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For: Sato M, Dehvari N, Oberg AI, Dallner OS, Sandström AL, Olsen JM, Csikasz RI, Summers RJ, Hutchinson DS, Bengtsson T. Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle. Diabetes 2014;63:4115-29. [PMID: 25008179 DOI: 10.2337/db13-1860] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]

For:	Sato M, Dehvari N, Oberg AI, Dallner OS, Sandström AL, Olsen JM, Csikasz RI, Summers RJ, Hutchinson DS, Bengtsson T. Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle. Diabetes 2014;63:4115-29. [PMID: 25008179 DOI: 10.2337/db13-1860] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]

Number

Cited by Other Article(s)

Wang T, Chen S, Zhou D, Hong Z. Exploring receptors for pro-resolving and non-pro-resolving mediators as therapeutic targets for sarcopenia. Metabolism 2025;165:156148. [PMID: 39892864 DOI: 10.1016/j.metabol.2025.156148] [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: 09/26/2024] [Revised: 01/01/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025]

Ansari P, Reberio AD, Ansari NJ, Kumar S, Khan JT, Chowdhury S, Abd El-Mordy FM, Hannan JMA, Flatt PR, Abdel-Wahab YHA, Seidel V. Therapeutic Potential of Medicinal Plants and Their Phytoconstituents in Diabetes, Cancer, Infections, Cardiovascular Diseases, Inflammation and Gastrointestinal Disorders. Biomedicines 2025;13:454. [PMID: 40002867 PMCID: PMC11853317 DOI: 10.3390/biomedicines13020454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/04/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open

Abstract

Conditions like diabetes mellitus (DM), cancer, infections, inflammation, cardiovascular diseases (CVDs), and gastrointestinal (GI) disorders continue to have a major global impact on mortality and morbidity. Medicinal plants have been used since ancient times in ethnomedicine (e.g., Ayurveda, Unani, Traditional Chinese Medicine, and European Traditional Medicine) for the treatment of a wide range of disorders. Plants are a rich source of diverse phytoconstituents with antidiabetic, anticancer, antimicrobial, antihypertensive, antioxidant, antihyperlipidemic, cardioprotective, immunomodulatory, and/or anti-inflammatory activities. This review focuses on the 35 plants most commonly reported for the treatment of these major disorders, with a particular emphasis on their traditional uses, phytoconstituent contents, pharmacological properties, and modes of action. Active phytomolecules with therapeutic potential include cucurbitane triterpenoids, diosgenin, and limonoids (azadiradione and gedunin), which exhibit antidiabetic properties, with cucurbitane triterpenoids specifically activating Glucose Transporter Type 4 (GLUT4) translocation. Capsaicin and curcumin demonstrate anticancer activity by deactivating NF-κB and arresting the cell cycle in the G2 phase. Antimicrobial activities have been observed for piperine, reserpine, berberine, dictamnine, chelerythrine, and allitridin, with the latter two triggering bacterial cell lysis. Quercetin, catechin, and genistein exhibit anti-inflammatory properties, with genistein specifically suppressing CD8+ cytotoxic T cell function. Ginsenoside Rg1 and ginsenoside Rg3 demonstrate potential for treating cardiovascular diseases, with ginsenoside Rg1 activating PPARα promoter, and the PI3K/Akt pathway. In contrast, ternatin, tannins, and quercitrin exhibit potential in gastrointestinal disorders, with quercitrin regulating arachidonic acid metabolism by suppressing cyclooxygenase (COX) and lipoxygenase activity. Further studies are warranted to fully investigate the clinical therapeutic benefits of these plants and their phytoconstituents, as well as to elucidate their underlying molecular mechanisms of action.

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Affiliation(s)

Prawej Ansari Department of Pharmacology, National Medical College and Teaching Hospital, Parsa, Birgunj 44300, Nepal Comprehensive Diabetes Center, Department of Genetics, Heersink School of Medicine, University of Alabama, Birmingham (UAB), Birmingham, AL 35233, USA; Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh (J.M.A.H.) Centre for Diabetes Research, School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK; (P.R.F.); (Y.H.A.A.-W.)
Alexa D. Reberio Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh (J.M.A.H.)
Nushrat J. Ansari Department of Radiology, National Medical College and Teaching Hospital, Parsa, Birgunj 44300, Nepal;
Sandeep Kumar Comprehensive Diabetes Center, Department of Genetics, Heersink School of Medicine, University of Alabama, Birmingham (UAB), Birmingham, AL 35233, USA;
Joyeeta T. Khan Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh (J.M.A.H.) Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72205, USA
Suraiya Chowdhury Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh (J.M.A.H.)
Fatma Mohamed Abd El-Mordy Department of Pharmacognosy and Medicinal Plants, Faculty of Pharmacy, Al-Azhar University, Cairo 11754, Egypt;
J. M. A. Hannan Department of Pharmacy, School of Pharmacy and Public Health, Independent University, Bangladesh (IUB), Dhaka 1229, Bangladesh (J.M.A.H.)
Peter R. Flatt Centre for Diabetes Research, School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK; (P.R.F.); (Y.H.A.A.-W.)
Yasser H. A. Abdel-Wahab Centre for Diabetes Research, School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK; (P.R.F.); (Y.H.A.A.-W.)
Veronique Seidel Natural Products Research Laboratory, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK;

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Solianik R, Dauksaite G, Jarutiene L, Brazaitis M. Sex-specific differences in insulin response and substrate oxidation after repeated, brief whole-body immersion in 45 °C water: A prospective, interventional study. J Therm Biol 2025;127:104029. [PMID: 39689669 DOI: 10.1016/j.jtherbio.2024.104029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 10/25/2024] [Accepted: 11/25/2024] [Indexed: 12/19/2024]

Wang T, Zhou D, Hong Z. Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2025;6:e70030. [PMID: 39764565 PMCID: PMC11702502 DOI: 10.1002/mco2.70030] [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: 07/16/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 03/17/2025] Open

Onslev J, Fiorenza M, Thomassen M, Havelund J, Bangsbo J, Færgeman N, Wojtaszewski JFP, Hostrup M. Beta2-agonist Impairs Muscle Insulin Sensitivity in Persons With Insulin Resistance. J Clin Endocrinol Metab 2024;110:275-288. [PMID: 38820114 DOI: 10.1210/clinem/dgae381] [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: 03/06/2024] [Revised: 05/19/2024] [Accepted: 05/30/2024] [Indexed: 06/02/2024]

Chen R, Yang C, Yang F, Yang A, Xiao H, Peng B, Chen C, Geng B, Xia Y. Targeting the mTOR-Autophagy Axis: Unveiling Therapeutic Potentials in Osteoporosis. Biomolecules 2024;14:1452. [PMID: 39595628 PMCID: PMC11591800 DOI: 10.3390/biom14111452] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/02/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open

Affiliation(s)

Rongjin Chen Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China Department of Orthopedics, Tianshui Hand and Foot Surgery Hospital, Tianshui 741000, China
Chenhui Yang Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China Department of Orthopedics, Tianshui Hand and Foot Surgery Hospital, Tianshui 741000, China
Fei Yang Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China
Ao Yang Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China
Hefang Xiao Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China
Bo Peng Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China
Changshun Chen Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China
Bin Geng Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China
Yayi Xia Department of Orthopedics, The Second Hospital of Lanzhou University, Lanzhou 730030, China; (R.C.); (C.Y.); (F.Y.); (A.Y.); (H.X.); (B.P.); (C.C.); (B.G.) Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China

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Xu W, Chen H, Xiao H. mTORC2: A neglected player in aging regulation. J Cell Physiol 2024;239:e31363. [PMID: 38982866 DOI: 10.1002/jcp.31363] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/21/2024] [Accepted: 06/19/2024] [Indexed: 07/11/2024]

Talamonti E, Davegardh J, Kalinovich A, van Beek SMM, Dehvari N, Halleskog C, Bokhari HM, Hutchinson DS, Ham S, Humphrys LJ, Dijon NC, Motso A, Sandstrom A, Zacharewicz E, Mutule I, Suna E, Spura J, Ditrychova K, Stoddart LA, Holliday ND, Wright SC, Lauschke VM, Nielsen S, Scheele C, Cheesman E, Hoeks J, Molenaar P, Summers RJ, Pelcman B, Yakala GK, Bengtsson T. The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis. Mol Metab 2024;85:101931. [PMID: 38796310 PMCID: PMC11258667 DOI: 10.1016/j.molmet.2024.101931] [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: 01/12/2024] [Revised: 03/09/2024] [Accepted: 03/29/2024] [Indexed: 05/28/2024] Open

Abstract

OBJECTIVE

Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs - and thus inducing cardiovascular complications - are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.

METHODS

In the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis.

RESULTS

Exposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis.

CONCLUSIONS

Our results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

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Affiliation(s)

Emanuela Talamonti Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden
Jelena Davegardh Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
Anastasia Kalinovich Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden
Sten M M van Beek Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden
Nodi Dehvari Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden
Carina Halleskog Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden
Hamza M Bokhari Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden
Dana S Hutchinson Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Seungmin Ham Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Laura J Humphrys School of Life Sciences, The Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, UK
Nicola C Dijon School of Life Sciences, The Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, UK
Aikaterini Motso Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Karolinska Institutet, Department of Physiology and Pharmacology, Stockholm, Sweden
Anna Sandstrom Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden
Evelyn Zacharewicz Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands
Ilga Mutule Latvian Institute of Organic Synthesis, Riga, Latvia
Edgars Suna Latvian Institute of Organic Synthesis, Riga, Latvia
Jana Spura Latvian Institute of Organic Synthesis, Riga, Latvia
Karolina Ditrychova Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Righospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
Leigh A Stoddart Excellerate Bioscience, The Triangle, NG2 Business Park, Nottingham, UK
Nicholas D Holliday School of Life Sciences, The Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, UK; Excellerate Bioscience, The Triangle, NG2 Business Park, Nottingham, UK
Shane C Wright Karolinska Institutet, Department of Physiology and Pharmacology, Stockholm, Sweden
Volker M Lauschke Karolinska Institutet, Department of Physiology and Pharmacology, Stockholm, Sweden; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Tübingen University, Tübingen, Germany
Soren Nielsen Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Righospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
Camilla Scheele Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Righospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
Elizabeth Cheesman Cardio-Vascular Molecular & Therapeutics Translational Research Group, Northside Clinical School of Medicine, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
Joris Hoeks Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands
Peter Molenaar Cardio-Vascular Molecular & Therapeutics Translational Research Group, Northside Clinical School of Medicine, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia; Queensland University of Technology (QUT), School of Biomedical Sciences, Institute of Health and Biomedical Innovation, 60 Musk Avenue, Kelvin Grove, Queensland, Australia
Roger J Summers Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Benjamin Pelcman Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden
Gopala K Yakala Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden.
Tore Bengtsson Atrogi AB, Tomtebodavagen 6, Solna, Stockholm, Sweden; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

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Wang Y, Vandewalle N, De Veirman K, Vanderkerken K, Menu E, De Bruyne E. Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy. Cell Commun Signal 2024;22:320. [PMID: 38862983 PMCID: PMC11165851 DOI: 10.1186/s12964-024-01699-3] [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: 02/13/2024] [Accepted: 06/03/2024] [Indexed: 06/13/2024] Open

Xu K, Zhang L, Wang T, Yu T, Zhao X, Zhang Y. Transcriptomics reveals dynamic changes in the "gene profiles" of rat supraspinatus tendon at three different time points after diabetes induction. BMC Med Genomics 2024;17:122. [PMID: 38711057 DOI: 10.1186/s12920-024-01899-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/30/2024] [Indexed: 05/08/2024] Open

Abstract

OBJECTIVE

There is increasing evidence that type 2 diabetes mellitus (T2DM) is an independent risk factor for the occur of tendinopathy. Therefore, this study is the first to explore the dynamic changes of the "gene profile" of supraspinatus tendon in rats at different time points after T2DM induction through transcriptomics, providing potential molecular markers for exploring the pathogenesis of diabetic tendinopathy.

METHODS

A total of 40 Sprague-Dawley rats were randomly divided into normal (NG, n = 10) and T2DM groups (T2DM, n = 30) and subdivided into three groups according to the duration of diabetes: T2DM-4w, T2DM-8w, and T2DM-12w groups; the duration was calculated from the time point of T2DM rat model establishment. The three comparison groups were set up in this study, T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG. Differentially expressed genes (DEGs) in 3 comparison groups were screened. The intersection of the three comparison groups' DEGs was defined as key genes that changed consistently in the supraspinatus tendon after diabetes induction. Cluster analysis, gene ontology (GO) functional annotation analysis and Kyoto encyclopedia of genes and genomes (KEGG) functional annotation and enrichment analysis were performed for DEGs.

RESULTS

T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG detected 519 (251 up-regulated and 268 down-regulated), 459 (342 up-regulated and 117 down-regulated) and 328 (255 up-regulated and 73 down-regulated) DEGs, respectively. 103 key genes of sustained changes in the supraspinatus tendon following induction of diabetes, which are the first identified biomarkers of the supraspinatus tendon as it progresses through the course of diabetes.The GO analysis results showed that the most significant enrichment in biological processes was calcium ion transmembrane import into cytosol (3 DEGs). The most significant enrichment in cellular component was extracellular matrix (9 DEGs). The most significant enrichment in molecular function was glutamate-gated calcium ion channel activity (3 DEGs). The results of KEGG pathway enrichment analysis showed that there were 17 major pathways (p < 0.05) that diabetes affected supratinusculus tendinopathy, including cAMP signaling pathway and Calcium signaling pathway.

CONCLUSIONS

Transcriptomics reveals dynamic changes in the"gene profiles"of rat supraspinatus tendon at three different time points after diabetes induction. The 103 DEGs identified in this study may provide potential molecular markers for exploring the pathogenesis of diabetic tendinopathy, and the 17 major pathways enriched in KEGG may provide new ideas for exploring the pathogenesis of diabetic tendinopathy.

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Ng YK, Blazev R, McNamara JW, Dutt M, Molendijk J, Porrello ER, Elliott DA, Parker BL. Affinity Purification-Mass Spectrometry and Single Fiber Physiology/Proteomics Reveals Mechanistic Insights of C18ORF25. J Proteome Res 2024;23:1285-1297. [PMID: 38480473 DOI: 10.1021/acs.jproteome.3c00716] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2024]

Affiliation(s)

Yaan-Kit Ng Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3052 VIC, Australia Centre for Muscle Research, The University of Melbourne, Parkville, 3052 VIC, Australia
Ronnie Blazev Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3052 VIC, Australia Centre for Muscle Research, The University of Melbourne, Parkville, 3052 VIC, Australia
James W McNamara Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3052 VIC, Australia Centre for Muscle Research, The University of Melbourne, Parkville, 3052 VIC, Australia Murdoch Children's Research Institute and Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Parkville, 3052 VIC, Australia Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, 3052 VIC, Australia Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, 3052 VIC, Australia
Mriga Dutt Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3052 VIC, Australia Centre for Muscle Research, The University of Melbourne, Parkville, 3052 VIC, Australia
Jeffrey Molendijk Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3052 VIC, Australia Centre for Muscle Research, The University of Melbourne, Parkville, 3052 VIC, Australia
Enzo R Porrello Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3052 VIC, Australia Murdoch Children's Research Institute and Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Parkville, 3052 VIC, Australia Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, 3052 VIC, Australia Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, 3052 VIC, Australia Department of Paediatrics, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, 3010 VIC, Australia
David A Elliott Murdoch Children's Research Institute and Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Parkville, 3052 VIC, Australia Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, 3052 VIC, Australia Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, 3052 VIC, Australia Department of Paediatrics, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, 3010 VIC, Australia
Benjamin L Parker Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3052 VIC, Australia Centre for Muscle Research, The University of Melbourne, Parkville, 3052 VIC, Australia

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Bralewska M, Pietrucha T, Sakowicz A. The Role of Catestatin in Preeclampsia. Int J Mol Sci 2024;25:2461. [PMID: 38473713 DOI: 10.3390/ijms25052461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/14/2024] [Accepted: 02/18/2024] [Indexed: 03/14/2024] Open

Ham S, Mukaida S, Sato M, Keov P, Bengtsson T, Furness S, Holliday ND, Evans BA, Summers RJ, Hutchinson DS. Role of G protein-coupled receptor kinases (GRKs) in β₂ -adrenoceptor-mediated glucose uptake. Pharmacol Res Perspect 2024;12:e1176. [PMID: 38332691 PMCID: PMC10853676 DOI: 10.1002/prp2.1176] [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: 09/12/2023] [Revised: 12/17/2023] [Accepted: 01/22/2024] [Indexed: 02/10/2024] Open

Abstract

Truncation of the C-terminal tail of the β2 -AR, transfection of βARKct or over-expression of a kinase-dead GRK mutant reduces isoprenaline-stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the β2 -AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO-GLUT4myc cells expressing wild-type and mutant β2 -ARs were generated and receptor affinity for [3 H]-CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by β2 -AR agonists, cAMP accumulation, GLUT4 translocation, [3 H]-2-deoxyglucose uptake, and β2 -AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between β2 -AR and β-arrestin2 or between β2 -AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to β2 -AR agonists. BRL37344 was a poor partial agonist for cAMP generation but displayed similar potency and efficacy to isoprenaline for glucose uptake and GLUT4 translocation. These responses to β2 -AR agonists occurred in CHO-GLUT4myc cells expressing β2 -ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild-type β2 -AR. However, β2 -ARs lacking phosphorylation sites failed to recruit β-arrestin2 and did not internalize. GRK2 knock-down or GRK2 inhibitors decreased isoprenaline-stimulated glucose uptake in rat L6 skeletal muscle cells. Thus, GRK phosphorylation of the β2 -AR is not associated with isoprenaline- or BRL37344-stimulated glucose uptake. However, GRKs acting as scaffold proteins are important for glucose uptake as GRK2 knock-down or GRK2 inhibition reduces isoprenaline-stimulated glucose uptake.

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Ragupathi A, Kim C, Jacinto E. The mTORC2 signaling network: targets and cross-talks. Biochem J 2024;481:45-91. [PMID: 38270460 PMCID: PMC10903481 DOI: 10.1042/bcj20220325] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/29/2023] [Accepted: 12/18/2023] [Indexed: 01/26/2024]

Dwaib H, Michel MC. Adrenoceptor Expression and Function in the Endocrine Pancreas. Handb Exp Pharmacol 2024;285:639-664. [PMID: 38872059 DOI: 10.1007/164_2024_717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]

Baker JG, Shaw DE. Asthma and COPD: A Focus on β-Agonists - Past, Present and Future. Handb Exp Pharmacol 2024;285:369-451. [PMID: 37709918 DOI: 10.1007/164_2023_679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/16/2023]

Jaunsleine K, Supe L, Spura J, van Beek S, Sandström A, Olsen J, Halleskog C, Bengtsson T, Mutule I, Pelcman B. Development of novel β₂-adrenergic receptor agonists for the stimulation of glucose uptake - The importance of chirality and ring size of cyclic amines. Bioorg Med Chem Lett 2024;97:129562. [PMID: 37967654 DOI: 10.1016/j.bmcl.2023.129562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 10/05/2023] [Accepted: 11/11/2023] [Indexed: 11/17/2023]

Baker JG, Summers RJ. Adrenoceptors: Receptors, Ligands and Their Clinical Uses, Molecular Pharmacology and Assays. Handb Exp Pharmacol 2024;285:55-145. [PMID: 38926158 DOI: 10.1007/164_2024_713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2024]

Hwang J, Balakrishnan R, Oh E, Veluthakal R, Thurmond DC. A Novel Role for DOC2B in Ameliorating Palmitate-Induced Glucose Uptake Dysfunction in Skeletal Muscle Cells via a Mechanism Involving β-AR Agonism and Cofilin. Int J Mol Sci 2023;25:137. [PMID: 38203312 PMCID: PMC10779393 DOI: 10.3390/ijms25010137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 12/15/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open

Xu W, Qadir MMF, Nasteska D, Mota de Sa P, Gorvin CM, Blandino-Rosano M, Evans CR, Ho T, Potapenko E, Veluthakal R, Ashford FB, Bitsi S, Fan J, Bhondeley M, Song K, Sure VN, Sakamuri SSVP, Schiffer L, Beatty W, Wyatt R, Frigo DE, Liu X, Katakam PV, Arlt W, Buck J, Levin LR, Hu T, Kolls J, Burant CF, Tomas A, Merrins MJ, Thurmond DC, Bernal-Mizrachi E, Hodson DJ, Mauvais-Jarvis F. Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells. Cell Rep 2023;42:112529. [PMID: 37200193 PMCID: PMC10312392 DOI: 10.1016/j.celrep.2023.112529] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 12/20/2022] [Accepted: 05/03/2023] [Indexed: 05/20/2023] Open

Affiliation(s)

Weiwei Xu Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA
M M Fahd Qadir Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA
Daniela Nasteska Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
Paula Mota de Sa Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA
Caroline M Gorvin Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
Manuel Blandino-Rosano Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Charles R Evans Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Thuong Ho Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI, USA
Evgeniy Potapenko Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI, USA
Rajakrishnan Veluthakal Department of Molecular and Cellular Endocrinology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
Fiona B Ashford Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
Stavroula Bitsi Division of Diabetes, Endocrinology & Metabolism, Section of Cell Biology and Functional Genomics, Imperial College London, London SW7 2AZ, UK
Jia Fan Center for Cellular and Molecular Diagnostics, Department of Molecular & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
Manika Bhondeley Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA
Kejing Song Center for Translational Research in Infection and Inflammation, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
Venkata N Sure Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
Siva S V P Sakamuri Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
Lina Schiffer Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
Wandy Beatty Molecular Imaging Facility, Washington University School of Medicine, St. Louis, MO 63110, USA
Rachael Wyatt Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
Daniel E Frigo Departments of Cancer Systems Imaging and Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Xiaowen Liu Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
Prasad V Katakam Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
Wiebke Arlt Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham B15 2TH, UK
Jochen Buck Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
Lonny R Levin Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
Tony Hu Center for Cellular and Molecular Diagnostics, Department of Molecular & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
Jay Kolls Center for Translational Research in Infection and Inflammation, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
Charles F Burant Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Alejandra Tomas Division of Diabetes, Endocrinology & Metabolism, Section of Cell Biology and Functional Genomics, Imperial College London, London SW7 2AZ, UK
Matthew J Merrins Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
Debbie C Thurmond Department of Molecular and Cellular Endocrinology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
Ernesto Bernal-Mizrachi Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
David J Hodson Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
Franck Mauvais-Jarvis Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA.

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Physiological and molecular mechanisms of cold-induced improvements in glucose homeostasis in humans beyond brown adipose tissue. Int J Obes (Lond) 2023;47:338-347. [PMID: 36774412 DOI: 10.1038/s41366-023-01270-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/13/2023]

Raymond-Pope CJ, Basten AM, Bruzina AS, McFaline-Figueroa J, Lillquist TJ, Call JA, Greising SM. Restricted physical activity after volumetric muscle loss alters whole-body and local muscle metabolism. J Physiol 2023;601:743-761. [PMID: 36536512 PMCID: PMC9931639 DOI: 10.1113/jp283959] [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: 10/10/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open

Abstract

Volumetric muscle loss (VML) is the traumatic loss of skeletal muscle, resulting in chronic functional deficits and pathological comorbidities, including altered whole-body metabolic rate and respiratory exchange ratio (RER), despite no change in physical activity in animal models. In other injury models, treatment with β2 receptor agonists (e.g. formoterol) improves metabolic and skeletal muscle function. We aimed first to examine if restricting physical activity following injury affects metabolic and skeletal muscle function, and second, to enhance the metabolic and contractile function of the muscle remaining following VML injury through treatment with formoterol. Adult male C57Bl/6J mice (n = 32) underwent VML injury to the posterior hindlimb compartment and were randomly assigned to unrestricted or restricted activity and formoterol treatment or no treatment; age-matched injury naïve mice (n = 4) were controls for biochemical analyses. Longitudinal 24 h evaluations of physical activity and whole-body metabolism were conducted following VML. In vivo muscle function was assessed terminally, and muscles were biochemically evaluated for protein expression, mitochondrial enzyme activity and untargeted metabolomics. Restricting activity chronically after VML had the greatest effect on physical activity and RER, reflected in reduced lipid oxidation, although changes were attenuated by formoterol treatment. Formoterol enhanced injured muscle mass, while mitigating functional deficits. These novel findings indicate physical activity restriction may recapitulate following VML clinically, and adjunctive oxidative treatment may create a metabolically beneficial intramuscular environment while enhancing the injured muscle's mass and force-producing capacity. Further investigation is needed to evaluate adjunctive oxidative treatment with rehabilitation, which may augment the muscle's regenerative and functional capacity following VML. KEY POINTS: The natural ability of skeletal muscle to regenerate and recover function is lost following complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), and physical inactivity following VML may incur additional deleterious consequences for muscle and metabolic health. Modelling VML injury-induced physical activity restriction altered whole-body metabolism, primarily by decreasing lipid oxidation, while preserving local skeletal muscle metabolic activity. The β2 adrenergic receptor agonist formoterol has shown promise in other severe injury models to improve regeneration, recover function and enhance metabolism. Treatment with formoterol enhanced mass of the injured muscle and whole-body metabolism while mitigating functional deficits resulting from injury. Understanding of chronic effects of the clinically available and FDA-approved pharmaceutical formoterol could be a translational option to support muscle function after VML injury.

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van Beek SMM, Bruls YMH, Vanweert F, Fealy CE, Connell NJ, Schaart G, Moonen-Kornips E, Jörgensen JA, Vaz FM, Smeets ETHC, Joris PJ, Gemmink A, Houtkooper RH, Hesselink MKC, Bengtsson T, Havekes B, Schrauwen P, Hoeks J. Effect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial. Nat Commun 2023;14:173. [PMID: 36635304 PMCID: PMC9835033 DOI: 10.1038/s41467-023-35798-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 01/03/2023] [Indexed: 01/13/2023] Open

Affiliation(s)

Sten M M van Beek Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Yvonne M H Bruls Department of Radiology and Nuclear Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
Froukje Vanweert Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Ciarán E Fealy Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Niels J Connell Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Gert Schaart Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Esther Moonen-Kornips Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Johanna A Jörgensen Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Frédéric M Vaz Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands.,Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands.,Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Ellen T H C Smeets Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Peter J Joris Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Anne Gemmink Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Riekelt H Houtkooper Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands.,Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
Matthijs K C Hesselink Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Tore Bengtsson Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
Bas Havekes Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.,Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
Patrick Schrauwen Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
Joris Hoeks Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.

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Han X, Yang Y, Liu S, Niu Y, Shao H, Fu L. Aerobic exercise ameliorates insulin resistance in C57BL/6 J mice via activating Sestrin3. Biochim Biophys Acta Mol Basis Dis 2023;1869:166568. [PMID: 36220588 DOI: 10.1016/j.bbadis.2022.166568] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/02/2022] [Accepted: 10/05/2022] [Indexed: 11/07/2022]

Wang Y, Wei J, Zhang P, Zhang X, Wang Y, Chen W, Zhao Y, Cui X. Neuregulin-1, a potential therapeutic target for cardiac repair. Front Pharmacol 2022;13:945206. [PMID: 36120374 PMCID: PMC9471952 DOI: 10.3389/fphar.2022.945206] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open

Gao Z, Min X, Kim KM, Liu H, Hu L, Wu C, Zhang X. The tyrosine phosphorylation of GRK2 is responsible for activated D2R-mediated insulin resistance. Biochem Biophys Res Commun 2022;628:40-48. [DOI: 10.1016/j.bbrc.2022.08.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/16/2022] [Accepted: 08/19/2022] [Indexed: 11/02/2022]

Soliman GA, Schooling CM. Insulin Receptor Genetic Variants Causal Association with Type 2 Diabetes: A Mendelian Randomization Study. Curr Dev Nutr 2022;6:nzac044. [PMID: 35611355 PMCID: PMC9121804 DOI: 10.1093/cdn/nzac044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/18/2022] [Accepted: 03/23/2022] [Indexed: 11/26/2022] Open

Abstract

Background

Type 2 diabetes (T2D) is a prevalent chronic disease associated with several comorbidities.

Objectives

This study investigated whether the risk of T2D varied with genetically predicted insulin (INS), insulin receptor (INS-R), or insulin-like growth factor 1 receptor (IGF-1R) using genetic variants in a Mendelian randomization (MR) study.

Methods

A 2-sample MR study was conducted using summary statistics from 2 genome-wide association studies (GWASs). Genetic predictors of the exposures (INS, INS-R, and IGF-1R) were obtained from a publicly available proteomics GWAS of the INTERVAL randomized controlled trial of blood donation in the United Kingdom. For T2D, the study leveraged the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium. The estimated associations of INS, INS-R, and IGF-1R proteins with T2D were based on independent single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10-6) predicting each exposure. These SNPs were applied to publicly available genetic associations with T2D from the DIAMANTE case (n = 74,124) and control (n = 824,006) study of people of European descent. SNP-specific Wald estimates were meta-analyzed using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median (WM) and MR-Egger.

Results

INS-R (based on 13 SNPs) was associated with a lower risk of T2D (OR: 0.95 per effect size; 95% CI: 0.92, 0.98; P = 0.001), with similar estimates from the WM and MR-Egger. Insulin (8 SNPs) and IGF-1R (10 SNPs) were not associated with T2D. However, 1 of the SNPs for INS-R was from the ABO blood group gene.

Conclusions

This study is consistent with a causally protective association of the INS-R with T2D. INS-R in RBCs regulates glycolysis and thus may affect their functionality and integrity. However, a pleiotropic effect via the blood group ABO gene cannot be excluded. The INS-R may be a target for intervention by repurposing existing therapeutics or otherwise to reduce the risk of T2D.

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Dirks ML. Improving skeletal muscle insulin sensitivity via beta2-agonist administration: a promising strategy to counteract metabolic disease and muscle loss. J Physiol 2022;600:2273-2274. [PMID: 35415892 PMCID: PMC9321888 DOI: 10.1113/jp282992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open

Jessen S, Baasch-Skytte T, Onslev J, Eibye K, Backer V, Bangsbo J, Hostrup M. Muscle hypertrophic effect of inhaled beta₂ -agonist is associated with augmented insulin-stimulated whole-body glucose disposal in young men. J Physiol 2022;600:2345-2357. [PMID: 35218559 PMCID: PMC9310637 DOI: 10.1113/jp282421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/15/2022] [Indexed: 11/13/2022] Open

Abstract

Abstract

Rodent studies highlight enhancement of glucose tolerance and insulin sensitivity as potential clinically relevant effects of chronic beta₂‐agonist treatment. However, the doses administered to rodents are not comparable with the therapeutic doses used for humans. Thus, we investigated the physiological effects of prolonged beta₂‐agonist treatment at inhaled doses resembling those used in respiratory diseases on insulin‐stimulated whole‐body glucose disposal and putative mechanisms in skeletal muscle and adipose tissue of healthy men. Utilizing a randomized placebo‐controlled parallel‐group design, we assigned 21 healthy men to 4 weeks daily inhalation of terbutaline (TER; 4 mg × day⁻¹, n = 13) or placebo (PLA, n = 8). Before and after treatments, we assessed subjects’ whole‐body insulin‐stimulated glucose disposal and body composition, and collected vastus lateralis muscle and abdominal adipose tissue biopsies. Glucose infusion rate increased by 27% (95% CI: 80 to 238 mg × min⁻¹, P = 0.001) in TER, whereas no significant changes occurred in PLA (95% CI: −37 to 195 mg × min⁻¹, P = 0.154). GLUT4 content in muscle or adipose tissue did not change, nor did hexokinase II content or markers of mitochondrial volume in muscle. Change in lean mass was associated with change in glucose infusion rate in TER (r = 0.59, P = 0.03). Beta₂‐agonist treatment in close‐to‐therapeutic doses may augment whole‐body insulin‐stimulated glucose disposal in healthy young men and part of the change is likely to be explained by muscle hypertrophy. These findings highlight the therapeutic potential of beta₂‐agonists for improving insulin sensitivity.

Key points

While studies in rodents have highlighted beta₂‐agonists as a means to augment insulin sensitivity, these studies utilized beta₂‐agonists at doses inapplicable to humans.

Herein we show that a 4‐week treatment period with daily therapeutic inhalation of beta₂‐agonist increases insulin‐stimulated whole‐body glucose disposal in young healthy lean men.

This effect was associated with an increase of lean mass but not with changes in GLUT4 and hexokinase II or basal glycogen content in skeletal muscle nor GLUT4 content in abdominal adipose tissue.

These findings suggest that the enhanced insulin‐stimulated whole‐body glucose disposal induced by a period of beta₂‐agonist treatment in humans, at least in part, is attributed to muscle hypertrophy.

Our observations extend findings in rodents and highlight the therapeutic potential of beta₂‐agonists to enhance the capacity for glucose disposal and whole‐body insulin sensitivity, providing important knowledge with potential application in insulin resistance.

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Onslev J, Thomassen M, Wojtaszewski J, Bangsbo J, Hostrup M. Salbutamol Increases Leg Glucose Uptake and Metabolic Rate but not Muscle Glycogen Resynthesis in Recovery From Exercise. J Clin Endocrinol Metab 2022;107:e1193-e1203. [PMID: 34665856 DOI: 10.1210/clinem/dgab752] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Indexed: 02/07/2023]

Abstract

CONTEXT

Exercise blunts the effect of beta2-agonists on peripheral glucose uptake and energy expenditure. Whether such attenuation extends into recovery is unknown.

OBJECTIVE

To examine the effect of a beta2-agonist on leg glucose uptake and metabolic rate in recovery from exercise.

METHODS

Using leg arteriovenous balance technique and analyses of thigh muscle biopsies, we investigated the effect of a beta2-agonist (24 mg of oral salbutamol) vs placebo on leg glucose, lactate, and oxygen exchange before and during quadriceps exercise, and 0.5 to 5 hours in recovery from quadriceps exercise, as well as on muscle glycogen resynthesis and activity in recovery. Twelve healthy, lean, young men participated.

RESULTS

Before exercise, leg glucose uptake was 0.42 ± 0.12 and 0.20 ± 0.02 mmol × min-1 (mean ± SD) for salbutamol and placebo (P = .06), respectively, while leg oxygen consumption was around 2-fold higher (P < .01) for salbutamol than for placebo (25 ± 3 vs 14 ± 1 mL × min-1). No treatment differences were observed in leg glucose uptake, lactate release, and oxygen consumption during exercise. But in recovery, cumulated leg glucose uptake, lactate release, and oxygen consumption was 21 mmol (95% CI 18-24, P = .018), 19 mmol (95% CI 16-23, P < .01), and 1.8 L (95% CI 1.6-2.0, P < .01) higher for salbutamol than for placebo, respectively. Muscle glycogen content was around 30% lower (P < .01) for salbutamol than for placebo in recovery, whereas no treatment differences were observed in muscle glycogen resynthesis or glycogen synthase activity.

CONCLUSION

Exercise blunts the effect of beta2-agonist salbutamol on leg glucose uptake, but this attenuation diminishes in recovery. Salbutamol increases leg lactate release in recovery, which may relate to glycolytic trafficking due to excessive myocellular glucose uptake.

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Meister J, Bone DBJ, Knudsen JR, Barella LF, Velenosi TJ, Akhmedov D, Lee RJ, Cohen AH, Gavrilova O, Cui Y, Karsenty G, Chen M, Weinstein LS, Kleinert M, Berdeaux R, Jensen TE, Richter EA, Wess J. Clenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells. Nat Commun 2022;13:22. [PMID: 35013148 PMCID: PMC8748640 DOI: 10.1038/s41467-021-27540-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 11/24/2021] [Indexed: 12/14/2022] Open

Affiliation(s)

Jaroslawna Meister Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.
Derek B J Bone Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA
Jonas R Knudsen Departments of Nutrition, Exercise and Sports, University of Copenhagen, København, Denmark
Luiz F Barella Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA
Thomas J Velenosi Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
Dmitry Akhmedov Departments of Integrative Biology and Pharmacology, Houston Medical School, Houston, TX, 77030, USA
Regina J Lee Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA
Amanda H Cohen Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA
Oksana Gavrilova Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA
Yinghong Cui Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA
Gerard Karsenty Departments of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
Min Chen Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA
Lee S Weinstein Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA
Maximilian Kleinert Departments of Nutrition, Exercise and Sports, University of Copenhagen, København, Denmark Muscle Physiology and Metabolism Group, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany
Rebecca Berdeaux Departments of Integrative Biology and Pharmacology, Houston Medical School, Houston, TX, 77030, USA
Thomas E Jensen Departments of Nutrition, Exercise and Sports, University of Copenhagen, København, Denmark
Erik A Richter Departments of Nutrition, Exercise and Sports, University of Copenhagen, København, Denmark
Jürgen Wess Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.

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Knudsen JR, Persson KW, Meister J, Carl CS, Raun SH, Andersen NR, Sylow L, Kiens B, Jensen TE, Richter EA, Kleinert M. Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle. Am J Physiol Endocrinol Metab 2022;322:E63-E73. [PMID: 34866401 PMCID: PMC8759970 DOI: 10.1152/ajpendo.00389.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]

Abstract

In mice, exercise is suggested to activate the mechanistic target of rapamycin complex 2 (mTORC2) in skeletal muscle, and mTORC2 is required for normal muscle glucose uptake during exercise. Whether this translates to human skeletal muscle and what signaling pathways facilitate the exercise-induced mTORC2 activation is unknown. We herein tested the hypothesis that exercise increases mTORC2 activity in human skeletal muscle and investigated if β₂-adrenergic receptor (AR) activation mediates exercise-induced mTORC2 activation. We examined several mTORC2 activity readouts (p-NDRG1 Thr346, p-Akt Ser473, p-mTOR S2481, and p-Akt Thr450) in human skeletal muscle biopsies after uphill walking or cycling exercise. In mouse muscles, we assessed mTORC2 activity readouts following acute activation of muscle β₂-adrenergic or G_S signaling and during in vivo and ex vivo muscle contractions. Exercise increased phosphorylation of NDRG1 Thr346 in human soleus, gastrocnemius, and vastus lateralis muscle, without changing p-Akt Ser473, p-Akt Thr450, and p-mTOR Ser2481. In mouse muscle, stimulation of β₂-adrenergic or G_S signaling and ex vivo contractions failed to increase p-NDRG1 Thr346, whereas in vivo contractions were sufficient to induce p-NDRG1 Thr346. In conclusion, the mTORC2 activity readout p-NDRG1 Thr346 is a novel exercise-responsive signaling protein in human skeletal muscle. Notably, contraction-induced p-NDRG1 Thr346 appears to require a systemic factor. Unlike exercise, and in contrast to published data obtained in cultured muscles cells, stimulation of β₂-adrenergic signaling is not sufficient to trigger NDRG1 phosphorylation in mature mouse skeletal muscle.NEW & NOTEWORTHY The mTORC2 readout p-NDRG Thr346 is a novel exercise-responsive protein in human skeletal muscle. β2-AR and G_S signaling are not sufficient to induce mTORC2 signaling in adult muscle. In vivo, but not ex vivo, contraction induced p-NDRG Thr346, which indicates requirement of a systemic factor for exercise-induced mTORC2 activation.

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Affiliation(s)

Jonas R Knudsen Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
Kaspar W Persson Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
Jaroslawna Meister Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
Christian S Carl Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
Steffen H Raun Section of Molecular Physiology, 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
Nicoline R Andersen Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
Lykke Sylow Section of Molecular Physiology, 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
Bente Kiens Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
Thomas E Jensen Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
Erik A Richter Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
Maximilian Kleinert Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark Muscle Physiology and Metabolism Group, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany

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Skagen C, Nyman TA, Peng XR, O'Mahony G, Kase ET, Rustan AC, Thoresen GH. Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021;2:100039. [PMID: 34909668 PMCID: PMC8663959 DOI: 10.1016/j.crphar.2021.100039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/28/2021] [Accepted: 06/02/2021] [Indexed: 12/04/2022] Open

Abstract

Objective

In vivo studies have reported several beneficial metabolic effects of β-adrenergic receptor agonist administration in skeletal muscle, including increased glucose uptake, fatty acid metabolism, lipolysis and mitochondrial biogenesis. Although these effects have been widely studied in vivo, the in vitro data are limited to mouse and rat cell lines. Therefore, we sought to discover the effects of the β₂-adrenergic receptor agonist terbutaline on metabolism and protein synthesis in human primary skeletal muscle cells.

Methods

Human cultured myotubes were exposed to terbutaline in various concentrations (0.01–30 μM) for 4 or 96 h. Thereafter uptake of [¹⁴C]deoxy-D-glucose, oxydation of [¹⁴C]glucose and [¹⁴C]oleic acid were measured. Incorporation of [¹⁴C]leucine, gene expression by qPCR and proteomics analyses by mass spectrometry by the STAGE-TIP method were performed after 96 h exposure to 1 and 10 μM of terbutaline.

Results

The results showed that 4 h treatment with terbutaline in concentrations up to 1 μM increased glucose uptake in human myotubes, but also decreased both glucose and oleic acid oxidation along with oleic acid uptake in concentrations of 10–30 μM. Moreover, administration of terbutaline for 96 h increased glucose uptake (in terbutaline concentrations up to 1 μM) and oxidation (1 μM), as well as oleic acid oxidation (0.1–30 μM), leucine incorporation into cellular protein (1–10 μM) and upregulated several pathways related to mitochondrial metabolism (1 μM). Data are available via ProteomeXchange with identifier PXD024063.

Conclusion

These results suggest that β₂-adrenergic receptor have direct effects in human skeletal muscle affecting fuel metabolism and net protein synthesis, effects that might be favourable for both type 2 diabetes and muscle wasting disorders.

•

The metabolic effects of terbutaline were studied in human primary myotubes.

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Acute treatment with terbutaline increased glucose uptake.

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Chronic treatment with terbutaline increased glucose and oleic acid oxidation.

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Chronic treatment with terbutaline increased protein synthesis.

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Proteomics analysis revealed an increase in mitochondrial proteins.

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In vivo metabolic effects after acute activation of skeletal muscle G_s signaling. Mol Metab 2021;55:101415. [PMID: 34883278 PMCID: PMC8728399 DOI: 10.1016/j.molmet.2021.101415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 11/21/2021] [Accepted: 12/02/2021] [Indexed: 11/21/2022] Open

Abstract

Objective

The goal of this study was to determine the glucometabolic effects of acute activation of G_s signaling in skeletal muscle (SKM) in vivo and its contribution to whole-body glucose homeostasis.

Methods

To address this question, we studied mice that express a G_s-coupled designer G protein-coupled receptor (Gs-DREADD or GsD) selectively in skeletal muscle. We also identified two G_s-coupled GPCRs that are endogenously expressed by SKM at relatively high levels (β₂-adrenergic receptor and CRF₂ receptor) and studied the acute metabolic effects of activating these receptors in vivo by highly selective agonists (clenbuterol and urocortin 2 (UCN2), respectively).

Results

Acute stimulation of GsD signaling in SKM impaired glucose tolerance in lean and obese mice by decreasing glucose uptake selectively into SKM. The acute metabolic effects following agonist activation of β₂-adrenergic and, potentially, CRF₂ receptors appear primarily mediated by altered insulin release. Clenbuterol injection improved glucose tolerance by increasing insulin secretion in lean mice. In SKM, clenbuterol stimulated glycogen breakdown. UCN2 injection resulted in decreased glucose tolerance associated with lower plasma insulin levels. The acute metabolic effects of UCN2 were not mediated by SKM G_s signaling.

Conclusions

Selective activation of G_s signaling in SKM causes an acute increase in blood glucose levels. However, acute in vivo stimulation of endogenous G_s-coupled receptors enriched in SKM has only a limited impact on whole-body glucose homeostasis, most likely due to the fact that these receptors are also expressed by pancreatic islets where they modulate insulin release.

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A novel mouse model allowed us to study the in vivo metabolic effects of acute activation of G_s signaling in skeletal muscle (SKM).

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Acute stimulation of this pathway resulted in impaired glucose tolerance in lean and obese mice due to decreased glucose uptake by SKM.

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Acute treatment of mice with selective β₂-adrenergic and CRF₂ receptor agonists (both receptors couple to G_s and are enriched in SKM) resulted in complex in vivo metabolic outcomes, primarily due to altered insulin release.

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Our study provides an excellent example of how different tissue expression patterns of receptors can affect the acute effects of GPCR agonists on whole-body glucose homeostasis

•

Our findings also highlight the importance of studying both acute and chronic effects of GPCR agonist treatment to properly assess translationally relevant metabolic outcomes.

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Ibrahim WS, Ahmed HMS, Mahmoud AAA, Mahmoud MF, Ibrahim IAAEH. Propranolol and low-dose isoproterenol ameliorate insulin resistance, enhance β-arrestin2 signaling, and reduce cardiac remodeling in high-fructose, high-fat diet-fed mice: Comparative study with metformin. Life Sci 2021;286:120055. [PMID: 34662551 DOI: 10.1016/j.lfs.2021.120055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 01/14/2023]

Abstract

AIMS

β-Arrestin2 signaling has emerged as a promising therapeutic target for the management of insulin resistance and related complications. Moreover, recent studies have shown that certain G protein-coupled receptor (GPCR) ligands can modulate β-arrestin2 signaling. The current study examined the effects of the β-blocker propranolol and a low dose of the agonist isoproterenol (L-D-ISOPROT) on β-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet (HFrHFD)-fed mice. In addition, the effects of these agents were compared to those of the clinical antidiabetic agent, metformin.

MATERIALS AND METHODS

Insulin resistance was induced by HFrHFD feeding for 16 weeks. Mice were then randomly allocated to groups receiving propranolol, L-D-ISOPROT, metformin, or vehicle (control) for 4 weeks starting on week 13 of HFrHFD feeding. Survival rate, body weight, visceral fat weight, blood glucose, serum insulin, insulin resistance index, hepatic β-arrestin2 signaling, heart weight, left and right ventricular thicknesses, cardiac fibrosis severity, serum endothelin-1, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling were then compared among groups.

KEY FINDINGS

HFrHFD for 16 weeks significantly increased insulin resistance index, cardiac fibrosis area, and serum endothelin-1, and reduced hepatic β-arrestin2 signaling, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling without significant changes in survival rate, body weight, visceral fat weight, heart weight, or left and right ventricular thicknesses. All three drugs reduced insulin resistance and cardiac remodeling parameters and enhanced β-arrestin2 signaling with variable efficacies.

SIGNIFICANCE

Propranolol and L-D-ISOPROT, like metformin, can reduce insulin-resistance and cardiac remodeling in HFrHFD-fed mice, possibly by upregulating β-arrestin2 signaling activity. Therefore, β-arrestin2-signaling modulation might be a promising strategy for insulin-resistance treatment.

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Pydi SP, Barella LF, Zhu L, Meister J, Rossi M, Wess J. β-Arrestins as Important Regulators of Glucose and Energy Homeostasis. Annu Rev Physiol 2021;84:17-40. [PMID: 34705480 DOI: 10.1146/annurev-physiol-060721-092948] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]

Ahmed HMS, Mohamed SG, Ibrahim WS, Rezk AM, Mahmoud AAA, Mahmoud MF, Ibrahim IAAEH. Acute and chronic metabolic effects of carvedilol in high-fructose, high-fat diet-fed mice: implication of β-arrestin2 pathway. Can J Physiol Pharmacol 2021;100:68-77. [PMID: 34570983 DOI: 10.1139/cjpp-2021-0299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]

O'Reilly CL, Uranga S, Fluckey JD. Culprits or consequences: Understanding the metabolic dysregulation of muscle in diabetes. World J Biol Chem 2021;12:70-86. [PMID: 34630911 PMCID: PMC8473417 DOI: 10.4331/wjbc.v12.i5.70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open

Wang Y, Liu Q, Kang SG, Huang K, Tong T. Dietary Bioactive Ingredients Modulating the cAMP Signaling in Diabetes Treatment. Nutrients 2021;13:nu13093038. [PMID: 34578916 PMCID: PMC8467569 DOI: 10.3390/nu13093038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open

A new approach to treat type 2 diabetes - Targeting a non-insulin dependent pathway. Drug Discov Today 2021;26:2487-2488. [PMID: 34339863 DOI: 10.1016/j.drudis.2021.07.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/07/2021] [Accepted: 07/20/2021] [Indexed: 11/22/2022]

Differences in DNA methylation between slow and fast muscle in Takifugu rubripes. Gene 2021;801:145853. [PMID: 34274464 DOI: 10.1016/j.gene.2021.145853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/22/2021] [Accepted: 07/13/2021] [Indexed: 12/20/2022]

Evolution of β-catenin-independent Wnt-GSK3-mTOR signalling in regulation of energy metabolism in isoproterenol-induced cardiotoxicity model. Inflamm Res 2021;70:743-747. [PMID: 34185111 DOI: 10.1007/s00011-021-01477-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 10/21/2022] Open

Wang X, Kang J, Liu Q, Tong T, Quan H. Fighting Diabetes Mellitus: Pharmacological and Non-pharmacological Approaches. Curr Pharm Des 2021;26:4992-5001. [PMID: 32723251 DOI: 10.2174/1381612826666200728144200] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 06/29/2020] [Indexed: 02/08/2023]

Abstract

BACKGROUND

The increasing worldwide prevalence of diabetes mellitus confers heavy public health issues and points to a large medical need for effective and novel anti-diabetic approaches with negligible adverse effects. Developing effective and novel anti-diabetic approaches to curb diabetes is one of the most foremost scientific challenges.

OBJECTIVES

This article aims to provide an overview of current pharmacological and non-pharmacological approaches available for the management of diabetes mellitus.

METHODS

Research articles that focused on pharmacological and non-pharmacological interventions for diabetes were collected from various search engines such as Science Direct and Scopus, using keywords like diabetes, glucagon-like peptide-1, glucose homeostasis, etc. Results: We review in detail several key pathways and pharmacological targets (e.g., the G protein-coupled receptors- cyclic adenosine monophosphate, 5'-adenosine monophosphate-activated protein kinase, sodium-glucose cotransporters 2, and peroxisome proliferator activated-receptor gamma signaling pathways) that are vital in the regulation of glucose homeostasis. The currently approved diabetes medications, the pharmacological potentials of naturally occurring compounds as promising interventions for diabetes, and the non-pharmacological methods designed to mitigate diabetes are summarized and discussed.

CONCLUSION

Pharmacological-based approaches such as insulin, metformin, sodium-glucose cotransporters 2 inhibitor, sulfonylureas, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase IV inhibitors represent the most important strategies in diabetes management. These approved diabetes medications work via targeting the central signaling pathways related to the etiology of diabetes. Non-pharmacological approaches, including dietary modification, increased physical activity, and microbiota-based therapy are the other cornerstones for diabetes treatment. Pharmacological-based approaches may be incorporated when lifestyle modification alone is insufficient to achieve positive outcomes.

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Halova L, Cobley D, Franz-Wachtel M, Wang T, Morrison KR, Krug K, Nalpas N, Maček B, Hagan IM, Humphrey SJ, Petersen J. A TOR (target of rapamycin) and nutritional phosphoproteome of fission yeast reveals novel targets in networks conserved in humans. Open Biol 2021;11:200405. [PMID: 33823663 PMCID: PMC8025308 DOI: 10.1098/rsob.200405] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/05/2021] [Indexed: 12/21/2022] Open

Barella LF, Jain S, Kimura T, Pydi SP. Metabolic roles of G protein-coupled receptor signaling in obesity and type 2 diabetes. FEBS J 2021;288:2622-2644. [PMID: 33682344 DOI: 10.1111/febs.15800] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/31/2021] [Accepted: 03/03/2021] [Indexed: 12/12/2022]

Mann PA, Lehrke M. Cardiac substrate utilization in heart failure: Where is the relevance of SGLT2 inhibition? J Thorac Cardiovasc Surg 2021;164:895-899. [DOI: 10.1016/j.jtcvs.2021.02.092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/14/2022]

van Beek SMM, Kalinovich A, Schaart G, Bengtsson T, Hoeks J. Prolonged β₂-adrenergic agonist treatment improves glucose homeostasis in diet-induced obese UCP1^-/- mice. Am J Physiol Endocrinol Metab 2021;320:E619-E628. [PMID: 33522400 DOI: 10.1152/ajpendo.00324.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]

Abstract

Prolonged supplementation with the β₂-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via β₂-adrenoceptor (β₂-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to-especially diabetic-humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to β₁- and β₃-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient (UCP1^-/-) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and UCP1^-/- C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and UCP1^-/- C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between weeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in UCP1^-/- mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in UCP1^-/- mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, β₂-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans.NEW & NOTEWORTHY Improvements in whole body glucose homeostasis of rodents upon prolonged β₂-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the β₂-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and UCP1^-/- mice, indicating that β₂-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.

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Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev 2021;101:1371-1426. [PMID: 33599151 DOI: 10.1152/physrev.00026.2020] [Citation(s) in RCA: 425] [Impact Index Per Article: 106.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open

Pydi SP, Barella LF, Meister J, Wess J. Key Metabolic Functions of β-Arrestins: Studies with Novel Mouse Models. Trends Endocrinol Metab 2021;32:118-129. [PMID: 33358450 PMCID: PMC7855863 DOI: 10.1016/j.tem.2020.11.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/17/2020] [Accepted: 11/20/2020] [Indexed: 12/14/2022]

ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes. J Biol Chem 2021;296:100332. [PMID: 33508319 PMCID: PMC7949114 DOI: 10.1016/j.jbc.2021.100332] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 01/16/2021] [Accepted: 01/22/2021] [Indexed: 01/03/2023] Open

Abstract

Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake, whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of thioredoxin-interacting protein (TXNIP) degradation. This, in turn, selectively induces glucose transporter 1 surface localization and glucose uptake in 3T3-L1 adipocytes and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL) and not hormone-sensitive lipase or monoacylglycerol lipase. Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion, and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake.

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