated improvement in peripheral insulin sensitivity, were negatively correlated with T2DM duration and positively with reduction in fluctuation of daily plasma glucose profiles before and after treatment. CONCLUSION SGLT2 inhibitor improved insulin sensitivity in the skeletal muscle independent of anthropometric changes. Patients with short duration of T2DM and insulin resistance can be good candidates for short-term SGLT2 inhibitor administration to improve insulin sensitivity in the skeletal muscle.
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Affiliation(s)
- Yuka Goto
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
| | - Yoshie Otsuka
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
| | - Kenji Ashida
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
- Correspondence should be addressed to K Ashida:
| | - Ayako Nagayama
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
| | - Nao Hasuzawa
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
| | - Shimpei Iwata
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
| | - Kento Hara
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
| | - Munehisa Tsuruta
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
| | - Nobuhiko Wada
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
| | - Seiichi Motomura
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
- Division of Endocrinology and Metabolism, Diabetes Center, Kurume Medical Center, Kokubu-machi, Kurume-city, Fukuoka, Japan
| | - Yuji Tajiri
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
- Division of Endocrinology and Metabolism, Diabetes Center, Kurume Medical Center, Kokubu-machi, Kurume-city, Fukuoka, Japan
| | - Masatoshi Nomura
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume-city, Fukuoka, Japan
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Lewis MT, Kasper JD, Bazil JN, Frisbee JC, Wiseman RW. Quantification of Mitochondrial Oxidative Phosphorylation in Metabolic Disease: Application to Type 2 Diabetes. Int J Mol Sci 2019; 20:E5271. [PMID: 31652915 PMCID: PMC6862501 DOI: 10.3390/ijms20215271] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/17/2019] [Accepted: 10/22/2019] [Indexed: 12/17/2022] Open
Abstract
Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014. T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage, and premature death. Skeletal muscle is a major site for insulin resistance and is responsible for up to 80% of glucose uptake during euglycemic hyperglycemic clamps. Glucose uptake in skeletal muscle is driven by mitochondrial oxidative phosphorylation and for this reason mitochondrial dysfunction has been implicated in T2D. In this review we integrate mitochondrial function with physiologic function to present a broader understanding of mitochondrial functional status in T2D utilizing studies from both human and rodent models. Quantification of mitochondrial function is explained both in vitro and in vivo highlighting the use of proper controls and the complications imposed by obesity and sedentary lifestyle. This review suggests that skeletal muscle mitochondria are not necessarily dysfunctional but limited oxygen supply to working muscle creates this misperception. Finally, we propose changes in experimental design to address this question unequivocally. If mitochondrial function is not impaired it suggests that therapeutic interventions and drug development must move away from the organelle and toward the cardiovascular system.
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Affiliation(s)
- Matthew T Lewis
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
| | - Jonathan D Kasper
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
- Present address: Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
| | - Jason N Bazil
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
| | - Jefferson C Frisbee
- Department of Medical Biophysics, University of Western Ontario, London, ON N6A 3K7, Canada.
| | - Robert W Wiseman
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
- Department of Radiology, Michigan State University, East Lansing, MI 48824, USA.
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Constantin-Teodosiu D, Constantin D, Pelsers MM, Verdijk LB, van Loon L, Greenhaff PL. Mitochondrial DNA copy number associates with insulin sensitivity and aerobic capacity, and differs between sedentary, overweight middle-aged males with and without type 2 diabetes. Int J Obes (Lond) 2019; 44:929-936. [PMID: 31641211 DOI: 10.1038/s41366-019-0473-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 09/19/2019] [Accepted: 09/30/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND/OBJECTIVES Increased risk of type 2 diabetes mellitus (T2DM) is linked to impaired muscle mitochondrial function and reduced mitochondrial DNA copy number (mtDNAnum). However, studies have failed to control for habitual physical activity levels, which directly influences both mtDNA copy number and insulin sensitivity. We, therefore, examined whether physical conditioning status (maximal oxygen uptake, V̇O2max) was associated with skeletal muscle mitochondrial volume and mtDNAnum, and was predictive of T2DM in overweight, middle-aged men. METHODS Whole-body physiological (ISI-insulin sensitivity index, HOMA-IR, V̇O2max) and muscle biochemical/molecular (vastus lateralis; mtDNAnum, mitochondrial and glycolytic enzymes activity, lipid content and markers of lipid peroxidation) measurements were performed in three groups of overweight, middle-aged male volunteers (n = 10 per group): sedentary T2DM (ST2DM); sedentary control (SC) and non-sedentary control (NSC), who differed in aerobic capacity (ST2DM < SC < NSC). RESULTS mtDNAnum was greater in NSC versus SC and ST2DM (P < 0.001; P < 0.001), and less in ST2DM versus SC (P < 0.01). Across all groups, mtDNAnum positively correlated with ISI (P < 0.001; r = 0.688) and V̇O2max (normalised to free fat mass; r = 0.684, P < 0.001), and negatively correlated to HOMA-IR (r = -0.544, P < 0.01). The activity of mitochondrial enzymes (GluDH, CS and β-HAD) was greater in NSC than ST2DM (P < 0.01, P < 0.001 and P < 0.05) and SC (P < 0.05, P < 0.01 and P < 0.05), but similar between ST2DM and SC. Intramuscular-free fatty acids, triglycerides and malondialdehyde contents were similar between ST2DM and SC. CONCLUSIONS Body composition and indices of muscle mitochondrial volume/function were similar between SC and ST2DM. However, mtDNAnum differed and was positively associated with ISI, HOMA-IR and V̇O2max across all groups. Collectively, the findings support the contention that habitual physical activity is a key component of T2DM development, possibly by influencing mtDNAnum.
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Affiliation(s)
- Dumitru Constantin-Teodosiu
- MRC/ARUK Centre for Musculoskeletal Ageing Research, National Institute for Health Research Nottingham Biomedical Research Centre, School of Life Sciences, Nottingham University Medical School, Nottingham, NG7 2UH, UK.
| | - Despina Constantin
- MRC/ARUK Centre for Musculoskeletal Ageing Research, National Institute for Health Research Nottingham Biomedical Research Centre, School of Life Sciences, Nottingham University Medical School, Nottingham, NG7 2UH, UK
| | - Maurice M Pelsers
- NUTRIM School for Nutrition and Translational Research in Metabolism, Department of Human Biology and Movement Sciences, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Lex B Verdijk
- NUTRIM School for Nutrition and Translational Research in Metabolism, Department of Human Biology and Movement Sciences, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Luc van Loon
- NUTRIM School for Nutrition and Translational Research in Metabolism, Department of Human Biology and Movement Sciences, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Paul L Greenhaff
- MRC/ARUK Centre for Musculoskeletal Ageing Research, National Institute for Health Research Nottingham Biomedical Research Centre, School of Life Sciences, Nottingham University Medical School, Nottingham, NG7 2UH, UK
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Sabaratnam R, Pedersen AJ, Eskildsen TV, Kristensen JM, Wojtaszewski JFP, Højlund K. Exercise Induction of Key Transcriptional Regulators of Metabolic Adaptation in Muscle Is Preserved in Type 2 Diabetes. J Clin Endocrinol Metab 2019; 104:4909-4920. [PMID: 31135885 DOI: 10.1210/jc.2018-02679] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 05/22/2019] [Indexed: 12/30/2022]
Abstract
CONTEXT Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. Regular exercise improves insulin sensitivity, mitochondrial function, and energy metabolism. Thus, an impaired response to exercise may contribute to insulin resistance. OBJECTIVE We hypothesized that key transcriptional regulators of metabolic adaptation to exercise show an attenuated response in skeletal muscle in T2D. DESIGN AND PATIENTS Skeletal muscle biopsies were obtained from 13 patients with T2D and 14 age- and weight-matched controls before, immediately after 1 hour acute exercise (70% maximal pulmonary oxygen uptake), and 3 hours into recovery to examine mRNA expression of key transcription factors and downstream targets and activity of key upstream kinases underlying the metabolic adaptation to exercise. RESULTS Acute exercise increased gene expression of the nuclear hormone receptor 4A (NR4A) subfamily (∼4- to 36-fold) and other key transcription factors, including ATF3, EGR1, JUNB, SIK1, PPARA, and PPARG (∼1.5- to 12-fold), but with no differences between groups. The expression of NR4A1 (approximately eightfold) and NR4A3 (∼75-fold) was further increased 3 hours into recovery, whereas most muscle transcripts sustained elevated or returned to basal levels, again with no differences between groups. Muscle expression of HKII and SLC2A4 and hexokinase II protein content were reduced in patients with T2D. The phosphorylation of p38 MAPK, Erk1/2, Ca2+/calmodulin-dependent kinase II, and cAMP-responsive element-binding protein was equally increased in response to exercise and/or recovery in both groups. CONCLUSION Acute exercise elicits a pronounced and overall similar increase in expression of key transcription factors and activation of key upstream kinases involved in muscle metabolic adaptation to exercise in patients with T2D and weight-matched controls.
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Affiliation(s)
- Rugivan Sabaratnam
- Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark
- Section of Molecular Diabetes and Metabolism, Department of Clinical Research, University of Southern Denmark, Odense C, Denmark
- Department of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
| | - Andreas J Pedersen
- Section of Molecular Diabetes and Metabolism, Department of Clinical Research, University of Southern Denmark, Odense C, Denmark
- Department of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
| | - Tilde V Eskildsen
- Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense M, Denmark
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense C, Denmark
| | - Jonas M Kristensen
- Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen F P Wojtaszewski
- Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense C, Denmark
- Section of Molecular Diabetes and Metabolism, Department of Clinical Research, University of Southern Denmark, Odense C, Denmark
- Department of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
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Tang W, Zhang B, Wang H, Li M, Wang H, Liu F, Zhu D, Bi Y. Improved skeletal muscle energy metabolism relates to the recovery of β cell function by intensive insulin therapy in drug naïve type 2 diabetes. Diabetes Metab Res Rev 2019; 35:e3177. [PMID: 31077529 DOI: 10.1002/dmrr.3177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 04/15/2019] [Accepted: 05/07/2019] [Indexed: 12/21/2022]
Abstract
AIMS Diminished energy turnover of skeletal muscle is involved in the development of type 2 diabetes. Intensive insulin therapy has been reported to maintain glycaemic control in newly diagnosed type 2 diabetes, while the underlying mechanism remains unclear. Herein, we aimed to characterize the contribution of muscular mitochondrial oxidative phosphorylation (OxPhos) activity to insulin-induced glycaemic control. MATERIALS AND METHODS There were 21 drug naïve patients with type 2 diabetes receiving continuous subcutaneous insulin infusion for 7 days. Nine nondiabetics matched for age, body mass index, and physical activity were recruited as controls. We applied 31 P magnetic resonance spectroscopy to record in vivo muscular phosphocreatine (PCr) flux in controls and diabetics before and after insulin therapy. The mitochondrial OxPhos rate was calculated as ΔPCr / Δtime during the first 50 seconds after cessation of exercise. RESULTS In drug naïve type 2 diabetes, muscular mitochondrial OxPhos rate was restored after insulin therapy. Notably, this alteration was positively associated with the improvements of 1,5-anhydroglucitol, a serum marker for glucose control over the last 1 week, as well as homeostasis model assessment of β cell function and C-peptide/glucose ratio t0 , two indices for basal insulin secretion. Furthermore, patients with diabetes family history and more severe glucotoxicity tend to achieve greater improvement in mitochondrial function by insulin. CONCLUSIONS This study provides evidence that intensive insulin therapy facilitates muscular energy metabolism in drug naïve type 2 diabetes. It correlates to the recovery of β cell function, contributing to insulin-induced glucose control.
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Affiliation(s)
- Wenjuan Tang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Bing Zhang
- Department of Radiology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Huiting Wang
- Department of Radiology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Ming Li
- Department of Radiology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Hongdong Wang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Fangcen Liu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
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Lewis MT, Kasper JD, Bazil JN, Frisbee JC, Wiseman RW. Skeletal muscle energetics are compromised only during high-intensity contractions in the Goto-Kakizaki rat model of type 2 diabetes. Am J Physiol Regul Integr Comp Physiol 2019; 317:R356-R368. [PMID: 31188651 PMCID: PMC6732426 DOI: 10.1152/ajpregu.00127.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/07/2019] [Accepted: 06/07/2019] [Indexed: 12/24/2022]
Abstract
Type 2 diabetes (T2D) presents with hyperglycemia and insulin resistance, affecting over 30 million people in the United States alone. Previous work has hypothesized that mitochondria are dysfunctional in T2D and results in both reduced ATP production and glucose disposal. However, a direct link between mitochondrial function and T2D has not been determined. In the current study, the Goto-Kakizaki (GK) rat model of T2D was used to quantify mitochondrial function in vitro and in vivo over a broad range of contraction-induced metabolic workloads. During high-frequency sciatic nerve stimulation, hindlimb muscle contractions at 2- and 4-Hz intensities, the GK rat failed to maintain similar bioenergetic steady states to Wistar control (WC) rats measured by phosphorus magnetic resonance spectroscopy, despite similar force production. Differences were not due to changes in mitochondrial content in red (RG) or white gastrocnemius (WG) muscles (cytochrome c oxidase, RG: 22.2 ± 1.6 vs. 23.3 ± 1.7 U/g wet wt; WG: 10.8 ± 1.1 vs. 12.1 ± 0.9 U/g wet wt; GK vs. WC, respectively). Mitochondria isolated from muscles of GK and WC rats also showed no difference in mitochondrial ATP production capacity in vitro, measured by high-resolution respirometry. At lower intensities (0.25-1 Hz) there were no detectable differences between GK and WC rats in sustained energy balance. There were similar phosphocreatine concentrations during steady-state contraction and postcontractile recovery (τ = 72 ± 6 s GK versus 71 ± 2 s WC). Taken together, these results suggest that deficiencies in skeletal muscle energetics seen at higher intensities are not due to mitochondrial dysfunction in the GK rat.
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Affiliation(s)
- Matthew T Lewis
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Jonathan D Kasper
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Jason N Bazil
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Jefferson C Frisbee
- Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada
| | - Robert W Wiseman
- Department of Physiology, Michigan State University, East Lansing, Michigan
- Department of Radiology, Michigan State University, East Lansing, Michigan
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Parsanathan R, Jain SK. Hydrogen sulfide regulates circadian-clock genes in C 2C 12 myotubes and the muscle of high-fat-diet-fed mice. Arch Biochem Biophys 2019; 672:108054. [PMID: 31351068 DOI: 10.1016/j.abb.2019.07.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/18/2019] [Accepted: 07/24/2019] [Indexed: 12/31/2022]
Abstract
Hydrogen sulfide (H2S) is an endogenous novel gasotransmitter which is implicated in the pathophysiology of the metabolic syndrome. Core clock genes (CCG) and its controlled genes disruption is implicated in the progression of metabolic syndrome. We examined whether H2S has any effect on CCG in the skeletal muscle of mice fed a high-fat diet (HFD) and in myotubes. In the muscle of HFD-mice, the expression of H2S biosynthesis enzyme genes (CSE, CBS, and 3-Mpst) along with antioxidant genes (GCLC, GCLM, GSS, and GSR) involved in GSH biosynthesis and recycling were reduced significantly, but the oxidative stress (OS) increased. Expression of the CCG (Bmal1, Clock, RORα, Cry2, Per2) and clock-controlled genes (PPARγ, PGC-1α, RXRα) was downregulated, whereas the levels of PPARα mRNA were upregulated. Similar to that in the muscle of HFD-mice, in vitro myotubes exposed to high glucose or palmitate to mimic metabolic syndrome, showed an increased OS and decreased in CSE mRNA, H2S production and CCG mRNA levels were also downregulated. TNF and MCP-1 treatment on the myotubes was similar to that observed in HFD-muscle, with that the Rev-erbα mRNA was upregulated. Inhibition (siRNA/pharmacological inhibitors) of both CSE and GCLC (the rate-limiting enzyme in GSH biosynthesis) decreased H2S, and increased OS; Bmal1 and Clock mRNA levels were downregulated, while Rev-erbα increased significantly in these conditions. CSE KD myotubes were post-treated with an H2S donor partially restored the mRNA levels of core clock genes. These findings report that the deficiencies of H2S/GSH impair expression of CCG and treatment with H2S donor or GSH precursor exert a positive effect over CCG. Thus, suggest that H2S as a new endogenous factor for regulating circadian clock, and its donors could provide a novel chrono-pharmacological therapy to manage metabolic disorders.
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Affiliation(s)
- Rajesh Parsanathan
- Department of Pediatrics and Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA, 71130, USA
| | - Sushil K Jain
- Department of Pediatrics and Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA, 71130, USA.
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Rossaneis MA, Andrade SMD, Gvozd R, Pissinati PDSC, Haddad MDCL. Factors associated with glycemic control in people with diabetes mellitus. CIENCIA & SAUDE COLETIVA 2019; 24:997-1005. [PMID: 30892520 DOI: 10.1590/1413-81232018243.02022017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 04/28/2017] [Indexed: 11/22/2022] Open
Abstract
Investigate the factors associated with the glycemic control in people with diabetes mellitus (DM). Cross-sectional study with 746 people with type-2 DM of age 40 or older. The following variables were selected: socioeconomic, clinical data, lifestyle and the risk of developing foot ulcers. Data collection occurred through interviews, medical record analysis and clinical examination of the lower limbs. We used the Poisson multiple regression model to determine the crude and adjusted prevalence ratios (PR) of the glycemic alteration. The alteration in the glycated hemoglobin (HbA1c) test was considered as a dependent variable in this study, which has been classified as high when the result was higher than 7%. The alteration in HbA1c was present in 68.9% of the participants and was more prevalent in individuals aged between 50 and 69 (PR = 1.38/IC95% = 1.09-1.75), who were taking insulin (PR = 1.35/IC95% = 1.24-1.47), obese (PR = 1.14/IC95% = 1.03-1.25) and who had foot ulceration risk (PR = 1.14/IC95% = 1.09-1.28). Individuals aged between 50 and 69; the ones who used insulin; the obese ones; and those who had a risk of foot ulceration, presented higher prevalence rates of alteration in the glycated hemoglobin.
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Affiliation(s)
- Mariana Angela Rossaneis
- Departamento de Enfermagem, Centro de Ciências da Saúde,Universidade Estadual de Londrina. Av. Robert Kock 60, Vila Operária. 86039-440 Londrina PR Brasil.
| | - Selma Maffei de Andrade
- Departamento de Saúde Coletiva, Centro de Ciências da Saúde, Universidade Estadual de Londrina. Londrina PR Brasil
| | - Raquel Gvozd
- Departamento de Enfermagem, Centro de Ciências da Saúde,Universidade Estadual de Londrina. Av. Robert Kock 60, Vila Operária. 86039-440 Londrina PR Brasil.
| | - Paloma de Souza Cavalcante Pissinati
- Departamento de Enfermagem, Centro de Ciências da Saúde,Universidade Estadual de Londrina. Av. Robert Kock 60, Vila Operária. 86039-440 Londrina PR Brasil.
| | - Maria do Carmo Lourenço Haddad
- Departamento de Enfermagem, Centro de Ciências da Saúde,Universidade Estadual de Londrina. Av. Robert Kock 60, Vila Operária. 86039-440 Londrina PR Brasil.
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Di Meo S, Napolitano G, Venditti P. Mediators of Physical Activity Protection against ROS-Linked Skeletal Muscle Damage. Int J Mol Sci 2019; 20:E3024. [PMID: 31226872 PMCID: PMC6627449 DOI: 10.3390/ijms20123024] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/12/2019] [Accepted: 06/17/2019] [Indexed: 12/24/2022] Open
Abstract
Unaccustomed and/or exhaustive exercise generates excessive free radicals and reactive oxygen and nitrogen species leading to muscle oxidative stress-related damage and impaired contractility. Conversely, a moderate level of free radicals induces the body's adaptive responses. Thus, a low oxidant level in resting muscle is essential for normal force production, and the production of oxidants during each session of physical training increases the body's antioxidant defenses. Mitochondria, NADPH oxidases and xanthine oxidases have been identified as sources of free radicals during muscle contraction, but the exact mechanisms underlying exercise-induced harmful or beneficial effects yet remain elusive. However, it is clear that redox signaling influences numerous transcriptional activators, which regulate the expression of genes involved in changes in muscle phenotype. The mitogen-activated protein kinase family is one of the main links between cellular oxidant levels and skeletal muscle adaptation. The family components phosphorylate and modulate the activities of hundreds of substrates, including transcription factors involved in cell response to oxidative stress elicited by exercise in skeletal muscle. To elucidate the complex role of ROS in exercise, here we reviewed the literature dealing on sources of ROS production and concerning the most important redox signaling pathways, including MAPKs that are involved in the responses to acute and chronic exercise in the muscle, particularly those involved in the induction of antioxidant enzymes.
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Affiliation(s)
- Sergio Di Meo
- Dipartimento di Biologia, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cinthia, I-80126 Napoli, Italy.
| | - Gaetana Napolitano
- Dipartimento di Scienze e Tecnologie, Università degli Studi di Napoli Parthenope, via Acton n. 38-I-80133 Napoli, Italy.
| | - Paola Venditti
- Dipartimento di Biologia, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cinthia, I-80126 Napoli, Italy.
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Fritzen AM, Thøgersen FB, Thybo K, Vissing CR, Krag TO, Ruiz-Ruiz C, Risom L, Wibrand F, Høeg LD, Kiens B, Duno M, Vissing J, Jeppesen TD. Adaptations in Mitochondrial Enzymatic Activity Occurs Independent of Genomic Dosage in Response to Aerobic Exercise Training and Deconditioning in Human Skeletal Muscle. Cells 2019; 8:cells8030237. [PMID: 30871120 PMCID: PMC6468422 DOI: 10.3390/cells8030237] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 03/08/2019] [Accepted: 03/09/2019] [Indexed: 12/15/2022] Open
Abstract
Mitochondrial DNA (mtDNA) replication is thought to be an integral part of exercise-training-induced mitochondrial adaptations. Thus, mtDNA level is often used as an index of mitochondrial adaptations in training studies. We investigated the hypothesis that endurance exercise training-induced mitochondrial enzymatic changes are independent of genomic dosage by studying mtDNA content in skeletal muscle in response to six weeks of knee-extensor exercise training followed by four weeks of deconditioning in one leg, comparing results to the contralateral untrained leg, in 10 healthy, untrained male volunteers. Findings were compared to citrate synthase activity, mitochondrial complex activities, and content of mitochondrial membrane markers (porin and cardiolipin). One-legged knee-extensor exercise increased endurance performance by 120%, which was accompanied by increases in power output and peak oxygen uptake of 49% and 33%, respectively (p < 0.01). Citrate synthase and mitochondrial respiratory chain complex I–IV activities were increased by 51% and 46–61%, respectively, in the trained leg (p < 0.001). Despite a substantial training-induced increase in mitochondrial activity of TCA and ETC enzymes, there was no change in mtDNA and mitochondrial inner and outer membrane markers (i.e., cardiolipin and porin). Conversely, deconditioning reduced endurance capacity by 41%, muscle citrate synthase activity by 32%, and mitochondrial complex I–IV activities by 29–36% (p < 0.05), without any change in mtDNA and porin and cardiolipin content in the previously trained leg. The findings demonstrate that the adaptations in mitochondrial enzymatic activity after aerobic endurance exercise training and the opposite effects of deconditioning are independent of changes in the number of mitochondrial genomes, and likely relate to changes in the rate of transcription of mtDNA.
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Affiliation(s)
- Andreas M Fritzen
- Copenhagen Neuromuscular Center, Section 3342, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Frank B Thøgersen
- Copenhagen Neuromuscular Center, Section 3342, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Kasper Thybo
- Copenhagen Neuromuscular Center, Section 3342, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Christoffer R Vissing
- Copenhagen Neuromuscular Center, Section 3342, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Thomas O Krag
- Copenhagen Neuromuscular Center, Section 3342, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
- Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Cristina Ruiz-Ruiz
- Copenhagen Neuromuscular Center, Section 3342, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Lotte Risom
- Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Flemming Wibrand
- Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Louise D Høeg
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Bente Kiens
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Morten Duno
- Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - John Vissing
- Copenhagen Neuromuscular Center, Section 3342, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
- Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Tina D Jeppesen
- Copenhagen Neuromuscular Center, Section 3342, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
- Department of Neurology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
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Xie M, Jiang L, Dun Y, Zhang W, Liu S. Trimetazidine combined with exercise improves exercise capacity and anti-fatal stress ability through enhancing mitochondrial quality control. Life Sci 2019; 224:157-168. [PMID: 30872179 DOI: 10.1016/j.lfs.2019.03.027] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/04/2019] [Accepted: 03/10/2019] [Indexed: 12/15/2022]
Abstract
AIMS To explore the effects of trimetazidine combined with exercise on EC and anti-fatal stress ability, and illustrate the underlying mechanism. METHODS C57BL/6 mice were randomly assigned to four groups (n = 11 in each group): the control, exercise, trimetazidine and trimetazidine + exercise (TE) groups. Mice were accordingly given saline (ig), Aerobic exercise (AE), trimetazidine (ig), or a combination of trimetazidine (ig) and AE for five weeks. After the intervention, each group was randomly subdivided into rest and exhaustive exercise (EE) subgroups. The mice in the control-EE and TE-EE subgroups underwent fatal stress experiments. EC and anti-fatal stress ability were assessed respectively. Mitochondrial quality control (MQC) in skeletal muscle were measured at the protein level and the organelle level. KEY FINDINGS A significantly increased exhaustive swimming time was observed in exercise (39.10 ± 12.58 min vs 14.18 ± 4.37 min), trimetazidine (33.73 ± 8.45 min vs 14.18 ± 4.37 min) and TE groups (73.78 ± 18.95 min vs 14.18 ± 4.37 min) compared with that in the control group, and a synergistic effect was detected (P < 0.05). Fatal stress experiments successfully induced skeletal muscle damage, including increased creatine kinase activity, myofibrosis, and impaired antioxidative enzyme system, all those were significantly alleviated by trimetazidine supplementation combined with AE precondition (P < 0.05). Meanwhile, AE and trimetazidine alone or combined, significantly enhanced the MQC in normal mice by activating mitochondrial biogenesis, dynamics and mitophagy, and that in mice underwent fatal stress stimulus (P < 0.05). SIGNIFICANCE This study for the first time found that trimetazidine and AE have synergistic effects on improving EC. Moreover, the combination of both interventions enhances anti-fatal stress ability. Enhancing MQC may be a key mechanism of AE combined with trimetazidine that improves EC and anti-fatal stress ability.
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Affiliation(s)
- Murong Xie
- Cardiac Rehabilitation Center, Department of Rehabilitation, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha 410008, China
| | - Lingjun Jiang
- Cardiac Rehabilitation Center, Department of Rehabilitation, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha 410008, China
| | - Yaoshan Dun
- Cardiac Rehabilitation Center, Department of Rehabilitation, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha 410008, China
| | - Wenliang Zhang
- Cardiac Rehabilitation Center, Department of Rehabilitation, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha 410008, China
| | - Suixin Liu
- Cardiac Rehabilitation Center, Department of Rehabilitation, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha 410008, China.
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Pinti MV, Fink GK, Hathaway QA, Durr AJ, Kunovac A, Hollander JM. Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis. Am J Physiol Endocrinol Metab 2019; 316:E268-E285. [PMID: 30601700 PMCID: PMC6397358 DOI: 10.1152/ajpendo.00314.2018] [Citation(s) in RCA: 248] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 11/27/2018] [Accepted: 12/19/2018] [Indexed: 12/20/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a systemic disease characterized by hyperglycemia, hyperlipidemia, and organismic insulin resistance. This pathological shift in both circulating fuel levels and energy substrate utilization by central and peripheral tissues contributes to mitochondrial dysfunction across organ systems. The mitochondrion lies at the intersection of critical cellular pathways such as energy substrate metabolism, reactive oxygen species (ROS) generation, and apoptosis. It is the disequilibrium of these processes in T2DM that results in downstream deficits in vital functions, including hepatocyte metabolism, cardiac output, skeletal muscle contraction, β-cell insulin production, and neuronal health. Although mitochondria are known to be susceptible to a variety of genetic and environmental insults, the accumulation of mitochondrial DNA (mtDNA) mutations and mtDNA copy number depletion is helping to explain the prevalence of mitochondrial-related diseases such as T2DM. Recent work has uncovered novel mitochondrial biology implicated in disease progressions such as mtDNA heteroplasmy, noncoding RNA (ncRNA), epigenetic modification of the mitochondrial genome, and epitranscriptomic regulation of the mtDNA-encoded mitochondrial transcriptome. The goal of this review is to highlight mitochondrial dysfunction observed throughout major organ systems in the context of T2DM and to present new ideas for future research directions based on novel experimental and technological innovations in mitochondrial biology. Finally, the field of mitochondria-targeted therapeutics is discussed, with an emphasis on novel therapeutic strategies to restore mitochondrial homeostasis in the setting of T2DM.
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Affiliation(s)
- Mark V Pinti
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
- West Virginia University School of Pharmacy , Morgantown, West Virginia
| | - Garrett K Fink
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
| | - Quincy A Hathaway
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
- Toxicology Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| | - Andrya J Durr
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| | - Amina Kunovac
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| | - John M Hollander
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
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Osborne B, Brandon AE, Smith GC, Turner N. Impact of Lifestyle and Clinical Interventions on Mitochondrial Function in Obesity and Type 2 Diabetes. MITOCHONDRIA IN OBESITY AND TYPE 2 DIABETES 2019:367-397. [DOI: 10.1016/b978-0-12-811752-1.00016-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kruse R, Højlund K. Proteomic study of skeletal muscle in obesity and type 2 diabetes: progress and potential. Expert Rev Proteomics 2018; 15:817-828. [PMID: 30251560 DOI: 10.1080/14789450.2018.1528147] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Skeletal muscle is the major site of insulin-stimulated glucose uptake and imparts the beneficial effects of exercise, and hence is an important site of insulin resistance in obesity and type 2 diabetes (T2D). Despite extensive molecular biology-oriented research the molecular mechanisms underlying insulin resistance in skeletal muscle remain to be established. Areas covered: The proteomic capabilities have greatly improved over the last decades. This review summarizes the technical challenges in skeletal muscle proteomics studies as well as the results of quantitative proteomic studies of skeletal muscle in relation to obesity, T2D, and exercise. Expert commentary: Current available proteomic studies contribute to the view that insulin resistance in obesity and T2D is associated with increased glycolysis and reduced mitochondrial oxidative metabolism in skeletal muscle, and that the latter can be improved by exercise. Future proteomics studies should be designed to markedly intensify the identification of abnormalities in metabolic and signaling pathways in skeletal muscle of insulin-resistant individuals to increase the understanding of the pathogenesis of T2D, but more importantly to identify multiple novel targets of treatment of which at least some can be safely targeted by novel drugs to treat and prevent T2D and reduce risk of cardiovascular disease.
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Affiliation(s)
- Rikke Kruse
- a The Section of Molecular Diabetes and Metabolism, Department of Clinical Research and Department of Molecular Medicine , University of Southern Denmark , Odense , Denmark.,b Steno Diabetes Center Odense , Odense University Hospital , Odense , Denmark
| | - Kurt Højlund
- a The Section of Molecular Diabetes and Metabolism, Department of Clinical Research and Department of Molecular Medicine , University of Southern Denmark , Odense , Denmark.,b Steno Diabetes Center Odense , Odense University Hospital , Odense , Denmark
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Larsen S, Lundby AM, Dandanell S, Oberholzer L, Keiser S, Andersen AB, Haider T, Lundby C. Four days of bed rest increases intrinsic mitochondrial respiratory capacity in young healthy males. Physiol Rep 2018; 6:e13793. [PMID: 30221830 PMCID: PMC6139706 DOI: 10.14814/phy2.13793] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 06/18/2018] [Accepted: 06/19/2018] [Indexed: 11/24/2022] Open
Abstract
Bed rest leads to impaired glucose tolerance. Whether this is linked to maladaptation's in skeletal muscle mitochondrial function and in particular to the level of reactive oxygen species (ROS) is at present unknown. The aim of this longitudinal study was to quantify skeletal muscle mitochondrial function (respiratory capacity and ROS production) together with glucose tolerance after 4 days of strict bed rest in healthy young male subjects (n = 14). Mitochondrial function was determined in permeabilized muscle fibers using high-resolution respirometry and fluorometry, mitochondrial content (citrate synthase [CS] activity) and antioxidant protein expression levels were assessed in parallel to this. Glucose tolerance was determined by means of oral glucose tolerance tests. Intrinsic mitochondrial respiratory capacity was augmented after the bed rest period (CI + IIP : 0.43 ± 0.12 vs. 0.55 ± 0.14 [pmol/sec/mg]/CS activity), due to a decreased CS activity (158 ± 39 vs. 129 ± 25 mU/mg dw.). No differences were observed in ROS production (per mg of tissue or when normalized to CS activity). Furthermore, the protein content for catalase was increased while superoxide dismutase and glutathione peroxidase remained unaffected. These findings were accompanied by an impaired glucose tolerance after the bed rest period (Matsuda index: 12 ± 6 vs. 9 ± 5). The change in intrinsic mitochondrial respiratory capacity could be an early indication in the development of impaired glucose tolerance. The increased catalase protein content might explain that no change was seen in ROS production after 4 days of bed rest. Whether these findings can be extrapolated to lifestyle-dependent decrements in physical activity and the development of type-2-diabetes remains unknown.
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Affiliation(s)
- Steen Larsen
- XlabCenter for Healthy AgingDepartment of Biomedical SciencesFaculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
- Clinical Research CentreMedical University of BialystokBialystokPoland
| | | | - Sune Dandanell
- XlabCenter for Healthy AgingDepartment of Biomedical SciencesFaculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
- Institute of PhysiologyUniversity of ZürichZürichSwitzerland
| | | | - Stefanie Keiser
- Institute of PhysiologyUniversity of ZürichZürichSwitzerland
| | | | - Thomas Haider
- Institute of PhysiologyUniversity of ZürichZürichSwitzerland
| | - Carsten Lundby
- Institute of PhysiologyUniversity of ZürichZürichSwitzerland
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Lund MT, Larsen S, Hansen M, Courraud J, Floyd AK, Støckel M, Helge JW, Dela F. Mitochondrial respiratory capacity remains stable despite a comprehensive and sustained increase in insulin sensitivity in obese patients undergoing gastric bypass surgery. Acta Physiol (Oxf) 2018; 223:e13032. [PMID: 29330917 DOI: 10.1111/apha.13032] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 01/05/2018] [Accepted: 01/05/2018] [Indexed: 12/15/2022]
Abstract
AIM It has been proposed, but not yet demonstrated by convincing evidence in published articles, that insulin resistance and mitochondrial respiratory function are causally related physiological phenomena. Here, we tested the prediction that weight loss-induced increase in insulin sensitivity will correlate with a corresponding change in mitochondrial respiratory capacity over the same time period. METHODS Insulin sensitivity was evaluated using the hyperinsulinaemic-euglycaemic clamp technique, and skeletal muscle mitochondrial respiratory capacity was evaluated by high-resolution respirometry in 26 patients with obesity. Each experiment was performed ~2 months and 1-2 weeks before, and ~4 and ~19 months after Roux-en-Y gastric bypass (RYGB) surgery. RESULTS A substantial weight loss was observed in all patients, and insulin sensitivity increased in all patients over the 21-months time period of the study. In contrast, skeletal muscle mitochondrial respiratory capacity, intrinsic mitochondrial respiratory capacity and mitochondrial content remained unchanged over the same time period. CONCLUSION Among obese patients with and without type 2 diabetes undergoing RYGB surgery, intrinsic mitochondrial respiratory capacity in skeletal muscle is not correlated with insulin sensitivity before or after the surgical intervention. Mitochondrial respiratory function may not be germane to the pathophysiology and/or aetiology of obesity and/or type 2 diabetes.
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Affiliation(s)
- M. T. Lund
- Xlab; Center for Healthy Aging; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
- Department of Surgery; Holbak Hospital; Holbak Denmark
| | - S. Larsen
- Xlab; Center for Healthy Aging; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
| | - M. Hansen
- Xlab; Center for Healthy Aging; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
| | - J. Courraud
- Xlab; Center for Healthy Aging; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
- Danish Center for Newborn screening; Department of Congenital Disorders; Statens Serum Institut; Copenhagen Denmark
| | - A. K. Floyd
- Department of Surgery; Holbak Hospital; Holbak Denmark
| | - M. Støckel
- Department of Surgery; Herlev University Hospital; Herlev Denmark
| | - J. W. Helge
- Xlab; Center for Healthy Aging; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
| | - F. Dela
- Xlab; Center for Healthy Aging; Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
- Department of Geriatrics; Bispebjerg University Hospital; Copenhagen Denmark
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