The role of glucagon-like peptides in osteosarcopenia

in Journal of Endocrinology
Authors:
Enaya Tufail Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow, Uttar Pradesh, India

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Somali Sanyal Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow, Uttar Pradesh, India

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Ambrish Mithal Chairman and Head of Endocrinology and Diabetes at Max Healthcare, New Delhi, India

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Sabyasachi Sanyal Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India

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https://orcid.org/0000-0002-8603-3828
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Naibedya Chattopadhyay Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India

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Correspondence should be addressed to S Sanyal: ssanyal@lko.amity.edu or to N Chattopadhyay: n_chattopadhyay@cdri.res.in

This paper forms part of a special collection exploring osteoporosis and sarcopenia. The guest editor for this section was Naibedya Chattopadhyay.

DOI:
https://doi.org/10.1530/JOE-24-0210
Volume/Issue:
Volume 264: Issue 2
Article Type:
Review Article
Article ID:
e240210
Online Publication Date:
10 Jan 2025
Copyright:
© the author(s) 2025
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Various metabolic abnormalities, including obesity, insulin resistance, hypertension, dyslipidemia, hyperthyroidism and low vitamin D levels, have been linked to both osteopenia and sarcopenia. Osteosarcopenia is also commonly observed in older age groups, notably in postmenopausal women. Glucagon-like peptide-1 (GLP-1), a labile incretin secreted from the intestinal L-cells, stimulates insulin secretion and sensitivity, making it an effective anti-diabetic medication. GLP-1 binds to its receptor, the GLP-1 receptor, a G-protein-coupled receptor, and leads to the stimulation of adenylate cyclase, increasing the levels of cyclic AMP (cAMP). Elevated cAMP then activates protein kinase A and other downstream signaling pathways. These signaling cascades result in various cellular responses, such as enhanced insulin secretion from pancreatic beta cells, improved insulin sensitivity and modulation of appetite and gastric emptying. In addition, GLP-1 signaling can promote cell growth and survival, contributing to its effects on muscle and bone health. Its role as an anti-diabetic medication has been enhanced through various modifications to extend its half-life, thereby improving its effectiveness and druggability. GLP-1 analogs, initially developed for diabetes management, have also been harnessed for obesity treatment due to the effect of GLP-1 to induce satiety and slow gastric emptying. Beyond their well-known anti-diabetic and anti-obesity effects, GLP-1 agonists can enhance muscle mass and bone density, making them valuable in addressing conditions such as sarcopenia and osteoporosis. This review focuses on the effects of GLP-1 analogs on musculoskeletal health by critically assessing the underlying signaling mechanisms in order to understand their translational potential for the treatment of osteosarcopenia.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© the author(s) 2025
Article ID:
e240210
Article Type:
Review Article
Received Date:
12 Jul 2024
Rev-recd:
24 Nov 2024
Accepted Date:
10 Dec 2024
Print Publication Date:
01 Feb 2025
Online Publication Date:
10 Jan 2025
Keywords:
glucagon-like peptide-1; G protein-coupled receptor; skeletal muscle; bone; osteosarcopenia

  • Akyay OZ, Canturk Z, Selek A, et al. 2023 The effects of exenatide and insulin glargine treatments on bone turnover markers and bone mineral density in postmenopausal patients with type 2 diabetes mellitus. Medicine 102 e35394. (https://doi.org/10.1097/MD.0000000000035394)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Aoyama E, Watari I, Podyma-Inoue KA, et al. 2014 Expression of glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor is regulated by the glucose concentration in mouse osteoblastic MC3T3-E1 cells. Int J Mol Med 34 475–482. (https://doi.org/10.3892/ijmm.2014.1787)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Athauda D & Foltynie T 2016 The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: mechanisms of action. Drug Discov Today 21 802–818. (https://doi.org/10.1016/j.drudis.2016.01.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Barrington P, Chien JY, Showalter HDH, et al. 2011 A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes Metab 13 426–433. (https://doi.org/10.1111/j.1463-1326.2011.01364.xx)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Brubaker PL 2007 Incretin-based therapies: mimetics versus protease inhibitors. Trends Endocrinol Metab 18 240–245. (https://doi.org/10.1016/j.tem.2007.06.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Buckinx F & Aubertin-Leheudre M 2022 Sarcopenia in menopausal women: current perspectives. Int J Women’s Health 14 805–819. (https://doi.org/10.2147/IJWH.S340537)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Burcelin R & Gourdy P 2017 Harnessing glucagon‐like peptide‐1 receptor agonists for the pharmacological treatment of overweight and obesity. Obes Rev 18 86–98. (https://doi.org/10.1111/obr.12465)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bush MA, Matthews JE, De Boever EH, et al. 2009 Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long‐acting glucagon‐like peptide‐1 mimetic, in healthy subjects. Diabetes Obes Metab 11 498–505. (https://doi.org/10.1111/j.1463-1326.2008.00992.xx)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cai T, Li H, Jiang L, et al. 2021 Effects of GLP-1 receptor agonists on bone mineral density in patients with type 2 diabetes mellitus: a 52-week clinical study. Biomed Res Int 2021 1–8. (https://doi.org/10.1155/2021/3361309)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cariati I, Bonanni R, Onorato F, et al. 2021 Role of physical activity in bone-muscle crosstalk: biological aspects and clinical implications. J Funct Morphol Kinesiol 6 55. (https://doi.org/10.3390/jfmk6020055)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen K, Gao P, Li Z, et al. 2022a Forkhead box O signaling pathway in skeletal muscle atrophy. Am J Pathol 192 1648–1657. (https://doi.org/10.1016/j.ajpath.2022.09.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen Y, Zhou Y, Lin J, et al. 2022b Challenges to improve bone healing under diabetic conditions. Front Endocrinol 13 861878. (https://doi.org/10.3389/fendo.2022.861878)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen S, Wang X, Jin Y, et al. 2024 Assessment of changes in body composition after 3 months of dulaglutide treatment. Diabetes Metab Syndr Obes 17 1301–1308. (https://doi.org/10.2147/DMSO.S443631)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chowdhury S, Schulz L, Palmisano B, et al. 2020 Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts. J Clin Invest 130 2888–2902. (https://doi.org/10.1172/JCI133572)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Colaianni G, Cuscito C, Mongelli T, et al. 2014 Irisin enhances osteoblast differentiation in vitro. Int J Endocrinol 2014 1–8. (https://doi.org/10.1155/2014/902186)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Collins L & Costello RA 2024 Glucagon-like peptide-1 receptor agonists. In StatPearls. Treasure Island, FL, USA: StatPearls Publishing. (https://www.ncbi.nlm.nih.gov/books/NBK551568/)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Daniilopoulou I, Vlachou E, Lambrou GI, et al. 2022 The impact of GLP1 agonists on bone metabolism: a systematic review. Medicina 58 224. (https://doi.org/10.3390/medicina58020224)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Deacon CF, Knudsen LB, Madsen K, et al. 1998 Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. Diabetologia 41 271–278. (https://doi.org/10.1007/s001250050903)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Essmat N, Soliman E, Mahmoud MF, et al. 2020 Antidepressant activity of anti-hyperglycemic agents in experimental models: a review. Diabetes Metabol Synd 14 1179–1186. (https://doi.org/10.1016/j.dsx.2020.06.021)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fathy MA, Anbaig A, Aljafil R, et al. 2023 Effect of liraglutide on osteoporosis in a rat model of type 2 diabetes mellitus: a histological, immunohistochemical, and biochemical study. Microsc Microanalysis 29 2053–2067. (https://doi.org/10.1093/micmic/ozad102)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ferron M, McKee MD, Levine RL, et al. 2012 Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 50 568–575. (https://doi.org/10.1016/j.bone.2011.04.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gibbons C, Blundell J, Tetens Hoff S, et al. 2021 Effects of oral semaglutide on energy intake, food preference, appetite, control of eating and body weight in subjects with type 2 diabetes. Diabetes Obes Metab 23 581–588. (https://doi.org/10.1111/dom.14255)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Glass DA, Bialek P, Ahn JD, et al. 2005 Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8 751–764. (https://doi.org/10.1016/j.devcel.2005.02.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gomarasca M, Banfi G & Lombardi G 2020 Myokines: the endocrine coupling of skeletal muscle and bone. Adv Clin Chem 94 155–218. (https://doi.org/10.1016/bs.acc.2019.07.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Green CJ, Henriksen TI, Pedersen BK, et al. 2012 Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia. PLoS One 7 e44284. (https://doi.org/10.1371/JOURNAL.PONE.0044284)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gromada J, Bokvist K, Ding WG, et al. 1998 Glucagon-like peptide 1(7-36) amide stimulates exocytosis in human pancreatic β-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes 47 57–65. (https://doi.org/10.2337/diab.47.1.57)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Guarnotta V, Bianco MJ, Vigneri E, et al. 2021 Effects of GLP-1 receptor agonists on myokine levels and pro-inflammatory cytokines in patients with type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis 31 3193–3201. (https://doi.org/10.1016/j.numecd.2021.07.015)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gurjar AA, Kushwaha S, Chattopadhyay S, et al. 2020 Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents. Metabolism 103 154044. (https://doi.org/10.1016/j.metabol.2019.154044)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hackam DG 2007 Translating animal research into clinical benefit. BMJ 334 163–164. (https://doi.org/10.1136/bmj.39104.362951.80)

  • Hamoudi D, Bouredji Z, Marcadet L, et al. 2020 Muscle weakness and selective muscle atrophy in osteoprotegerin-deficient mice. Hum Mol Genet 29 483–494. (https://doi.org/10.1093/hmg/ddz312)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hansen MS, Wölfel EM, Jeromdesella S, et al. 2024 Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial. EClinicalMedicine 72 102624. (https://doi.org/10.1016/j.eclinm.2024.102624)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hardy OT, Czech MP & Corvera S 2012 What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes 19 81–87. (https://doi.org/10.1097/MED.0b013e3283514e13)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hatakeyama J, Inoue S, Jiang H, et al. 2024 Exercise-induced interactions between skeletal muscle and bone via myokines and osteokine in mice: role of FNDC5/irisin, IGF-1, and osteocalcin. Bone 190 117314. (https://doi.org/10.1016/J.BONE.2024.117314)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • He C, He W, Hou J, et al. 2020 Bone and muscle crosstalk in aging. Front Cell Dev Biol 8 585644. (https://doi.org/10.3389/fcell.2020.585644)

  • He Z, Li H, Zhang Y, et al. 2024 Enhanced bone regeneration via endochondral ossification using exendin-4-modified mesenchymal stem cells. Bioactive Mater 34 98–111. (https://doi.org/10.1016/j.bioactmat.2023.12.007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hofbauer LC, Khosla S, Dunstan CR, et al. 2000 The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15 2–12. (https://doi.org/10.1359/jbmr.2000.15.1.2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Holz GG, IV, Kiihtreiber WM & Habener JF 1993 Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature 361 362–365. (https://doi.org/10.1038/361362a0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hong Y, Lee JH, Jeong KW, et al. 2019 Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy. J Cachexia Sarcopenia Muscle 10 903–918. (https://doi.org/10.1002/jcsm.12434)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hu E-H, Tsai M-L, Lin Y, et al. 2024 A review and meta-analysis of the safety and efficacy of using glucagon-like peptide-1 receptor agonists. Medicina 60 357. (https://doi.org/10.3390/medicina60030357)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hunter K & Hölscher C 2012 Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13 33. (https://doi.org/10.1186/1471-2202-13-33)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Iwai S, Kaji K, Nishimura N, et al. 2023 Glucagon-like peptide-1 receptor agonist, semaglutide attenuates chronic liver disease-induced skeletal muscle atrophy in diabetic mice. Biochim Biophys Acta Mol Basis Dis 1869 166770. (https://doi.org/10.1016/j.bbadis.2023.166770)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jiang Y, Wang Z, Ma B, et al. 2018 GLP-1 improves adipocyte insulin sensitivity following induction of endoplasmic reticulum stress. Front Pharmacol 9 1168. (https://doi.org/10.3389/fphar.2018.01168)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jiao H, Xiao E & Graves DT 2015 Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep 13 327–335. (https://doi.org/10.1007/s11914-015-0286-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kamiya M, Mizoguchi F & Yasuda S 2022 Amelioration of inflammatory myopathies by glucagon-like peptide-1 receptor agonist via suppressing muscle fibre necroptosis. J Cachexia Sarcopenia Muscle 13 2118–2131. (https://doi.org/10.1002/jcsm.13025)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Karsenty G 2023 Osteocalcin: a multifaceted bone-derived hormone. Annu Rev Nutr 43 55–71. (https://doi.org/10.1146/annurev-nutr-061121-091348)

  • Kim B-J 2022 Effects of muscles on bone metabolism-with a focus on myokines. Ann Geriatr Med Res 26 63–71. (https://doi.org/10.4235/agmr.22.0054)

  • Kim J-Y, Lee S-K, Jo K-J, et al. 2013 Exendin-4 increases bone mineral density in type 2 diabetic OLETF rats potentially through the down-regulation of SOST/sclerostin in osteocytes. Life Sci 92 533–540. (https://doi.org/10.1016/j.lfs.2013.01.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim JA, Roh E, Hong S-H, et al. 2019 Association of serum sclerostin levels with low skeletal muscle mass: the Korean Sarcopenic Obesity Study (KSOS). Bone 128 115053. (https://doi.org/10.1016/j.bone.2019.115053)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kitaura H, Ogawa S, Ohori F, et al. 2021 Effects of incretin-related diabetes drugs on bone formation and bone resorption. Int J Mol Sci 22 6578. (https://doi.org/10.3390/ijms22126578)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Knudsen LB, Nielsen PF, Huusfeldt PO, et al. 2000 Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 43 1664–1669. (https://doi.org/10.1021/jm9909645)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Koistinen HA, Zierath JR & Zierath JR 2009 Regulation of glucose transport in human skeletal muscle. Ann Med 34 410–418. (https://doi.org/10.1080/078538902321012351)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kuritzky L, Kuritzky G, Ekoé JM, et al. 2014 Safety and efficacy of dulaglutide, a once weekly GLP-1 receptor agonist, for the management of type 2 diabetes. Postgrad Med 126 60–72. (https://doi.org/10.3810/pgm.2014.10.2821)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kuryłowicz A 2023 Estrogens in adipose tissue physiology and obesity-related dysfunction. Biomedicines 11 690. (https://doi.org/10.3390/biomedicines11030690)

  • Kuwata H, Yabe D, Murotani K, et al. 2021 Effects of glucagon-like peptide-1 receptor agonists on secretions of insulin and glucagon and gastric emptying in Japanese individuals with type 2 diabetes: a prospective, observational study. J Diabetes Invest 12 2162–2171. (https://doi.org/10.1111/jdi.13598)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kwan Tat S, Padrines M, Théoleyre S, et al. 2004 IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev 15 49–60. (https://doi.org/10.1016/j.cytogfr.2003.10.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee S & Lee DY 2017 Glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes. Ann Pediatr Endocrinol Metab 22 15. (https://doi.org/10.6065/apem.2017.22.1.15)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Leiter LA, Carr MC, Stewart M, et al. 2014 Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study. Diabetes Care 37 2723–2730. (https://doi.org/10.2337/dc13-2855)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li C-J, Yu Q, Yu P, et al. 2014 Changes in liraglutide-induced body composition are related to modifications in plasma cardiac natriuretic peptides levels in obese type 2 diabetic patients. Cardiovasc Diabetology 13 36. (https://doi.org/10.1186/1475-2840-13-36)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li Z, Li S, Wang N, et al. 2020 Liraglutide, a glucagon-like peptide-1 receptor agonist, suppresses osteoclastogenesis through the inhibition of NF-κB and MAPK pathways via GLP-1R. Biomed Pharmacother 130 110523. (https://doi.org/10.1016/j.biopha.2020.110523)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Light PE, Manning Fox JE, Riedel MJ, et al. 2002 Glucagon-like peptide-1 inhibits pancreatic ATP-sensitive potassium channels via a protein kinase A- and ADP-dependent mechanism. Mol Endocrinol 16 2135–2144. (https://doi.org/10.1210/me.2002-0084)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu H, Tian F, Hu Y, Ping S, et al. 2023 Liraglutide in combination with insulin has a superior therapeutic effect to either alone on fracture healing in diabetic rats. Diabetes Metab Synd Obes 16 1235–1245. (https://doi.org/10.2147/DMSO.S404392)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • López-Gómez JJ, Pérez Castrillón JL & de Luis Román DA 2016 Impact of obesity on bone metabolism. Endocrinol Nutr 63 551–559. (https://doi.org/10.1016/j.endonu.2016.08.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu W, Xiao W, Xie W, et al. 2021 The role of osteokines in sarcopenia: therapeutic directions and application prospects. Front Cell Dev Biol 9 735374. (https://doi.org/10.3389/fcell.2021.735374)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lundkvist P, Sjöström CD, Amini S, et al. 2017 Dapagliflozin once-daily and exenatide once-weekly dual therapy: a 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes Obes Metab 19 49–60. (https://doi.org/10.1111/dom.12779)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ma X, Meng J, Jia M, et al. 2013 Exendin-4, a glucagon-like peptide-1 receptor agonist, prevents osteopenia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats. J Bone Miner Res 28 1641–1652. (https://doi.org/10.1002/jbmr.1898)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ma X, Liu Z, Ilyas I, et al. 2021 GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential. Int J Biol Sci 17 2050–2068. (https://doi.org/10.7150/ijbs.59965)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mann R, Nasr N, Sinfield J, et al. 2010 The major determinant of exendin‐4/glucagon‐like peptide 1 differential affinity at the rat glucagon‐like peptide 1 receptor N‐terminal domain is a hydrogen bond from SER‐32 of exendin‐4. Br J Pharmacol 160 1973–1984. (https://doi.org/10.1111/j.1476-5381.2010.00834.xx)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Martiniakova M, Biro R, Kovacova V, et al. 2024 Current knowledge of bone-derived factor osteocalcin: its role in the management and treatment of diabetes mellitus, osteoporosis, osteopetrosis and inflammatory joint diseases. J Mol Med 102 435–452. (https://doi.org/10.1007/s00109-024-02418-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mashayekhi M, Nian H, Mayfield D, et al. 2024 Weight loss–independent effect of liraglutide on insulin sensitivity in individuals with obesity and prediabetes. Diabetes 73 38–50. (https://doi.org/10.2337/DB23-0356)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Matthews JE, Stewart MW, De Boever EH, et al. 2008 Pharmacodynamics, pharmacokinetics, safety and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab 93 4810–4817. (https://doi.org/10.1210/jc.2008-1518)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mayendraraj A, Rosenkilde MM & Gasbjerg LS 2022 GLP-1 and GIP receptor signaling in beta cells – a review of receptor interactions and co-stimulation. Peptides 151 170749. (https://doi.org/10.1016/j.peptides.2022.170749)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McClean PL & Hölscher C 2014 Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer’s disease. Neuropharmacology 76 57–67. (https://doi.org/10.1016/J.NEUROPHARM.2013.08.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McClean PL, Parthsarathy V, Faivre E, et al. 2011 The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 31 6587–6594. (https://doi.org/10.1523/JNEUROSCI.0529-11.2011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Meng J, Ma X, Wang N, et al. 2016 Activation of GLP-1 receptor promotes bone marrow stromal cell osteogenic differentiation through β-catenin. Stem Cell Rep 6 579–591. (https://doi.org/10.1016/j.stemcr.2016.02.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mera P, Laue K, Wei J, et al. 2016 Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab 5 1042–1047. (https://doi.org/10.1016/j.molmet.2016.07.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mirzoev TM, Sharlo KA & Shenkman BS 2021 The role of GSK-3β in the regulation of protein turnover, myosin phenotype, and oxidative capacity in skeletal muscle under disuse conditions. Int J Mol Sci 22 5081. (https://doi.org/10.3390/ijms22105081)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moseley KF 2012 Type 2 diabetes and bone fractures. Curr Opin Endocrinol Diabetes Obes 19 128–135. (https://doi.org/10.1097/MED.0b013e328350a6e1)

  • Müller TD, Finan B, Bloom SR, et al. 2019 Glucagon-like peptide 1 (GLP-1). Mol Metab 30 72–130. (https://doi.org/10.1016/j.molmet.2019.09.010)

  • Nauck MA & Meier JJ 2018 Incretin hormones: their role in health and disease. Diabetes Obes Metab 20 5–21. (https://doi.org/10.1111/dom.13129)

  • Nauck M, Stöckmann F, Ebert R, et al. 1986 Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29 46–52. (https://doi.org/10.1007/BF02427280)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Neumiller JJ & Campbell RK 2009 Liraglutide: a once-daily incretin mimetic for the treatment of type 2 diabetes mellitus. Ann Pharmacother 43 1433–1444. (https://doi.org/10.1345/aph.1M134)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nguyen TTN, Choi H & Jun HS 2020 Preventive effects of dulaglutide on disuse muscle atrophy through inhibition of inflammation and apoptosis by induction of Hsp72 expression. Front Pharmacol 11 90. (https://doi.org/10.3389/fphar.2020.00090)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nuche-Berenguer B, Moreno P, Portal-Nuñez S, et al. 2010a Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states. Regul Pept 159 61–66. (https://doi.org/10.1016/j.regpep.2009.06.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nuche-Berenguer B, Portal-Núñez S, Moreno P, et al. 2010b Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor. J Cell Physiol 225 585–592. (https://doi.org/10.1002/jcp.22243)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ono T, Hayashi M, Sasaki F, et al. 2020 RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen 40 2. (https://doi.org/10.1186/s41232-019-0111-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pal S, Maurya SK, Chattopadhyay S, et al. 2019 The osteogenic effect of liraglutide involves enhanced mitochondrial biogenesis in osteoblasts. Biochem Pharmacol 164 34–44. (https://doi.org/10.1016/j.bcp.2019.03.024)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • De Paoli M, Zakharia A & Werstuck GH 2021 The role of estrogen in insulin resistance. Am J Pathol 191 1490–1498. (https://doi.org/10.1016/j.ajpath.2021.05.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Park JS, Kwon J, Choi HJ, et al. 2021 Clinical effectiveness of liraglutide on weight loss in South Koreans: first real-world retrospective data on Saxenda in Asia. Medicine 100 e23780. (https://doi.org/10.1097/MD.0000000000023780)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pereira M, Jeyabalan J, Jørgensen CS, et al. 2015 Chronic administration of glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice. Bone 81 459–467. (https://doi.org/10.1016/j.bone.2015.08.006)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Perel P, Roberts I, Sena E, et al. 2007 Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 334 197. (https://doi.org/10.1136/bmj.39048.407928.BE).

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Perna S, Guido D, Bologna C, et al. 2016 Liraglutide and obesity in elderly: efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study. Aging Clin Exp Res 28 1251–1257. (https://doi.org/10.1007/s40520-015-0525-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Portha B, Tourrel-Cuzin C & Movassat J 2011 Activation of the GLP-1 receptor signalling pathway: a relevant strategy to repair a deficient beta-cell mass. Exp Diabetes Res 2011 1–11. (https://doi.org/10.1155/2011/376509)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Qin Y, Peng Y, Zhao W, et al. 2017 Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: a novel mechanism in muscle-bone communication. J Biol Chem 292 11021–11033. (https://doi.org/10.1074/jbc.M116.770941)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rajan S, Dickson LM, Mathew E, et al. 2015 Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic β-cells via protein kinase A. Mol Metab 4 265–276. (https://doi.org/10.1016/j.molmet.2015.01.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ratner RE, Rosenstock J & Boka G 2010 Dose‐dependent effects of the once‐daily GLP‐1 receptor agonist lixisenatide in patients with type 2 diabetes inadequately controlled with metformin: a randomized, double‐blind, placebo‐controlled trial. Diabetic Med 27 1024–1032. (https://doi.org/10.1111/j.1464-5491.2010.03020.xx)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rhea EM, Babin A, Thomas P, et al. 2023 Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer’s and Parkinson’s diseases. Tissue Barriers 12 2292461. (https://doi.org/10.1080/21688370.2023.2292461)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rizzo MR, Barbieri M, Fava I, et al. 2016 Sarcopenia in elderly diabetic patients: role of dipeptidyl peptidase 4 inhibitors. J Am Med Directors Assoc 17 896–901. (https://doi.org/10.1016/j.jamda.2016.04.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Runge S, Wulff BS, Madsen K, et al. 2003 Different domains of the glucagon and glucagon‐like peptide‐1 receptors provide the critical determinants of ligand selectivity. Br J Pharmacol 138 787–794. (https://doi.org/10.1038/sj.bjp.0705120)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Salameh TS, Rhea EM, Talbot K, et al. 2020 Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer’s and Parkinson’s disease therapeutics. Biochem Pharmacol 180 114187. (https://doi.org/10.1016/j.bcp.2020.114187)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Santini S, Vionnet N, Pasquier J, et al. 2023 Marked weight loss on liraglutide 3.0 mg: real-life experience of a Swiss cohort with obesity. Obesity 31 74–82. (https://doi.org/10.1002/oby.23596)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sargeant JA, Henson J, King JA, et al. 2019 A review of the effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on lean body mass in humans. Endocrinol Metab 34 247–262. (https://doi.org/10.3803/EnM.2019.34.3.247)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Smith NK, Hackett TA, Galli A, et al. 2019 GLP-1: molecular mechanisms and outcomes of a complex signaling system. Neurochem Int 128 94–105. (https://doi.org/10.1016/j.neuint.2019.04.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Smits MM, Tonneijck L, Muskiet MHA, et al. 2016 Gastrointestinal actions of glucagon‐like peptide‐1‐based therapies: glycaemic control beyond the pancreas. Diabetes Obes Metab 18 224–235. (https://doi.org/10.1111/dom.12593)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Toft-Nielsen M-B, Damholt MB, Madsbad S, et al. 2001 Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 86 3717–3723. (https://doi.org/10.1210/jcem.86.8.7750)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Udagawa N, Koide M, Nakamura M, et al. 2021 Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Mineral Metab 39 19–26. (https://doi.org/10.1007/s00774-020-01162-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ueno S, Seino Y, Hidaka S, et al. 2023 Blockade of glucagon increases muscle mass and alters fiber type composition in mice deficient in proglucagon-derived peptides. J Diabetes Invest 14 1045–S1055. (https://doi.org/10.1111/jdi.14032)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Verma S, Poulter NR, Bhatt DL, et al. 2018 Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke. Circulation 138 2884–2894. (https://doi.org/10.1161/CIRCULATIONAHA.118.034516)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Volpe S, Lisco G, Fanelli M, et al. 2023 Oral semaglutide improves body composition and preserves lean mass in patients with type 2 diabetes: a 26-week prospective real-life study. Front Endocrinol 14 1240263. (https://doi.org/10.3389/fendo.2023.1240263)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang L 2022 Designing a dual GLP-1R/GIPR agonist from tirzepatide: comparing residues between tirzepatide, GLP-1, and GIP. Drug Des Development Ther 16 1547–1559. (https://doi.org/10.2147/DDDT.S358989)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang JS, Mazur CM & Wein MN 2021 Sclerostin and osteocalcin: candidate bone-produced hormones. Front Endocrinol 12 584147. (https://doi.org/10.3389/fendo.2021.584147)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang R, Na H, Cheng S, et al. 2023 Effects of glucagon-like peptide-1 receptor agonists on fracture healing in a rat osteoporotic model. Exp Ther Med 26 412. (https://doi.org/10.3892/etm.2023.12111)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wootten D, Reynolds CA, Koole C, et al. 2016 A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism: lessons from class B crystal structures. Mol Pharmacol 89 335–347. (https://doi.org/10.1124/mol.115.101246)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu L, Zhou M, Li T, et al. 2022 GLP-1 regulates exercise endurance and skeletal muscle remodeling via GLP-1R/AMPK pathway. Biochim Biophys Acta Mol Cell Res 1869 119300. (https://doi.org/10.1016/j.bbamcr.2022.119300)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xie B, Chen S, Xu Y, et al. 2021 The impact of glucagon-like peptide 1 receptor agonists on bone metabolism and its possible mechanisms in osteoporosis treatment. Front Pharmacol 12 697442. (https://doi.org/10.3389/fphar.2021.697442)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yajima T, Yajima K, Takahashi H, et al. 2018 The effect of dulaglutide on body composition in type 2 diabetes mellitus patients on hemodialysis. J Diabetes Complications 32 759–763. (https://doi.org/10.1016/j.jdiacomp.2018.05.018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yamada C, Yamada Y, Tsukiyama K, et al. 2008 The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 149 574–579. (https://doi.org/10.1210/en.2007-1292)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang D, de Graaf C, Yang L, et al. 2016 Structural determinants of binding the seven-transmembrane domain of the glucagon-like peptide-1 receptor (GLP-1R). J Biol Chem 291 12991–13004. (https://doi.org/10.1074/jbc.M116.721977)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang L, Yang J, Pan T, et al. 2019 Liraglutide increases bone formation and inhibits bone resorption in rats with glucocorticoid-induced osteoporosis. J Endocrinological Invest 42 1125–1131. (https://doi.org/10.1007/s40618-019-01034-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yoshida T & Delafontaine P 2020 Mechanisms of IGF-1-mediated regulation of skeletal muscle hypertrophy and atrophy. Cells 9 1970. (https://doi.org/10.3390/cells9091970)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang M, Xie Y, Zhou Y, et al. 2019 Exendin-4 enhances proliferation of senescent osteoblasts through activation of the IGF-1/IGF-1R signaling pathway. Biochem Biophysical Res Commun 516 300–306. (https://doi.org/10.1016/j.bbrc.2019.06.112)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang N, Zhou H, Xu Y, et al. 2024 Liraglutide promotes UCP1 expression and lipolysis of adipocytes by promoting the secretion of irisin from skeletal muscle cells. Mol Cell Endocrinol 588 112225. (https://doi.org/10.1016/j.mce.2024.112225)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhao C, Liang J, Yang Y, et al. 2017 The impact of glucagon-like peptide-1 on bone metabolism and its possible mechanisms. Front Endocrinol 8 98. (https://doi.org/10.3389/fendo.2017.00098)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhao Z, Yan K, Guan Q, et al. 2024 Mechanism and physical activities in bone-skeletal muscle crosstalk. Front Endocrinol 14 1287972. (https://doi.org/10.3389/fendo.2023.1287972)

    • PubMed
    • Search Google Scholar
    • Export Citation