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Parker CH, Slattery C, Brennan DJ, le Roux CW. Glucagon-like peptide 1 (GLP-1) receptor agonists' use during pregnancy: Safety data from regulatory clinical trials. Diabetes Obes Metab 2025. [PMID: 40329607 DOI: 10.1111/dom.16437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/19/2025] [Accepted: 04/22/2025] [Indexed: 05/08/2025]
Abstract
AIMS The prevalence of diabetes and obesity continues to rise in women of reproductive age, with significant implications for both mother and foetus. Glucagon-like peptide-1 receptor agonists are effective treatments of diabetes and obesity. However, no Glucagon-like peptide-1 receptor agonists are currently approved for use during pregnancy. We describe the outcomes of unplanned pregnancies during regulatory clinical trials of Glucagon-like peptide-1 receptor agonists submitted to the Food and Drug Administration and European Medicines Agency. MATERIALS AND METHODS A search was conducted of the regulatory documentation published by the European Medicines Agency and the Food and Drug Administration on unplanned pregnancies during regulatory clinical trials of Glucagon-like peptide-1 receptor agonists. Clinical and Medical Reviews published by the Center for Drug Evaluation and Research at the Food and Drug Administration for every Glucagon-like peptide-1 receptor agonist prior to market authorisation were assessed to gather information on unplanned pregnancies that occurred while females were partaking in the clinical development programmes of such drugs. RESULTS Evidence in women having planned pregnancies is lacking, and the only evidence thus far relies on pregnancies occurring inadvertently during Glucagon-like peptide-1 receptor agonist trials. The incidence of congenital abnormalities in humans appears relatively low following Glucagon-like peptide-1 receptor agonist use during pregnancy. CONCLUSIONS Key knowledge gaps must be addressed before the introduction of the Glucagon-like peptide-1 receptor agonist class of drugs for pregnant women. Currently, Glucagon-like peptide-1 receptor agonists should be stopped as soon as the patient becomes aware of a pregnancy. The establishment of patient registries designed to capture data relating to cases of Glucagon-like peptide-1 receptor agonist exposure during pregnancy is a high priority, and where data already exist, the findings need to be published.
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Affiliation(s)
- Claire H Parker
- Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, USA
| | - Craig Slattery
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Donal J Brennan
- University College Dublin School of Medicine, Catherine McCauley Research Centre, Mater Misericoridiae University Hospital, Dublin, Ireland
| | - Carel W le Roux
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
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Roberts TD, Hutchinson DS, Wootten D, De Blasio MJ, Ritchie RH. Advances in incretin therapies for targeting cardiovascular disease in diabetes. J Mol Cell Cardiol 2025; 202:102-115. [PMID: 40086589 DOI: 10.1016/j.yjmcc.2025.03.007] [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: 11/01/2024] [Revised: 02/12/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
The global prevalence of obesity is skyrocketing at an alarming rate, with recent data estimating that one-in-eight people are now living with the disease. Obesity is a chronic metabolic disorder that shares underlying pathophysiology with other metabolically-linked diseases such as type 2 diabetes mellitus, cardiovascular disease and diabetic cardiomyopathy. There is a distinct correlation between type 2 diabetes status and the likelihood of heart failure. Of note, there is an apparent sexual dimorphism, with women disproportionately affected with respect to the degree of severity of the cardiac phenotype of diabetic cardiomyopathy that results from diabetes. The current pharmacotherapies available for the attenuation of hyperglycaemia in type 2 diabetes are not always effective, and have varying degrees of efficacy in the setting of heart failure. Insulin can worsen heart failure prognosis whereas metformin, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and more recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs), have demonstrated cardioprotection with their administration. This review will highlight the advancement of incretin therapies for individuals with diabetes and heart failure and explore newly-reported evidence of the clinical usefulness of GLP-1R agonists in this distinct phenotype of heart failure.
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Affiliation(s)
- Timothy D Roberts
- Heart Failure Pharmacology Laboratory, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia
| | - Dana S Hutchinson
- Metabolic G Protein-Coupled Receptor Laboratory, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia
| | - Denise Wootten
- Metabolic G Protein-Coupled Receptor Laboratory, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia; ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia
| | - Miles J De Blasio
- Heart Failure Pharmacology Laboratory, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia.
| | - Rebecca H Ritchie
- Heart Failure Pharmacology Laboratory, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia.
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3
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Cho YY, Kim S, Kim P, Jo MJ, Park SE, Choi Y, Jung SM, Kang HJ. G-Protein-Coupled Receptor (GPCR) Signaling and Pharmacology in Metabolism: Physiology, Mechanisms, and Therapeutic Potential. Biomolecules 2025; 15:291. [PMID: 40001594 PMCID: PMC11852853 DOI: 10.3390/biom15020291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/10/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
G-protein coupled receptors (GPCRs), the largest family of integral membrane proteins, enable cells to sense and appropriately respond to the environment through mediating extracellular signaling to intercellular messenger molecules. GPCRs' pairing with a diverse array of G protein subunits and related downstream secondary messengers, combined with their ligand versatility-from conventional peptide hormone to numerous bioactive metabolites, allow GPCRs to comprehensively regulate metabolism and physiology. Consequently, GPCRs have garnered significant attention for their therapeutic potential in metabolic diseases. This review focuses on six GPCRs, GPR40, GPR120, GLP-1R, and ß-adrenergic receptors (ADRB1, ADRB2, and ADRB3), with GLP-1R recognized as a prominent regulator of system-level metabolism, while the roles of GPR40, GPR120 and ß-adrenergic receptors in central carbon metabolism and energy homeostasis are increasingly appreciated. Here, we discuss their physiological functions in metabolism, the current pharmacological landscape, and the intricacies of their signaling pathways via G protein and ß-arrestin activation. Additionally, we discuss the limitations of existing GPCR-targeted strategies for treating metabolic diseases and offer insights into future perspectives for advancing GPCR pharmacology.
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Affiliation(s)
- Yun Yeong Cho
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (Y.Y.C.); (P.K.); (M.J.J.); (S.-E.P.)
| | - Soyeon Kim
- Department of Biological Sciences, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea; (S.K.); (Y.C.)
| | - Pankyung Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (Y.Y.C.); (P.K.); (M.J.J.); (S.-E.P.)
| | - Min Jeong Jo
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (Y.Y.C.); (P.K.); (M.J.J.); (S.-E.P.)
| | - Song-E Park
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (Y.Y.C.); (P.K.); (M.J.J.); (S.-E.P.)
| | - Yiju Choi
- Department of Biological Sciences, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea; (S.K.); (Y.C.)
| | - Su Myung Jung
- Department of Biological Sciences, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea; (S.K.); (Y.C.)
| | - Hye Jin Kang
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; (Y.Y.C.); (P.K.); (M.J.J.); (S.-E.P.)
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Duran M, Willis JR, Dalvi N, Fokakis Z, Virkus SA, Hardaway JA. Integration of Glucagon-Like Peptide 1 Receptor Actions Through the Central Amygdala. Endocrinology 2025; 166:bqaf019. [PMID: 39888375 PMCID: PMC11850305 DOI: 10.1210/endocr/bqaf019] [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: 10/16/2024] [Revised: 12/31/2024] [Accepted: 01/25/2025] [Indexed: 02/01/2025]
Abstract
Understanding the detailed mechanism of action of glucagon-like peptide 1 receptor (GLP-1R) agonists on distinct topographic and genetically defined brain circuits is critical for improving the efficacy and mitigating adverse side effects of these compounds. In this mini-review, we propose that the central nucleus of the amygdala (CeA) is a critical mediator of GLP-1R agonist-driven hypophagia. Here, we review the extant literature demonstrating CeA activation via GLP-1R agonists across multiple species and through multiple routes of administration. The precise role of GLP-1Rs within the CeA is unclear but the site-specific GLP-1Rs may mediate distinct behavioral and physiological hallmarks of GLP-1R agonists on food intake. Thus, we propose important novel directions and methods to test the role of the CeA in mediating GLP-1R actions.
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Affiliation(s)
- Miguel Duran
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jennifer R Willis
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Nilay Dalvi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Zoe Fokakis
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Sonja A Virkus
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - J Andrew Hardaway
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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5
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Hankir MK, Lutz TA. Novel neural pathways targeted by GLP-1R agonists and bariatric surgery. Pflugers Arch 2025; 477:171-185. [PMID: 39644359 PMCID: PMC11761532 DOI: 10.1007/s00424-024-03047-3] [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: 10/17/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 12/09/2024]
Abstract
The glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide has revolutionized the treatment of obesity, with other gut hormone-based drugs lined up that show even greater weight-lowering ability in obese patients. Nevertheless, bariatric surgery remains the mainstay treatment for severe obesity and achieves unparalleled weight loss that generally stands the test of time. While their underlying mechanisms of action remain incompletely understood, it is clear that the common denominator between GLP-1R agonists and bariatric surgery is that they suppress food intake by targeting the brain. In this Review, we highlight recent preclinical studies using contemporary neuroscientific techniques that provide novel concepts in the neural control of food intake and body weight with reference to endogenous GLP-1, GLP-1R agonists, and bariatric surgery. We start in the periphery with vagal, intestinofugal, and spinal sensory nerves and then progress through the brainstem up to the hypothalamus and finish at non-canonical brain feeding centers such as the zona incerta and lateral septum. Further defining the commonalities and differences between GLP-1R agonists and bariatric surgery in terms of how they target the brain may not only help bridge the gap between pharmacological and surgical interventions for weight loss but also provide a neural basis for their combined use when each individually fails.
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Affiliation(s)
- Mohammed K Hankir
- Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Thomas A Lutz
- Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.
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6
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Mocciaro G, George AL, Allison M, Frontini M, Huang‐Doran I, Reiman F, Gribble F, Griffin JL, Vidal‐Puig A, Azzu V, Kay R, Vacca M. Oxidised Apolipoprotein Peptidome Characterises Metabolic Dysfunction-Associated Steatotic Liver Disease. Liver Int 2025; 45:e16200. [PMID: 39822152 PMCID: PMC11740006 DOI: 10.1111/liv.16200] [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: 09/18/2024] [Revised: 11/07/2024] [Accepted: 11/25/2024] [Indexed: 01/19/2025]
Abstract
BACKGROUND Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) encompasses a spectrum of histological conditions ranging from simple steatosis to fibrosing steatohepatitis, and is a risk factor for cardiovascular diseases (CVD). While oxidised apolipoproteins A and B have been linked to obesity and CVD, the association between other oxidised apolipoproteins and MASLD is yet to be established. To fill this gap, we characterised the circulating serum peptidome of patients with MASLD. METHODS We studied the serum of 87 biopsy-confirmed MASLD patients and 20 age- and sex-matched control (CTRL) subjects. We first employed an untargeted LC-MS/MS peptidomics approach (9 CTRL, 32 MASLD) to identify key hits differentially modulated, and subsequently validated the most relevant findings through targeted peptidomics in an enlarged study population (87 MASLD and 20 CTRL). RESULTS Untargeted serum peptidomics identified several oxidised apolipoprotein peptide fragments, including ApoE and ApoC-III, significantly upregulated in MASLD compared to CTRL. Specifically focusing on the oxidative status of intact ApoC-III, studied through its major glycoforms (ApoC-III0, ApoC-IIIi and ApoC-IIIii), we observed a marked reduction in non-oxidised forms of these circulating peptides alongside substantially increased levels of their oxidised proteoforms in MASLD versus controls (but not within the disease stages). Oxidised ApoE and ApoC-III peptide fragments were also significantly correlated with obesity, insulin resistance, dyslipidaemia and transaminases, suggesting a potential link between circulating apolipoprotein oxidation and systemic/hepatic metabolic dysfunction. CONCLUSION Our data reveals a previously unreported oxidised apolipoprotein profile associated with MASLD. The functional and clinical implications of these findings warrant further mechanistic investigation.
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Grants
- Wellcome Trust
- MR/S010483/1 Medical Research Council
- This research was supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) funding to V.A., M.A., and M.V.The initial establishment of the cohorts was supported by the Evelyn Trust (funding to M.A. and A.V.P.), Mason Medical Research Trust (funding to V.A.), and the Academy of Medical Sciences (funding to V.A.). V.A. was supported by the University of Cambridge. M.A. is supported by Cambridge University Hospitals NHS Foundation Trust. M.V. is supported by the University of Bari (Horizon Europe Seed cod. id. S06-miRNASH), the Foundation for Liver Research (Intramural Funding), Associazione Italiana Ricerca sul Cancro (IG2022 Grant n. 27521) and Ministry of University and Research on Next Generation EU Funds [COD: P202222FCC, CUP: H53D23009960001, D.D. MUR 1366 (01-09-2023), Title: "System Biology" approaches in HCV Patients with Residual Hepatic Steatosis after Viral Eradication; Cod PE00000003, CUP: H93C22000630001, DD MUR 1550, Title: "ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security - Working ON Foods"; Cod: CN00000041, CUP: H93C22000430007, Title PNRR "National Center for Gene Therapy and Drugs based on RNA Technology", M4C2-Investment 1.4; Code: CN00000013, CUP: H93C22000450007, Title PNNR: "National Centre for HPC, Big Data and Quantum Computing").A.V.P. is funded by MRC MDU, MRC Metabolic Diseases Unit (MC_UU_00014/5): Disease Model Core, Biochemistry Assay Lab, Histology Core and British Heart Foundation. M.F. is supported by the British Heart Foundation (FS/18/53/33863) and the British Heart Foundation Cambridge Centre for Research Excellence (RE/18/1/34212). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. We would like to thank all participants in this study and the NIHR National BioResource. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. JLG is funded by the Medical Research Council (MR/S010483/1; MR/P011705/1; MR/P01836X/1; MR/X012700/1). F.G., F.R., R.K. and A.L.G. were funded by the Wellcome Trust (grants 106262/Z/14/Z, 106263/Z/14/Z), the MRC Metabolic Diseases Unit (grants MRC MC UU 12012/3, MRC MC UU12012/5) and by the NIHR Cambridge Biomedical Research Centre. The mass spectrometers were obtained using the Medical Research Council "Enhancing UK Clinical Research" grant (MR/M009041/1). The views expressed are those of the author(s) and not necessarily those of the relevant funding or supporting institutions. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript
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Affiliation(s)
- Gabriele Mocciaro
- Roger Williams Institute of Liver StudiesFoundation for Liver ResearchLondonUK
| | - Amy L. George
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Michael Allison
- Liver Unit, Cambridge NIHR Biomedical Research CentreCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Mattia Frontini
- Faculty of Health and Life Sciences, Clinical and Biomedical SciencesUniversity of Exeter Medical SchoolExeterUK
| | - Isabel Huang‐Doran
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Frank Reiman
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Fiona Gribble
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Julian L. Griffin
- The Rowett Institute, Foresterhill CampusUniversity of AberdeenAberdeenUK
| | - Antonio Vidal‐Puig
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Vian Azzu
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
- Liver Unit, Cambridge NIHR Biomedical Research CentreCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Richard Kay
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Michele Vacca
- Roger Williams Institute of Liver StudiesFoundation for Liver ResearchLondonUK
- University of Bari "Aldo Moro"Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni"BariItaly
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Sawyer JR, Audie JA, Swanson J, Diller D, Santiago S, Gribkoff VK, Ackerman A, Hruby VJ, Gobbo G, Bellucci MA, Glauser WA, Pentelute BL, Sawyer TK. Design, Structure-Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists. Molecules 2024; 30:12. [PMID: 39795070 PMCID: PMC11721672 DOI: 10.3390/molecules30010012] [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: 04/05/2024] [Revised: 07/24/2024] [Accepted: 07/29/2024] [Indexed: 01/13/2025] Open
Abstract
A systematic structure-activity and computational modeling analysis of a series of glucagon-like peptide-1 receptor (GLP-1R) agonists based upon an ultra-short GLP-1 peptide, H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2, was conducted. This highly potent 11-mer peptide led to a deeper understanding of the α-helical bias of strategic α-methylation within the linear parent template as well as optimization of GLP-1R agonist potency by 1000-fold. These data were correlated with previously reported co-structures of both full-length GLP-1 analogs and progenitor N-terminal GLP-1 fragment analogs related to such ultra-short GLP-1R agonist peptides. Furthermore, the development of a quantitative structure-activity relationship (QSAR) model to analyze these findings is described in this study.
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Affiliation(s)
- Jonathon R. Sawyer
- Resolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USA; (S.S.); (V.K.G.); (A.A.); (B.L.P.); (T.K.S.)
- Department of Chemistry and Biochemistry, The University of Arizona, 1306 E. University Blvd, Tucson, AZ 85721, USA;
- Peptide Scientia, 8 Nathan Stone Lane, Southborough, MA 01772, USA
| | - Joseph A. Audie
- Eudoxia Life Sciences, 520 Squire Hill Rd., Cheshire, CT 06410, USA; (J.S.); (D.D.)
| | - Jon Swanson
- Eudoxia Life Sciences, 520 Squire Hill Rd., Cheshire, CT 06410, USA; (J.S.); (D.D.)
| | - David Diller
- Eudoxia Life Sciences, 520 Squire Hill Rd., Cheshire, CT 06410, USA; (J.S.); (D.D.)
| | - Solimar Santiago
- Resolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USA; (S.S.); (V.K.G.); (A.A.); (B.L.P.); (T.K.S.)
| | - Valentin K. Gribkoff
- Resolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USA; (S.S.); (V.K.G.); (A.A.); (B.L.P.); (T.K.S.)
| | - Allison Ackerman
- Resolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USA; (S.S.); (V.K.G.); (A.A.); (B.L.P.); (T.K.S.)
| | - Victor J. Hruby
- Department of Chemistry and Biochemistry, The University of Arizona, 1306 E. University Blvd, Tucson, AZ 85721, USA;
| | - Gianpaolo Gobbo
- XtalPi US, XtalPi Inc., 245 Main Street, Cambridge, MA 02142, USA; (G.G.); (M.A.B.); (W.A.G.)
| | - Michael A. Bellucci
- XtalPi US, XtalPi Inc., 245 Main Street, Cambridge, MA 02142, USA; (G.G.); (M.A.B.); (W.A.G.)
| | - William A. Glauser
- XtalPi US, XtalPi Inc., 245 Main Street, Cambridge, MA 02142, USA; (G.G.); (M.A.B.); (W.A.G.)
| | - Brad L. Pentelute
- Resolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USA; (S.S.); (V.K.G.); (A.A.); (B.L.P.); (T.K.S.)
| | - Tomi K. Sawyer
- Resolute Bio, 48 Dunham Rd., Suite 5400, Beverly, MA 01915, USA; (S.S.); (V.K.G.); (A.A.); (B.L.P.); (T.K.S.)
- Maestro Therapeutics, 8 Nathan Stone Lane, Southborough, MA 01772, USA
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8
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Freet CS, Evans B, Brick TR, Deneke E, Wasserman EJ, Ballard SM, Stankoski DM, Kong L, Raja-Khan N, Nyland JE, Arnold AC, Krishnamurthy VB, Fernandez-Mendoza J, Cleveland HH, Scioli AD, Molchanow A, Messner AE, Ayaz H, Grigson PS, Bunce SC. Ecological momentary assessment and cue-elicited drug craving as primary endpoints: study protocol for a randomized, double-blind, placebo-controlled clinical trial testing the efficacy of a GLP-1 receptor agonist in opioid use disorder. Addict Sci Clin Pract 2024; 19:56. [PMID: 39061093 PMCID: PMC11282646 DOI: 10.1186/s13722-024-00481-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 06/07/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Despite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment. METHOD This preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2-19), and following (Study Days 20-21) residential treatment. DISCUSSION This manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. TRIAL REGISTRATION ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728 . PROTOCOL VERSION 10 May 2023.
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Affiliation(s)
- Christopher S Freet
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Brianna Evans
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Timothy R Brick
- Department of Human Development and Family Studies, The Pennsylvania State University, University Park, PA, USA
- Institute for Computational and Data Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Erin Deneke
- Fran and Doug Tieman Center for Research, Caron Treatment Centers, Wernersville, PA, USA
| | - Emily J Wasserman
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Sarah M Ballard
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Dean M Stankoski
- Fran and Doug Tieman Center for Research, Caron Treatment Centers, Wernersville, PA, USA
| | - Lan Kong
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Nazia Raja-Khan
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Department of Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Department of Obstetrics & Gynecology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Jennifer E Nyland
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Amy C Arnold
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Venkatesh Basappa Krishnamurthy
- Department of Medicine and Psychiatry, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Julio Fernandez-Mendoza
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - H Harrington Cleveland
- Department of Human Development and Family Studies, The Pennsylvania State University, University Park, PA, USA
| | - Adam D Scioli
- Fran and Doug Tieman Center for Research, Caron Treatment Centers, Wernersville, PA, USA
| | | | | | - Hasan Ayaz
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Patricia S Grigson
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Scott C Bunce
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
- Penn State University College of Medicine, Milton S. Hershey Medical Center, H073, 500 University Drive, Hershey, PA, 17033-0850, USA.
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9
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Novikoff A, Müller TD. Pharmacological Advances in Incretin-Based Polyagonism: What We Know and What We Don't. Physiology (Bethesda) 2024; 39:142-156. [PMID: 38353610 PMCID: PMC11368522 DOI: 10.1152/physiol.00032.2023] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 02/21/2024] Open
Abstract
The prevalence of obesity continues to rise in both adolescents and adults, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes, heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side effects. However, while the history of antiobesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1R) and unimolecular coagonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although the GIP receptor:GLP-1R coagonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism.
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Affiliation(s)
- Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
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10
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Boshchenko AA, Maslov LN, Mukhomedzyanov AV, Zhuravleva OA, Slidnevskaya AS, Naryzhnaya NV, Zinovieva AS, Ilinykh PA. Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists. Int J Mol Sci 2024; 25:4900. [PMID: 38732142 PMCID: PMC11084666 DOI: 10.3390/ijms25094900] [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: 03/18/2024] [Revised: 04/10/2024] [Accepted: 04/14/2024] [Indexed: 05/13/2024] Open
Abstract
The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1β, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3β, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), KATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists.
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Affiliation(s)
- Alla A. Boshchenko
- Department of Atherosclerosis and Chronic Coronary Heart Disease, Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634012 Tomsk, Russia
| | - Leonid N. Maslov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634012 Tomsk, Russia
| | - Alexander V. Mukhomedzyanov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634012 Tomsk, Russia
| | - Olga A. Zhuravleva
- Department of Atherosclerosis and Chronic Coronary Heart Disease, Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634012 Tomsk, Russia
| | - Alisa S. Slidnevskaya
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634012 Tomsk, Russia
| | - Natalia V. Naryzhnaya
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634012 Tomsk, Russia
| | - Arina S. Zinovieva
- Department of Atherosclerosis and Chronic Coronary Heart Disease, Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634012 Tomsk, Russia
| | - Philipp A. Ilinykh
- Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA
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11
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Prajapati S. Advances in the Management of Diabetes and Overweight using Incretin-based Pharmacotherapies. Curr Diabetes Rev 2024; 20:e131123223544. [PMID: 37962047 DOI: 10.2174/0115733998256797231009062744] [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: 04/19/2023] [Revised: 08/20/2023] [Accepted: 08/30/2023] [Indexed: 11/15/2023]
Abstract
Throughout the previous three decades, the secretion of glucagon-like peptide-1 hormone has attracted much attention to attain possible therapy goals for the treatment of both hypoglycaemic along type II diabetes militates and overweight. The pharmaceutical generation of peptides similar to hypoglycaemia-based medicines is exemplified by agonists of the GLP- 1R (Glucagon-like peptide-1 receptors). Pharmacokinetic profiles are continuously being improved, beginning with the native hormone with a two- to three-minute quarter and progressing through growth every day with once-drug combinations. Due to contradictory data that indicate stimulation or inhibition of the Glucagon-like peptide receptor, the Glucose-dependent insulin tropic peptide receptor offers favorable effects on systemic metabolism. The recent Glp-1R (Glucagon-like peptide-1 receptor-) targeting monomolecular drugs has demonstrated therapeutic effectiveness and has stoked interest in Glucose-dependent insulin tropic polypeptide antagonism as a treatment for overweight and diabetes mellitus. These drugs have been shown to dramatically improve carbohydrates with body weight management in sick people who have obesity and type II diabetes mellitus. In this study, recent breakthroughs in compelling therapeutic interventions are discussed, and the biology and pharmacology of the glucose-like peptide are reviewed.
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Affiliation(s)
- Shatrudhan Prajapati
- Department of Pharmacy, Golgotias University, Greater Noida, Uttar Pradesh, India
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12
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Mariam Z, Niazi SK. Glucagon-like peptide agonists: A prospective review. Endocrinol Diabetes Metab 2024; 7:e462. [PMID: 38093651 PMCID: PMC10782143 DOI: 10.1002/edm2.462] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/03/2023] [Accepted: 11/19/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising therapeutic options for addressing Type-2 diabetes, obesity, and related conditions. Among these, semaglutide, tirzepatide, liraglutide etc., all notable GLP-1RA, have gained attention owing to their favourable pharmacological properties and clinical efficacy. AIMS This comprehensive review aims to provide a detailed analysis of both the currently available GLP-1RAs in the market and those undergoing clinical trials. The focus is on examining their mechanism of action, pharmacokinetics, efficacy in glycemic control and weight management, safety profile, and potential applications. MATERIALS & METHODS The review employs a systematic approach to gather information on GLP-1RAs. Relevant literature from the currently literature and ongoing clinical trials is thoroughly examined. Detailed scrutiny is applied to understand the mechanism of action, pharmacokinetic properties, and clinical outcomes of these agents. RESULTS The review presents a comprehensive overview of the GLP-1RAs, highlighting their distinct mechanisms of action, pharmacokinetic profiles, and clinical effectiveness in glycemic control and weight management. Safety profiles are also discussed, providing a holistic understanding of these therapeutic agents. DISCUSSION The findings are discussed in the context of advancements in the field of GLP-1RAs. Potential applications beyond diabetes and obesity are explored, shedding light on the broader implications of these agents in managing related conditions. CONCLUSION In conclusion, this review underscores the significance of GLP-1RAs, with a specific focus on semaglutide, in the management of type 2 diabetes, obesity, and beyond. By synthesizing information on their mechanisms, pharmacokinetics, efficacy, and safety, this review provides valuable insights into the potential benefits these agents offer, contributing to the ongoing discourse in the field.
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13
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Hanssen R, Rigoux L, Kuzmanovic B, Iglesias S, Kretschmer AC, Schlamann M, Albus K, Edwin Thanarajah S, Sitnikow T, Melzer C, Cornely OA, Brüning JC, Tittgemeyer M. Liraglutide restores impaired associative learning in individuals with obesity. Nat Metab 2023; 5:1352-1363. [PMID: 37592007 PMCID: PMC10447249 DOI: 10.1038/s42255-023-00859-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 07/07/2023] [Indexed: 08/19/2023]
Abstract
Survival under selective pressure is driven by the ability of our brain to use sensory information to our advantage to control physiological needs. To that end, neural circuits receive and integrate external environmental cues and internal metabolic signals to form learned sensory associations, consequently motivating and adapting our behaviour. The dopaminergic midbrain plays a crucial role in learning adaptive behaviour and is particularly sensitive to peripheral metabolic signals, including intestinal peptides, such as glucagon-like peptide 1 (GLP-1). In a single-blinded, randomized, controlled, crossover basic human functional magnetic resonance imaging study relying on a computational model of the adaptive learning process underlying behavioural responses, we show that adaptive learning is reduced when metabolic sensing is impaired in obesity, as indexed by reduced insulin sensitivity (participants: N = 30 with normal insulin sensitivity; N = 24 with impaired insulin sensitivity). Treatment with the GLP-1 receptor agonist liraglutide normalizes impaired learning of sensory associations in men and women with obesity. Collectively, our findings reveal that GLP-1 receptor activation modulates associative learning in people with obesity via its central effects within the mesoaccumbens pathway. These findings provide evidence for how metabolic signals can act as neuromodulators to adapt our behaviour to our body's internal state and how GLP-1 receptor agonists work in clinics.
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Affiliation(s)
- Ruth Hanssen
- Max Planck Institute for Metabolism Research, Cologne, Germany
- Faculty of Medicine and University Hospital Cologne, Policlinic for Endocrinology, Diabetology and Preventive Medicine (PEPD), University of Cologne, Cologne, Germany
| | - Lionel Rigoux
- Max Planck Institute for Metabolism Research, Cologne, Germany
| | | | - Sandra Iglesias
- Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Alina C Kretschmer
- Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD) and Excellence Center for Medical Mycology (ECMM), University of Cologne, Cologne, Germany
| | - Marc Schlamann
- Faculty of Medicine and University Hospital Cologne, Institute for Diagnostic and Interventional Radiology, University of Cologne, Cologne, Germany
| | - Kerstin Albus
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Sharmili Edwin Thanarajah
- Max Planck Institute for Metabolism Research, Cologne, Germany
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Tamara Sitnikow
- Faculty of Medicine and University Hospital Cologne, Policlinic for Endocrinology, Diabetology and Preventive Medicine (PEPD), University of Cologne, Cologne, Germany
| | - Corina Melzer
- Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Oliver A Cornely
- Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD) and Excellence Center for Medical Mycology (ECMM), University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
- Faculty of Medicine and University Hospital Cologne, Clinical Trials Centre Cologne (ZKS Köln), University of Cologne, Cologne, Germany
| | - Jens C Brüning
- Max Planck Institute for Metabolism Research, Cologne, Germany
- Faculty of Medicine and University Hospital Cologne, Policlinic for Endocrinology, Diabetology and Preventive Medicine (PEPD), University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Marc Tittgemeyer
- Max Planck Institute for Metabolism Research, Cologne, Germany.
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
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14
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Guglielmi V, Bettini S, Sbraccia P, Busetto L, Pellegrini M, Yumuk V, Colao AM, El Ghoch M, Muscogiuri G. Beyond Weight Loss: Added Benefits Could Guide the Choice of Anti-Obesity Medications. Curr Obes Rep 2023; 12:127-146. [PMID: 37209215 PMCID: PMC10250472 DOI: 10.1007/s13679-023-00502-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 05/22/2023]
Abstract
PURPOSE OF REVIEW To highlight the added benefits of approved and upcoming, centrally-acting, anti-obesity drugs, focusing not only on the most common metabolic and cardiovascular effects but also on their less explored clinical benefits and drawbacks, in order to provide clinicians with a tool for more comprehensive, pharmacological management of obesity. RECENT FINDINGS Obesity is increasingly prevalent worldwide and has become a challenge for healthcare systems and societies. Reduced life expectancy and cardiometabolic complications are some of the consequences of this complex disease. Recent insights into the pathophysiology of obesity have led to the development of several promising pharmacologic targets, so that even more effective drugs are on the horizon. The perspective of having a wider range of treatments increases the chance to personalize therapy. This primarily has the potential to take advantage of the long-term use of anti-obesity medication for safe, effective and sustainable weight loss, and to concomitantly address obesity complications/comorbidities when already established. The evolving scenario of the availability of anti-obesity drugs and the increasing knowledge of their added effects on obesity complications will allow clinicians to move into a new era of precision medicine.
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Affiliation(s)
- Valeria Guglielmi
- Dept. of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Internal Medicine Unit - Obesity Center, University Hospital Policlinico Tor Vergata, Rome, Italy
| | - Silvia Bettini
- Center for the Study and the Integrated Treatment of Obesity, Internal Medicine 3, Padua University Hospital, Padua, Italy
| | - Paolo Sbraccia
- Dept. of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Internal Medicine Unit - Obesity Center, University Hospital Policlinico Tor Vergata, Rome, Italy
| | - Luca Busetto
- Center for the Study and the Integrated Treatment of Obesity, Internal Medicine 3, Padua University Hospital, Padua, Italy
| | - Massimo Pellegrini
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Volkan Yumuk
- Division of Endocrinology, Metabolism & Diabetes Istanbul University Cerrahpaşa Medical Faculty, Istanbul, Türkiye
| | - Anna Maria Colao
- Italian Centre for the Care and Well-Being of Patients With Obesity (C.I.B.O), Dipartimento Di Medicina Clinica E Chirurgia, Università Federico II, 80131 Naples, Italy
- Dipartimento Di Medicina Clinica E Chirurgia, Diabetologia E Andrologia, Unità Di Endocrinologia, Università Degli Studi Di Napoli Federico II, Via Sergio Pansini 5, 80131 Naples, Italy
- Cattedra Unesco ”Educazione Alla Salute E Allo Sviluppo Sostenibile”, University Federico II, Naples, Italy
| | - Marwan El Ghoch
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Beirut Arab University, P.O. Box 11-5020, Riad El Solh, Beirut, Lebanon
| | - Giovanna Muscogiuri
- Dipartimento Di Medicina Clinica E Chirurgia, Diabetologia E Andrologia, Unità Di Endocrinologia, Università Degli Studi Di Napoli Federico II, Via Sergio Pansini 5, 80131 Naples, Italy
- Cattedra Unesco ”Educazione Alla Salute E Allo Sviluppo Sostenibile”, University Federico II, Naples, Italy
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15
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Heinla K, Vasar E, Reppo I, Sedman T, Volke V. GLP-1 Receptor Agonists Induce Growth Hormone Secretion in Healthy Volunteers. Diabetes Ther 2023; 14:777-786. [PMID: 36800161 PMCID: PMC10064408 DOI: 10.1007/s13300-023-01381-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
INTRODUCTION Growth hormone (GH) is an essential regulator of growth, body composition and fuel metabolism and, consequently, GH secretion is under the feedback control of numerous nutritional and endocrine mediators. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to exert pleiotropic effects, including stimulation of the activity of the hypothalamic-pituitary-adrenal axis. As GLP-1RAs exert multiple metabolic effects, we hypothesised that they may also affect the secretion of GH and examined the effect of a short-acting and a long-acting GLP-1 RA on GH secretion. METHODS This is a post hoc analysis of data from clinical trials. Two separate single-group open-label clinical trials were carried out in the ambulatory care setting with a duration of 1 and 21 days, respectively. Healthy adult male and female volunteers with no chronic illnesses or use of daily medicines were recruited for the study. The two interventions were: study 1, single dose of 10 µg exenatide administered subcutaneously (s.c.); study 2, 0.6 mg liraglutide administered s.c. once daily for 21 days. RESULTS Administration of a single dose of exenatide (study 1) caused a clear increase in GH levels, peaking between 60 and 120 min post-administration. There was also a small but statistically significant decrease in luteinising hormone and testosterone levels 120 min after exenatide dosing. Administration of the long-acting GLP-1RA liraglutide daily for 21 days (study 2) elicited an increase in GH levels with no change in insulin-like growth factor-1 (IGF-1) concentrations after 3 weeks of treatment. CONCLUSIONS The results show that the administration of GLP-1RAs may elicit an increase in growth hormone levels. GLP-1 signalling may be a novel mechanism of regulation of GH secretion. This finding needs to be replicated in the placebo-controlled trial. CLINICAL TRIAL REGISTRATION NUMBERS NCT02089256 and NCT03160261.
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Affiliation(s)
- Keiu Heinla
- Department of Physiology, Institute of Biomedicine and Translational Medicine, Centre of Excellence in Genomics and Translational Medicine, University of Tartu, Ravila 19, 50110, Tartu, Estonia
| | - Eero Vasar
- Department of Physiology, Institute of Biomedicine and Translational Medicine, Centre of Excellence in Genomics and Translational Medicine, University of Tartu, Ravila 19, 50110, Tartu, Estonia
| | - Ingrid Reppo
- Endocrinology Unit, Tartu University Hospital, Tartu, Estonia
| | - Tuuli Sedman
- Psychiatry Clinic, Tartu University Hospital, Tartu, Estonia
| | - Vallo Volke
- Department of Physiology, Institute of Biomedicine and Translational Medicine, Centre of Excellence in Genomics and Translational Medicine, University of Tartu, Ravila 19, 50110, Tartu, Estonia.
- Endocrinology Unit, Tartu University Hospital, Tartu, Estonia.
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16
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Ding R, Zhao Z, He J, Tao Y, Zhang H, Yuan R, Sun K, Shi Y. Preparation, Drug Distribution, and In Vivo Evaluation of the Safety of Protein Corona Liposomes for Liraglutide Delivery. NANOMATERIALS (BASEL, SWITZERLAND) 2023; 13:nano13030540. [PMID: 36770503 PMCID: PMC9920406 DOI: 10.3390/nano13030540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/17/2023] [Accepted: 01/17/2023] [Indexed: 05/13/2023]
Abstract
The development of oral drug delivery systems is challenging, and issues related to the mucus layer and low intestinal epithelial permeability have not yet been surmounted. The purpose of this study was to develop a promising formulation that is more adapted to in vivo absorption and to facilitate the administration of oral liraglutide. Cationic liposomes (CLs) linked to AT-1002 were prepared using a double-emulsion method, and BSA was adsorbed on the surface of the AT-CLs, resulting in protein corona cationic liposomes with AT-1002 (Pc-AT-CLs). The preparation method was determined by investigating various process parameters. The particle size, potential, and encapsulation efficiency (EE%) of the Pc-AT-CLs were 202.9 ± 12.4 nm, 1.76 ± 4.87 mV, and 84.63 ± 5.05%, respectively. The transmission electron microscopy (TEM) imaging revealed a nearly spherical structure of the Pc-AT-CLs, with a recognizable coating. The circular dichroism experiments confirmed that the complex preparation process did not affect the secondary structure of liraglutide. With the addition of BSA and AT-1002, the mucosal accumulation of the Pc-AT-CLs was nearly two times lower than that of the AT-CLs, and the degree of enteric metaplasia was 1.35 times higher than that of the PcCLs. The duration of the intestinal absorption of the Pc-AT-CLs was longer, offering remarkable biological safety.
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Affiliation(s)
- Ruihuan Ding
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 261400, China
| | - Zhenyu Zhao
- School of Life Science, Yantai University, Yantai 261400, China
| | - Jibiao He
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 261400, China
| | - Yuping Tao
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 261400, China
| | - Houqian Zhang
- School of Life Science, Yantai University, Yantai 261400, China
| | - Ranran Yuan
- School of Life Science, Yantai University, Yantai 261400, China
| | - Kaoxiang Sun
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 261400, China
- Correspondence: (K.S.); (Y.S.)
| | - Yanan Shi
- School of Life Science, Yantai University, Yantai 261400, China
- Correspondence: (K.S.); (Y.S.)
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17
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GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023; 24:ijms24021703. [PMID: 36675217 PMCID: PMC9865319 DOI: 10.3390/ijms24021703] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.
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18
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Kurtzhals P, Østergaard S, Nishimura E, Kjeldsen T. Derivatization with fatty acids in peptide and protein drug discovery. Nat Rev Drug Discov 2023; 22:59-80. [PMID: 36002588 DOI: 10.1038/s41573-022-00529-w] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 01/28/2023]
Abstract
Peptides and proteins are widely used to treat a range of medical conditions; however, they often have to be injected and their effects are short-lived. These shortcomings of the native structure can be addressed by molecular engineering, but this is a complex undertaking. A molecular engineering technology initially applied to insulin - and which has now been successfully applied to several biopharmaceuticals - entails the derivatization of peptides and proteins with fatty acids. Various protraction mechanisms are enabled by the specific characteristics and positions of the attached fatty acid. Furthermore, the technology can ensure a long half-life following oral administration of peptide drugs, can alter the distribution of peptides and may hold potential for tissue targeting. Due to the inherent safety and well-defined chemical nature of the fatty acids, this technology provides a versatile approach to peptide and protein drug discovery.
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19
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Sharma N, Singh S. Clinical potential of glucagon-like peptide-1 analogs in the management of diabesity. JOURNAL OF DIABETOLOGY 2023. [DOI: 10.4103/jod.jod_102_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2023] Open
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20
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DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N, Mantzoros C. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism 2022; 137:155332. [PMID: 36240884 DOI: 10.1016/j.metabol.2022.155332] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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Affiliation(s)
- Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Niyoti Reddy
- Department of Medicine, School of Medicine, Boston University, Boston, USA
| | - Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Filippaios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Elliot Sternthal
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Sindos, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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21
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Evans B, Stoltzfus B, Acharya N, Nyland JE, Arnold AC, Freet CS, Bunce SC, Grigson PS. Dose titration with the glucagon-like peptide-1 agonist, liraglutide, reduces cue- and drug-induced heroin seeking in high drug-taking rats. Brain Res Bull 2022; 189:163-173. [PMID: 36038016 PMCID: PMC10757750 DOI: 10.1016/j.brainresbull.2022.08.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 01/13/2023]
Abstract
Opioid use disorder (OUD), like other substance use disorders (SUDs), is widely understood to be a disorder of persistent relapse. Despite the use of three FDA-approved medications for OUD, typically in conjunction with behavioral treatments, relapse rates remain unacceptably high. Whereas medication assisted therapy (MAT) reduces the risk of opioid overdose mortality, the benefits of MAT are negated when people discontinue the medications. Currently approved medications present barriers to efficient use, including daily visits to a treatment center or work restrictions. With spiking increases in opioid relapse and death, it is imperative to identify new treatments that can reduce the risk of relapse. Recent evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently FDA-approved to treat obesity and type two diabetes, may be promising candidates to reduce relapse. GLP-1RAs have been shown to reduce relapse in rats, whether elicited by cues, drug, and/or stress. However, GLP-1RAs also can cause gastrointestinal malaise, and therefore, in humans, the medication typically is titrated up to full dose when initiating treatment. Here, we used a rodent model to test whether cue- and drug-induced heroin seeking can be reduced by the GLP-1RA, liraglutide, when the dose is titrated across the abstinence period and prior to test. The results show this titration regimen is effective in reducing both cue-induced heroin seeking and drug-induced reinstatement of heroin seeking, particularly in rats with a history of high drug-taking. Importantly, this treatment regimen had no effect on either circulating glucose or insulin. GLP-1RAs, then, appear strong candidates for the non-opioid prevention of relapse to opioids.
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Affiliation(s)
- Brianna Evans
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Addiction Center for Translation, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Brooke Stoltzfus
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Nikhil Acharya
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Addiction Center for Translation, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Jennifer E Nyland
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Addiction Center for Translation, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Amy C Arnold
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Addiction Center for Translation, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Christopher S Freet
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Addiction Center for Translation, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Scott C Bunce
- Department of Psychiatry and Behavioral Health, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Addiction Center for Translation, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Patricia S Grigson
- Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Addiction Center for Translation, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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22
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Pappa E, Kostara C, Bairaktari E, Arvaniti E, Tsimihodimos V. Effect of fixed-dose combination of insulin degludec and liraglutide on apoB-containing lipoprotein subclasses and HDL lipidome in type 2 diabetes. J Diabetes Complications 2022; 36:108286. [PMID: 36115184 DOI: 10.1016/j.jdiacomp.2022.108286] [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: 03/06/2022] [Revised: 08/10/2022] [Accepted: 08/14/2022] [Indexed: 11/25/2022]
Abstract
AIMS Administration of insulin degludec and liraglutide (IDegLira) correlates to fasting lipid profile changes of diabetic patients, while data concerning apoB-containing lipoprotein subclasses and HDL lipidome are scarce. We evaluated its effect on fasting lipid parameters, apolipoproteins, apoB-containing lipoprotein subclasses and HDL lipidome in patients with type 2 diabetes. METHODS Sixty three patients with HbA1c > 7 % on oral glucose-lowering drugs received either IDegLira or insulin degludec for 3 months. Lipoprotein subfraction profile was determined through Lipoprint method, whereas HDL lipid composition via 1H NMR. RESULTS Compared to insulin degludec, IDegLira administration resulted in significantly greater reduction of total and LDL-cholesterol. On the other hand, the effect of the two drugs on apolipoprotein-B-containing lipoprotein subfractions concentration was minimal and did not differ between the 2 interventions. IDegLira, but not insulin degludec, induced an atheroprotective shift in HDL's fatty acid composition and particle core depletion in triglycerides. CONCLUSIONS IDegLira administration is accompanied by total and LDL-cholesterol reduction, while sdLDL concentration only reduced in patients experiencing triglyceride reduction. IDegLira induced compositional changes of HDL particles. These changes may contribute to the cardioprotective properties of liraglutide.
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Affiliation(s)
- Eleni Pappa
- Department of Internal Medicine, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece.
| | - Christina Kostara
- Laboratory of Clinical Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Eleni Bairaktari
- Laboratory of Clinical Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Eleni Arvaniti
- Department of Internal Medicine, General Hospital of Ioannina "G. Hatzikosta", Ioannina, Greece
| | - Vasilis Tsimihodimos
- Department of Internal Medicine, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
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23
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Ozeki Y, Masaki T, Kamata A, Miyamoto S, Yoshida Y, Okamoto M, Gotoh K, Shibata H. The Effectiveness of GLP-1 Receptor Agonist Semaglutide on Body Composition in Elderly Obese Diabetic Patients: A Pilot Study. MEDICINES (BASEL, SWITZERLAND) 2022; 9:47. [PMID: 36135828 PMCID: PMC9502467 DOI: 10.3390/medicines9090047] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/25/2022] [Accepted: 09/13/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND AND OBJECTIVES This study aimed to investigate the changes in obesity severity, glucose metabolism, and body composition in patients with obesity and type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP1-RA) semaglutide. MATERIALS AND METHODS Body weight (BW), metabolic parameters, and body composition were examined before and 3 months after semaglutide administration. The mass of body fat (FM), fat weight percentage (%FM), mass of skeletal muscle (MM), skeletal MM percentage (%MM), and limb muscles were measured using the bioelectrical impedance method. RESULTS Semaglutide dramatically reduced the weight, the body mass index (BMI), and the levels of the glucose metabolic markers, including fasting blood glucose and hemoglobin A1c, and accelerated the loss of excess BW. FM, MM, and %FM after semaglutide treatment also decreased. Conversely, semaglutide had no effect on the %MM after 3 months. In limb muscle analyses, right upper and lower leg muscle percentages, left upper and lower leg muscles, and the ratios of the lower/upper muscles were maintained by semaglutide treatment. CONCLUSIONS These results suggest that the GLP1-RA semaglutide effectively reduces body adiposity while maintaining the MM in obese type 2 diabetic patients.
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Affiliation(s)
- Yoshinori Ozeki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Takayuki Masaki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Akari Kamata
- Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Shotaro Miyamoto
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Yuichi Yoshida
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Mitsuhiro Okamoto
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Koro Gotoh
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
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24
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Oo WM, Mobasheri A, Hunter DJ. A narrative review of anti-obesity medications for obese patients with osteoarthritis. Expert Opin Pharmacother 2022; 23:1381-1395. [PMID: 35855642 DOI: 10.1080/14656566.2022.2104636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : The prevalence of both obesity and osteoarthritis (OA) are increasing worldwide (twindemic), and the association between the two chronic diseases is also well-established. AREAS COVERED : In this narrative review, we will briefly describe the double burdens of both diseases, the impact of weight loss or gain on OA incidence and structural progression and discuss the biomechanical and anti-inflammatory mechanisms mediating these effects. FDA-approved anti-obesity drugs are summarized in terms of their clinical efficacy and safety profile, and the completed or ongoing phase 2/3 clinical trials of such drugs in OA patients with obesity are examined. EXPERT OPINION : We will discuss the perspectives related to principles of prescription of anti-obesity drugs, the potential role of phenotype-guided approach, time to drug effects in clinical trials, sustainability of weight loss based on the real-world studies, the importance of concomitant therapies such as dieting and exercises, and the role of weight loss on non-weight bearing OA joints. Although obesity is the major risk factor for OA pathogenesis and progression, and there are a variety of anti-obesity medications on the market, research on the use of these disease-modifying drugs in OA (DMOAD) is still sparse..
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Affiliation(s)
- Win Min Oo
- Rheumatology Department, Royal North Shore Hospital, and Institute of Bone and Joint Research, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.,Department of Physical Medicine and Rehabilitation, Mandalay General Hospital, University of Medicine, Mandalay, Mandalay, Myanmar
| | - Ali Mobasheri
- Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland.,Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.,Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,World Health Organization Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, Liege, Belgium
| | - David J Hunter
- Rheumatology Department, Royal North Shore Hospital, and Institute of Bone and Joint Research, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.,Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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25
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A novel strategy for production of liraglutide precursor peptide and development of a new long-acting incretin mimic. PLoS One 2022; 17:e0266833. [PMID: 35500009 PMCID: PMC9060347 DOI: 10.1371/journal.pone.0266833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/29/2022] [Indexed: 11/27/2022] Open
Abstract
Nowadays, a small number of incretin mimics are used to treat type 2 diabetes mellitus (T2DM) due to their longer half-life. The present study aimed to introduce a novel method for producing the liraglutide precursor peptide (LPP) and developing a potentially new incretin mimic. Here, human αB-crystallin (αB-Cry) was ligated to the LPP at the gene level, and the gene construct was expressed in Escherichia coli with a relatively good efficiency. The hybrid protein (αB-lir) was then purified by a precipitation method followed by anion exchange chromatography. After that, the peptide was released from the carrier protein by a chemical cleavage method yielding about 70%. The LPP was then purified by gel filtration chromatography, and HPLC estimated its purity to be about 98%. Also, the molecular mass of the purified peptide was finally confirmed by mass spectroscopy analysis. Assessment of the secondary structures suggested a dominant α-helical structure for the LPP and a β-sheet rich structure for the hybrid protein. The subcutaneous injection of the LPP and the αB-lir hybrid protein significantly reduced the blood sugar levels in healthy and diabetic mice and stimulated insulin secretion. Also, the hybrid protein exerts its bioactivities more effectively than the LPP over a relatively longer period of time. The results of this study suggested a novel method for the easy and cost-effective production of the LPP and introduced a new long-acting incretin mimic that can be potentially used for the treatment of T2DM patients.
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26
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Sun X, Zhang Z, Liu M, Zhang P, Nie L, Liu Y, Chen Y, Xu F, Liu Z, Zeng Y. Small-molecule albumin ligand modification to enhance the anti-diabetic ability of GLP-1 derivatives. Biomed Pharmacother 2022; 148:112722. [DOI: 10.1016/j.biopha.2022.112722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 11/02/2022] Open
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27
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Masaki T, Ozeki Y, Yoshida Y, Okamoto M, Miyamoto S, Gotoh K, Shibata H. Glucagon-Like Peptide-1 Receptor Agonist Semaglutide Improves Eating Behavior and Glycemic Control in Japanese Obese Type 2 Diabetic Patients. Metabolites 2022; 12:147. [PMID: 35208221 PMCID: PMC8878247 DOI: 10.3390/metabo12020147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 02/04/2023] Open
Abstract
We evaluated time-course changes and the relationship between eating behavior and glycemic profile during the treatment of 34 obese type 2 diabetic patients with the glucagon-like peptide-1 receptor agonist (GLP1-RA) semaglutide. Changes in dietary habits were evaluated using the Japan Society for the Study of Obesity questionnaire. Semaglutide improved body weight and hemoglobin A1C (HbA1c) 3 and 6 months after treatment. In addition, semaglutide led to marked improvements in the total scores for eating behavior items on the questionnaire. In particular, changes in the scores regarding the sensation of hunger, food preference, eating style, regularity of eating habits and emotional eating behavior were significantly improved during semaglutide treatment. By contrast, there were no significant changes in the scores for the recognition of weight and constitution and external eating behavior. Furthermore, changes in the scores regarding the sensation of hunger and food preference were correlated with changes in HbA1c after semaglutide treatment. Multivariable regression analyses showed that the change in the sensation of hunger was related to HbA1c during treatment. In conclusion, the GLP1-RA semaglutide regulates eating behavior, and, in particular, the sensation of hunger is closely related to the improvement in HbA1c by semaglutide in obese patients with type 2 diabetes.
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Affiliation(s)
- Takayuki Masaki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Japan; (Y.O.); (Y.Y.); (M.O.); (S.M.); (K.G.); (H.S.)
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28
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Guan Z, Du Y, Li R, Zhang S, Xu Y, Zhang X, Zhang F, Yin Y, Wu K, Li X, Li Y. Association between glucagon-like peptide-1 receptor gene polymorphism and treatment response to GLP1R agonists in Chinese patients with type 2 diabetes: a prospective cohort study. Eur J Clin Pharmacol 2022; 78:793-799. [PMID: 35079845 DOI: 10.1007/s00228-021-03249-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/02/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE Clinical response to glucagon-like peptide-1 receptor agonists (GLP1RAs) varies considerably among patients with type 2 diabetes mellitus (T2DM). The aim of the current study was to examine the potential association between the genetic variants in GLP1R gene polymorphism with the therapeutic efficacy as well as gastrointestinal adverse drug reactions (ADRs) of GLP1RAs in Chinese T2DM patients. METHODS Adult T2DM patients were eligible to participate in this prospective cohort study. Subjects received 12-week treatment with either exenatide (20 μg/day) or liraglutide (1.2 mg/day). GLP1R rs10305420 and rs3765467 genotyping was performed using the Sanger sequencing method. Clinical response to GLP1RAs was assessed in the patients who completed the 12-week treatment and defined by the change of fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and body mass index (BMI) from the baseline. RESULTS A total of 176 subjects (mean age 50.9 ± 12.7 years, 111 men) were enrolled. The planned 12-week treatment was completed by 156 patients. HbA1c reduction was significantly larger in subjects carrying the rs3765467 GG genotype vs. GA + AA genotypes (1.7% ± 2.4% vs. 0.8% ± 1.8%; P = 0.002). Similarly, the 7.0% target HbA1c attainment rate was significantly higher in subjects carrying the rs3765467 GG genotype vs. GA + AA genotypes (50.9% vs. 23.8%; P = 0.002). Gastrointestinal ADRs did not differ significantly among different genotypes. CONCLUSION GLP1R rs3765467 polymorphism is associated with therapeutic response to GLP1RAs in Chinese T2DM patients. HbA1c reduction is more pronounced in subjects with the GG genotype.
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Affiliation(s)
- Ziwan Guan
- School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Yue Du
- School of Pharmaceutical Sciences, Shandong First Medical University, Taian, China
| | - Rui Li
- School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Shufang Zhang
- School of Pharmaceutical Sciences, Shandong First Medical University, Taian, China
| | - Yuedong Xu
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated With Shandong First Medical University, Jinan, China
| | - Xiaoqian Zhang
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated With Shandong First Medical University, Jinan, China
| | - Fan Zhang
- Department of Pharmacy, Liaocheng People's Hospital, Liaocheng, China
| | - Ying Yin
- School of Pharmaceutical Sciences, Shandong First Medical University, Taian, China
| | - Kunrong Wu
- School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Xiaoli Li
- School of Pharmaceutical Sciences, Shandong First Medical University, Taian, China
| | - Yan Li
- Department of Clinical Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated With Shandong First Medical University, 16766 Jingshi Road, Jinan, 250014, China.
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Vanderschuren K, Arranz-Gibert P, Khang M, Hadar D, Gaudin A, Yang F, Folta-Stogniew E, Saltzman WM, Amiram M, Isaacs FJ. Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids. Proc Natl Acad Sci U S A 2022; 119:e2103099119. [PMID: 35046019 PMCID: PMC8794819 DOI: 10.1073/pnas.2103099119] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 12/01/2021] [Indexed: 12/11/2022] Open
Abstract
The use of biologics in the treatment of numerous diseases has increased steadily over the past decade due to their high specificities, low toxicity, and limited side effects. Despite this success, peptide- and protein-based drugs are limited by short half-lives and immunogenicity. To address these challenges, we use a genomically recoded organism to produce genetically encoded elastin-like polypeptide-protein fusions containing multiple instances of para-azidophenylalanine (pAzF). Precise lipidation of these pAzF residues generated a set of sequence-defined synthetic biopolymers with programmable binding affinity to albumin without ablating the activity of model fusion proteins, and with tunable blood serum half-lives spanning 5 to 94% of albumin's half-life in a mouse model. Our findings present a proof of concept for the use of genetically encoded bioorthogonal conjugation sites for multisite lipidation to tune protein stability in mouse serum. This work establishes a programmable approach to extend and tune the half-life of protein or peptide therapeutics and a technical foundation to produce functionalized biopolymers endowed with programmable chemical and biophysical properties with broad applications in medicine, materials science, and biotechnology.
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Affiliation(s)
- Koen Vanderschuren
- Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, CT 06520
- Systems Biology Institute, Yale University, West Haven, CT 06516
| | - Pol Arranz-Gibert
- Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, CT 06520
- Systems Biology Institute, Yale University, West Haven, CT 06516
| | - Minsoo Khang
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520
| | - Dagan Hadar
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Alice Gaudin
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520
| | - Fan Yang
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520
| | - Ewa Folta-Stogniew
- W. M. Keck Biotechnology Research Laboratory, Yale University School of Medicine, New Haven, CT 06511
| | - W Mark Saltzman
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520
- Department of Chemical & Environmental Engineering, Yale University, New Haven, CT 06520
- Department of Cellular & Molecular Physiology, Yale University, New Haven, CT 06511
| | - Miriam Amiram
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
| | - Farren J Isaacs
- Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, CT 06520;
- Systems Biology Institute, Yale University, West Haven, CT 06516
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520
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30
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Pedersen KM, Gradel AKJ, Ludvigsen TP, Christoffersen BØ, Fuglsang-Damgaard CA, Bendtsen KM, Madsen SH, Manfé V, Refsgaard HHF. Optimization of pig models for translation of subcutaneous pharmacokinetics of therapeutic proteins: Liraglutide, insulin aspart and insulin detemir. Transl Res 2022; 239:71-84. [PMID: 34428585 DOI: 10.1016/j.trsl.2021.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/16/2021] [Accepted: 08/17/2021] [Indexed: 11/19/2022]
Abstract
Prediction of human pharmacokinetics (PK) from data obtained in animal studies is essential in drug development. Here, we present a thorough examination of how to achieve good pharmacokinetic data from the pig model for translational purposes by using single-species allometric scaling for selected therapeutic proteins: liraglutide, insulin aspart and insulin detemir. The predictions were based on non-compartmental analysis of intravenous and subcutaneous PK data obtained from two injection regions (neck, thigh) in two pig breeds, domestic pig and Göttingen Minipig, that were compared with PK parameters reported in humans. The effects of pig breed, injection site and injection depth (insulin aspart only) on the PK of these proteins were also assessed. Results show that the prediction error for human PK was within two-fold for most PK parameters in both pig breeds. Furthermore, pig breed significantly influenced the plasma half-life and mean absorption time (MAT), both being longer in Göttingen Minipigs compared to domestic pigs (P <0.01). In both breeds, thigh vs neck dosing was associated with a higher dose-normalized maximum plasma concentration and area under the curve as well as shorter MAT and plasma half-life (P <0.01). Finally, more superficial injections resulted in faster absorption, higher Cmax/dose and bioavailability of insulin aspart (P <0.05, 3.0 vs 5.0 mm injection depth). In conclusion, pig breed and injection region affected the PK of liraglutide, insulin aspart and insulin detemir and reliable predictions of human PK were demonstrated when applying single-species allometric scaling with the pig as a pre-clinical animal model.
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Affiliation(s)
| | - Anna Katrina Jógvansdóttir Gradel
- Global Drug Discovery, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Måløv; Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, University of Copenhagen.
| | | | | | | | | | - Suzi Høgh Madsen
- Translational Medicine, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Måløv
| | - Valentina Manfé
- Global Research Technologies, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Måløv
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Tan Q, Akindehin SE, Orsso CE, Waldner RC, DiMarchi RD, Müller TD, Haqq AM. Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes. Front Endocrinol (Lausanne) 2022; 13:838410. [PMID: 35299971 PMCID: PMC8921987 DOI: 10.3389/fendo.2022.838410] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/07/2022] [Indexed: 01/01/2023] Open
Abstract
The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2-3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies.
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Affiliation(s)
- Qiming Tan
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Seun E. Akindehin
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Germany and German Center for Diabetes Research (DZD), Munich, Germany
| | - Camila E. Orsso
- Department of Agricultural Food & Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | | | | | - Timo D. Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Germany and German Center for Diabetes Research (DZD), Munich, Germany
- *Correspondence: Timo D. Müller, ; Andrea M. Haqq,
| | - Andrea M. Haqq
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Department of Agricultural Food & Nutritional Science, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Timo D. Müller, ; Andrea M. Haqq,
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Wang X, Zhao B, Sun H, You H, Qu S. Effects of sitagliptin on intrahepatic lipid content in patients with non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2022; 13:866189. [PMID: 36072931 PMCID: PMC9441565 DOI: 10.3389/fendo.2022.866189] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
PURPOSE Dipeptidyl peptidase-4 inhibitors (DPP-4I), key regulators of the actions of incretin hormones, exert anti-hyperglycemic effects in type 2 diabetes mellitus (T2DM) patients. A major unanswered question concerns the potential ability of DPP-4I to improve intrahepatic lipid (IHL) content in nonalcoholic fatty liver disease (NAFLD) patients. The aim of this study was to evaluate the effects of sitagliptin on IHL in NAFLD patients. METHODS A prospective, 24-week, single-center, open-label, comparative study enrolled 68 Chinese NAFLD patients with T2DM. Subjects were randomly divided into 4 groups: control group who did not take medicine (14 patients); sitagliptin group who received sitagliptin treatment (100mg per day) (17 patients); metformin group who received metformin (500mg three times per day) (17 patients); and sitagliptin plus metformin group who received sitagliptin (100mg per day) and metformin (500 mg three times per day) (20 patients). IHL, physical examination (waist circumstances, WC; body mass index, BMI), glucose-lipid metabolism (fasting plasma glucose, FPG; hemoglobin A1c, Hb1A1c; triglycerides; cholesterol; alanine aminotransferase, ALT; aspartate aminotransferase, AST) were measured at baseline and at 24 weeks. RESULTS 1) WC and BMI were decreased significantly in all groups except control group (all P<0.05). 2) There was no statistically significant difference in IHL among the sitagliptin, metformin, and sitagliptin plus metformin groups before and after treatment(all P>0.05). Only the metformin group showed a statistically significant difference in IHL before and after treatment(P<0.05). 3) Sitagliptin treatment led to a significant decrease in FBG and HbA1c when compared with the control group (all P<0.01). Additionally, HhA1c was significant decreased in the sitagliptin group when compared with the metformin group (P< 0.05). 4) HbA1c and FBG were decreased by 0.8% and 0.7 mmol/l respectively and the percentage of patients with HbA1c less than 7% was 65% with sitagliptin treatment. CONCLUSION Sitagliptin improves abnormalities in glucose metabolism, but not reduces the IHL in T2DM with NAFLD, indicating that sitagliptin might be a therapeutic option for treatment of NAFLD indirectly while not directly on IHL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier CTR# NCT05480007.
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Affiliation(s)
- Xingchun Wang
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- Shanghai Center of Thyroid Diseases, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bangfeng Zhao
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Hang Sun
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Hui You
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- Shanghai Center of Thyroid Diseases, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Shen Qu,
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Recombinant human GLP-1 beinaglutide regulates lipid metabolism of adipose tissues in diet-induced obese mice. iScience 2021; 24:103382. [PMID: 34841227 PMCID: PMC8605346 DOI: 10.1016/j.isci.2021.103382] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/19/2021] [Accepted: 10/27/2021] [Indexed: 01/18/2023] Open
Abstract
GLP-1 analogs are a class of glucose-lowering agents with multiple benefits in diabetes, but its role in adipose tissues remains to be elucidated. The aim of this study was to determine the action of recombinant human GLP-1 (rhGLP-1) Beinaglutide (BN) in the insulin sensitivity and lipid metabolism of adipose tissues. We have shown that, after BN injection, obese mice displayed lower body weight, fat mass, and plasma lipid levels. In addition, BN promoted the insulin sensitivity in the white adipose tissues. Furthermore, we have found that the BN treatment caused significant changes in content and composition of different lipid classes, including glycerolipids, glycerophospholipids, and sphingolipids, as well as expression of genes in lipid metabolic pathways in the adipose tissues. Taken together, our data demonstrate that BN could resist HFD-induced obesity by targeting the composition of major lipid classes and the expression of genes in lipid metabolism of adipose tissues.
Recombinant human GLP-1 Beinaglutide (BN) reduces high-fat-diet-induced obesity BN increases insulin sensitivity of adipocytes in vivo and in vitro BN alters lipidomic and transcriptomic profiles in adipose tissues of obese mice BN promotes thermogenic gene expression in adipose tissues
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Dong Y, Carty J, Goldstein N, He Z, Hwang E, Chau D, Wallace B, Kabahizi A, Lieu L, Peng Y, Gao Y, Hu L, Betley JN, Williams KW. Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo. Mol Metab 2021; 54:101352. [PMID: 34626854 PMCID: PMC8590079 DOI: 10.1016/j.molmet.2021.101352] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/30/2021] [Accepted: 10/02/2021] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), like liraglutide and semaglutide, are viable treatments for diabetes and obesity. Liraglutide directly activates hypothalamic proopiomelanocortin (POMC) neurons while indirectly inhibiting Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons ex vivo. While temporal control of GLP-1R agonist concentration as well as accessibility to tissues/cells can be achieved with relative ease ex vivo, in vivo this is dependent upon the pharmacokinetics of these agonists and relative penetration into structures of interest. Thus, whether liraglutide or semaglutide modifies the activity of POMC and NPY/AgRP neurons in vivo as well as mechanisms required for any changes in cellular activity remains undefined. METHODS In order to resolve this issue, we utilized neuron-specific transgenic mouse models to examine changes in the activity of POMC and NPY/AgRP neurons after injection of either liraglutide or semaglutide (intraperitoneal - I.P. and subcutaneous - S·C.). POMC and NPY/AgRP neurons were targeted for patch-clamp electrophysiology as well as in vivo fiber photometry. RESULTS We found that liraglutide and semaglutide directly activate and increase excitatory tone to POMC neurons in a time-dependent manner. This increased activity of POMC neurons required GLP-1Rs in POMC neurons as well as a downstream mixed cation channel comprised of TRPC5 subunits. We also observed an indirect upregulation of excitatory input to POMC neurons originating from glutamatergic cells that also required TRPC5 subunits. Conversely, GLP-1Ra's decreased excitatory input to and indirectly inhibited NPY/AgRP neurons through activation of K-ATP and TRPC5 channels in GABAergic neurons. Notably, the temporal activation of POMC and inhibition of NPY/AgRP neuronal activity after liraglutide or semaglutide was injected [either intraperitoneal (I.P.) or subcutaneous (S·C.)] was dependent upon the nutritional state of the animals (fed vs food-deprived). CONCLUSIONS Our results support a mechanism of liraglutide and semaglutide in vivo to activate POMC while inhibiting NPY/AgRP neurons, which depends upon metabolic state and mirrors the pharmacokinetic profile of these compounds in vivo.
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Affiliation(s)
- Yanbin Dong
- Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Jamie Carty
- Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Nitsan Goldstein
- Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Zhenyan He
- Department of Neurosurgery, the affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, 450008, China
| | - Eunsang Hwang
- Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Dominic Chau
- Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Briana Wallace
- Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Anita Kabahizi
- Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Linh Lieu
- Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Yunqian Peng
- Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Yong Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ling Hu
- Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - J Nicholas Betley
- Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Kevin W Williams
- Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
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Singh AK, Italiya KS, Narisepalli S, Chitkara D, Mittal A. Role of Chain Length and Degree of Unsaturation of Fatty Acids in the Physicochemical and Pharmacological Behavior of Drug-Fatty Acid Conjugates in Diabetes. J Med Chem 2021; 64:14217-14229. [PMID: 34581574 DOI: 10.1021/acs.jmedchem.1c00391] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Several drug-fatty acid (FA) prodrugs have been reported to exhibit desirable physicochemical and pharmacological profile; however, comparative beneficial effects rendered by different FAs have not been explored. In the present study, four different FAs (linoleic acid, oleic acid, palmitic acid, and α-lipoic acid) were selected based on their chain length and degree of unsaturation and conjugated to Lisofylline (LSF), an antidiabetic molecule to obtain different drug-FA prodrugs and characterized for molecular weight, hydrophobicity, purity, self-assembly, and efficacy in vitro and in vivo in type 1 diabetes model. Prodrugs demonstrated a 2- to 6-fold increase in the plasma half-life of LSF. Diabetic animals treated with prodrugs, once daily for 5 weeks, maintained a steady fasting blood glucose level with a significant increase in insulin level, considerable restoration of biochemical parameters, and preserved β-cells integrity. Among the different LSF-FA prodrugs, LSF-OA and LSF-PA demonstrated the most favorable physicochemical, systemic pharmacokinetic, and pharmacodynamic profiles.
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Affiliation(s)
- Arihant Kumar Singh
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333031, India
| | - Kishan S Italiya
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333031, India
| | - Saibhargav Narisepalli
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333031, India
| | - Deepak Chitkara
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333031, India
| | - Anupama Mittal
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333031, India
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Di L. An update on the importance of plasma protein binding in drug discovery and development. Expert Opin Drug Discov 2021; 16:1453-1465. [PMID: 34403271 DOI: 10.1080/17460441.2021.1961741] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Introduction: Plasma protein binding (PPB) remains a controversial topic in drug discovery and development. Fraction unbound (fu) is a critical parameter that needs to be measured accurately, because it has significant impacts on the predictions of drug-drug interactions (DDI), estimations of therapeutic indices (TI), and developments of PK/PD relationships. However, it is generally not advisable to change PPB through structural modifications, because PPB on its own has little relevance for in vivo efficacy.Areas covered: PPB fundamentals are discussed including the three main classes of drug binding proteins (i.e., albumin, alpha1-acid glycoprotein, and lipoproteins) and their physicochemical properties, in vivo half-life, and synthesis rate. State-of-the-art methodologies for PPB are highlighted. Applications of PPB in drug discovery and development are presented.Expert opinion: PPB is an old topic in pharmacokinetics, but there are still many misconceptions. Improving the accuracy of PPB for highly bound compounds is an ongoing effort in the field with high priority. As the field continues to generate high quality data, the regulatory agencies will increase their confidence in our ability to accurately measure PPB of highly bound compounds, and experimental fu values below 0.01 will more likely be used for DDI predictions in the future.
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Affiliation(s)
- Li Di
- Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT, US
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Azevedo C, Pinto S, Benjakul S, Nilsen J, Santos HA, Traverso G, Andersen JT, Sarmento B. Prevention of diabetes-associated fibrosis: Strategies in FcRn-targeted nanosystems for oral drug delivery. Adv Drug Deliv Rev 2021; 175:113778. [PMID: 33887405 DOI: 10.1016/j.addr.2021.04.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/29/2021] [Accepted: 04/16/2021] [Indexed: 01/02/2023]
Abstract
Diabetes mellitus is a chronic disease with an elevated risk of micro- and macrovascular complications, such as fibrosis. To prevent diabetes-associated fibrosis, the symptomatology of diabetes must be controlled, which is commonly done by subcutaneous injection of antidiabetic peptides. To minimize the pain and distress associated with such injections, there is an urgent need for non-invasive oral transmucosal drug delivery strategies. However, orally administered peptide-based drugs are exposed to harsh conditions in the gastrointestinal tract and poorly cross the selective intestinal epithelium. Thus, targeting of drugs to receptors expressed in epithelial cells, such as the neonatal Fc receptor (FcRn), may therefore enhance uptake and transport through mucosal barriers. This review compiles how in-depth studies of FcRn biology and engineering of receptor-binding molecules may pave the way for design of new classes of FcRn-targeted nanosystems. Tailored strategies may open new avenues for oral drug delivery and provide better treatment options for diabetes and, consequently, fibrosis prevention.
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Vestlund J, Bergquist F, Licheri V, Adermark L, Jerlhag E. Activation of glucagon-like peptide-1 receptors and skilled reach foraging. Addict Biol 2021; 26:e12953. [PMID: 32770792 PMCID: PMC8244104 DOI: 10.1111/adb.12953] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/15/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023]
Abstract
Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex4), liraglutide and dulaglutide, regulate glucose homeostasis and are thus used to treat diabetes type II. GLP‐1 also contributes towards a variety of additional physiological functions, including suppression of reward and improvement of learning. Acute activation of GLP‐1R in the nucleus accumbens (NAc) shell, an area essential for motivation, reduces the motivation to consume sucrose or alcohol when assessed in a simple motor task. However, the effects of repeated administration of the different GLP‐1R agonists on behaviours in a more complex motor task are unknown. The aim was therefore to investigate the effects of repeated Ex4, liraglutide or dulaglutide on the motivation and learning of a complex motor tasks such as skilled reach foraging in the Montoya staircase test. To explore the neurophysiological correlates of the different GLP‐1R agonists on motivation, ex vivo electrophysiological recordings were conducted. In rats with an acquired skilled reach performance, Ex4 or liraglutide but not dulaglutide reduced the motivation of skilled reach foraging. In trained rats, Ex4 infusion into NAc shell decreased this motivated behaviour, and both Ex4 and liraglutide supressed the evoked field potentials in NAc shell. In rats without prior Montoya experience, dulaglutide but not Ex4 or liraglutide enhanced the learning of skilled reach foraging. Taken together, these findings indicate that the tested GLP‐1R agonists have different behavioural outcomes depending on the context.
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Affiliation(s)
- Jesper Vestlund
- Department of Pharmacology, Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden
| | - Filip Bergquist
- Department of Pharmacology, Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden
| | - Valentina Licheri
- Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden
| | - Louise Adermark
- Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden
| | - Elisabet Jerlhag
- Department of Pharmacology, Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden
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Affiliation(s)
- Gautam Das
- Gautam Das, MD, MRCP (Diabetes and Endocrinology), FRCP, FACE, Consultant in Diabetes and Endocrinology, Prince Charles Hospital, Cwm Taf Morgannwg University Health Board Merthyr Tydfil Wales, UK
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Kim SH, Abbasi F, Nachmanoff C, Stefanakis K, Kumar A, Kalra B, Savjani G, Mantzoros CS. Effect of the glucagon-like peptide-1 analogue liraglutide versus placebo treatment on circulating proglucagon-derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial. Diabetes Obes Metab 2021; 23:489-498. [PMID: 33140542 PMCID: PMC7856054 DOI: 10.1111/dom.14242] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/15/2020] [Accepted: 10/29/2020] [Indexed: 11/29/2022]
Abstract
AIM To examine how circulating glucagon-like peptide-1 (GLP-1) concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon-derived peptides (PGDPs), including endogenous GLP-1, glucagon-like peptide-2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control. MATERIALS AND METHODS Adults who were overweight/obese (body mass index 27-40 kg/m2 ) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP-1 agonist [GLP-1A]) and endogenous (GLP-1E) GLP-1, alongside five other PGDP concentrations during a mixed meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady-state plasma glucose (SSPG) concentration for insulin resistance and insulin secretion rate (ISR) were previously measured. MMTT area-under-the-curve (AUC) was calculated for ISR, glucose and levels of PGDPs. RESULTS Participants on liraglutide versus placebo had significantly (P ≤ .004) decreased weight (mean -3.6%, 95% CI [-5.2% to -2.1%]), SSPG (-32% [-43% to -22%]) and glucose AUC (-7.0% [-11.5% to -2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP-1A AUC at study end was significantly (P ≤ .04) linearly associated with % decrease in weight (r = -0.54) and SSPG (r = -0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP-1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP-1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP-1 receptor agonists to decrease their endogenous production in contrast to weight loss-dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells. CONCLUSIONS Circulating GLP-1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.
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Affiliation(s)
- Sun H. Kim
- Division of Endocrinology, Gerontology and Metabolism, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, S025, Stanford, CA 94305-5103
- Stanford Diabetes Research Center, Stanford University School of Medicine, 279 Campus Drive, B300, Stanford, CA 94305
| | - Fahim Abbasi
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, 870 Quarry Road, Stanford, CA 94305
- Stanford Diabetes Research Center, Stanford University School of Medicine, 279 Campus Drive, B300, Stanford, CA 94305
| | - Clara Nachmanoff
- Division of Endocrinology, Gerontology and Metabolism, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, S025, Stanford, CA 94305-5103
| | - Konstantinos Stefanakis
- Department of Medicine, Boston VA Healthcare system and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 330 Brookline Avenue, Boston, MA 02215
| | - Ajay Kumar
- Ansh Labs, 445 Medical Center Blvd, Webster, TX 77598
| | - Bhanu Kalra
- Ansh Labs, 445 Medical Center Blvd, Webster, TX 77598
| | - Gopal Savjani
- Ansh Labs, 445 Medical Center Blvd, Webster, TX 77598
| | - Christos S. Mantzoros
- Department of Medicine, Boston VA Healthcare system and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 330 Brookline Avenue, Boston, MA 02215
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Hanssen R, Kretschmer AC, Rigoux L, Albus K, Edwin Thanarajah S, Sitnikow T, Melzer C, Cornely OA, Brüning JC, Tittgemeyer M. GLP-1 and hunger modulate incentive motivation depending on insulin sensitivity in humans. Mol Metab 2021; 45:101163. [PMID: 33453418 PMCID: PMC7859312 DOI: 10.1016/j.molmet.2021.101163] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/22/2020] [Accepted: 01/08/2021] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVE To regulate food intake, our brain constantly integrates external cues, such as the incentive value of a potential food reward, with internal state signals, such as hunger feelings. Incentive motivation refers to the processes that translate an expected reward into the effort spent to obtain the reward; the magnitude and probability of a reward involved in prompting motivated behaviour are encoded by the dopaminergic (DA) midbrain and its mesoaccumbens DA projections. This type of reward circuity is particularly sensitive to the metabolic state signalled by peripheral mediators, such as insulin or glucagon-like peptide 1 (GLP-1). While in rodents the modulatory effect of metabolic state signals on motivated behaviour is well documented, evidence of state-dependent modulation and the role of incentive motivation underlying overeating in humans is lacking. METHODS In a randomised, placebo-controlled, crossover design, 21 lean (body mass index [BMI] < 25 kg/m2) and 16 obese (BMI³ 30 kg/m2) volunteer participants received either liraglutide as a GLP-1 analogue or placebo on two separate testing days. Incentive motivation was measured using a behavioural task in which participants were required to exert physical effort using a handgrip to win different amounts of food and monetary rewards. Hunger levels were measured using visual analogue scales; insulin, glucose, and systemic insulin resistance as assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) were quantified at baseline. RESULTS In this report, we demonstrate that incentive motivation increases with hunger in lean humans (F(1,42) = 5.31, p = 0.026, β = 0.19) independently of incentive type (food and non-food reward). This effect of hunger is not evident in obese humans (F(1,62) = 1.93, p = 0.17, β = -0.12). Motivational drive related to hunger is affected by peripheral insulin sensitivity (two-way interaction, F(1, 35) = 6.23, p = 0.017, β = -0.281). In humans with higher insulin sensitivity, hunger increases motivation, while poorer insulin sensitivity dampens the motivational effect of hunger. The GLP-1 analogue application blunts the interaction effect of hunger on motivation depending on insulin sensitivity (three-way interaction, F(1, 127) = 5.11, p = 0.026); no difference in motivated behaviour could be found between humans with normal or impaired insulin sensitivity under GLP-1 administration. CONCLUSION We report a differential effect of hunger on motivation depending on insulin sensitivity. We further revealed the modulatory role of GLP-1 in adaptive, motivated behaviour in humans and its interaction with peripheral insulin sensitivity and hunger. Our results suggest that GLP-1 might restore dysregulated processes of midbrain DA function and hence motivational behaviour in insulin-resistant humans.
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Affiliation(s)
- Ruth Hanssen
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931, Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEPD), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
| | - Alina Chloé Kretschmer
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931, Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEPD), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Lionel Rigoux
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931, Cologne, Germany
| | - Kerstin Albus
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Sharmili Edwin Thanarajah
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931, Cologne, Germany; Department of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University Hospital Frankfurt, Heinrich-Hoffmann-Strasse 10, 60528, Frankfurt am Main, Germany
| | - Tamara Sitnikow
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931, Cologne, Germany
| | - Corina Melzer
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931, Cologne, Germany
| | - Oliver A Cornely
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; University of Cologne Faculty of Medicine, University Hospital Cologne Chair Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Joseph-Stelzmann-Straße 26, 50931, Cologne, Germany; Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Clinical Trials Centre Cologne (ZKS Köln), University Hospital Cologne, Gleueler Str. 269, 50935 Cologne, Germany
| | - Jens C Brüning
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931, Cologne, Germany; Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEPD), University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany
| | - Marc Tittgemeyer
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany
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Marty VN, Farokhnia M, Munier JJ, Mulpuri Y, Leggio L, Spigelman I. Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats. Front Neurosci 2020; 14:599646. [PMID: 33424537 PMCID: PMC7785877 DOI: 10.3389/fnins.2020.599646] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/03/2020] [Indexed: 12/21/2022] Open
Abstract
Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.
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Affiliation(s)
- Vincent N Marty
- Laboratory of Neuropharmacology, Section of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Bethesda, MD, United States.,Center on Compulsive Behaviors, National Institutes of Health, Bethesda, MD, United States.,Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States
| | - Joseph J Munier
- Laboratory of Neuropharmacology, Section of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Yatendra Mulpuri
- Laboratory of Neuropharmacology, Section of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Bethesda, MD, United States.,Center on Compulsive Behaviors, National Institutes of Health, Bethesda, MD, United States.,Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, United States.,Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, United States.,Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United States.,Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United States
| | - Igor Spigelman
- Laboratory of Neuropharmacology, Section of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
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Ferrari F, Fierabracci P, Salvetti G, Jaccheri R, Vitti J, Scartabelli G, Meola A, Magno S, Ceccarini G, Santini F. Weight loss effect of liraglutide in real-life: the experience of a single Italian obesity center. J Endocrinol Invest 2020; 43:1779-1785. [PMID: 32594453 DOI: 10.1007/s40618-020-01334-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Several randomized controlled clinical trials (RCCTs) have shown that the use of Liraglutide (L) in addition to diet and exercise in patients with obesity or overweight (OO), compared to dietary behavioral changes alone, leads to a significantly greater weight loss. This retrospective study aimed at evaluating the effectiveness of L therapy in a real-life setting. METHODS 93 consecutive non-diabetic OO, referring to a single Obesity Center, started L therapy from October 2016 to December 2018: 21/93 OO discontinued the treatment within 90 days for various reasons. 72/93 OO (55 females, 17 males), mean ± SD age 49 ± 12.5 years (18-78) and mean body mass index 39.1 ± 5.8 (28.3-55.3) were included for further analysis. 60/72 OO reached the final dose of 3.0 mg/day. RESULTS Mean weight loss was 7.1% in the OO who reached the dose of 3.0 mg; 68.3%, 20.0% and 10.0% of OO lost ≥ 5%, 10% and 15% of body weight, respectively. A linear correlation between early and final weight loss was found. Moreover, we observed a significant reduction of mean systolic and diastolic blood pressure and a significant increase of mean heart rate. The overall incidence of side effects was 18.3% (17/93). CONCLUSION L treatment of OO in a real life setting yielded results comparable to those reported by the major RCCTs. Combining the results of RCCTs with the observations from real life may increase their power and overcome their respective limitations.
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Affiliation(s)
- F Ferrari
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - P Fierabracci
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - G Salvetti
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - R Jaccheri
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - J Vitti
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - G Scartabelli
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - A Meola
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - S Magno
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - G Ceccarini
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy
| | - F Santini
- Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy.
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Yousefpour P, Varanko A, Subrahmanyan R, Chilkoti A. Recombinant Fusion of Glucagon‐Like Peptide‐1 and an Albumin Binding Domain Provides Glycemic Control for a Week in Diabetic Mice. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Parisa Yousefpour
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
| | - Anastasia Varanko
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
| | | | - Ashutosh Chilkoti
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
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45
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Teshome G, Ambachew S, Fasil A, Abebe M. Efficacy of Glucagon-Like Peptide-1 Analogs in Nonalcoholic Fatty Liver Disease: A Systematic Review. Hepat Med 2020; 12:139-151. [PMID: 33061687 PMCID: PMC7522518 DOI: 10.2147/hmer.s265631] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is believed to be the hepatic manifestation of the metabolic syndrome. Many treatment approaches have been suggested so far, and several types of studies have been done to find treatment for NAFLD, the most promising of which are those with lifestyle interventions. Objective The aim of this systematic review was to evaluate the efficacy and safety of glucagon-like peptide-1 (GLP-1) analogs on the management of NAFLD. Methods The PubMed, MEDLINE, and Cochrane Central Library were searched to identify randomized controlled trials, single arm trials, and cohorts that compared GLP-1 analogs with a control treatment or baseline values with respect to efficacy and safety in patients living with NAFLD. The key outcomes were a change in serum transaminase, resolution of disease status measured by imaging or histological techniques, improvement in insulin resistance, and reduction in body weight. Results Initial searching retrieved 201 peer-reviewed articles and abstracts. Ten studies met all inclusion criteria. The review included a total of 590 participants with NAFLD. Following administration of GLP-1 analogs, a decrease in serum transaminases, improvement in liver histology and insulin resistance, and a reduction in body weight were observed. Compared with baseline, body weight, alanine aminotransferase, aspartate aminotransferase, and gamma glutamyltransferase were decreased by 5.5%, 59.5%, 52.8%, and 44.8%, respectively, due to GLP-1. Likewise, a reduction of proinflammatory cytokines and fibrosis markers and an enhancement of protective adipokines were observed in some of the studies. Conclusion The decrease in a key biochemical marker of liver injury following treatment with GLP-1 analogs, as well as improvements in imaging and histology, suggests that these agents may be effective alternatives for managing NAFLD. Registration CRD42018087262.
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Affiliation(s)
- Getnet Teshome
- University of Gondar Comprehensive Specialized Hospital, University of Gondar, Gondar, Amhara, Ethiopia
| | - Sintayehu Ambachew
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
| | - Alebachew Fasil
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
| | - Molla Abebe
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
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Hartman RE, Rao PSS, Churchwell MD, Lewis SJ. Novel therapeutic agents for the treatment of diabetic kidney disease. Expert Opin Investig Drugs 2020; 29:1277-1293. [PMID: 32799584 DOI: 10.1080/13543784.2020.1811231] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Diabetic kidney disease (DKD) involves multifaceted pathophysiology which increases the risk of cardiorenal events and mortality. Conventional therapy is limited to renin-angiotensin aldosterone system inhibition and management of hyperglycemia and hypertension. Recent clinical trials have demonstrated promising nephroprotective effects of antihyperglycemic agents thus modifying guideline treatment recommendations for type 2 diabetic patients with chronic kidney disease. AREAS OF COVERED Relevant studies and clinical trials were searched via PubMed and clinicaltrials.gov through August 2020. Authors offer an update on clinical evidence regarding nephroprotective effects and side effects of sodium-glucose-cotransporter-2 (SGLT2) inhibitors, glucagon-like-peptide-1 (GLP1) agonists and dipeptidylpeptidase-4 (DPP4) inhibitors. They discuss the potential benefits of novel therapy targeting DKD pathogenic processes including inflammation, oxidative stress, fibrosis, and vasoconstriction shown in early phases of clinical trials and offer an opinion on key challenges and directions for future progress. EXPERT OPINION SGLT2 inhibitors are the most promising agents for DKD and improving cardiorenal outcomes. Mineralocorticoid-receptor antagonists and janus kinase inhibitors are also promising investigational therapies that target oxidative stress, nitric oxide synthesis, and inflammation. Novel therapeutic targets and the identification of clinically useful biomarkers may provide future therapies that detect early stages of DKD enabling a slower kidney function decline.
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Affiliation(s)
| | - P S S Rao
- Department of Pharmaceutical Science, University of Findlay , Findlay, OH, USA
| | | | - Susan J Lewis
- Department of Pharmacy Practice, University of Findlay , Findlay, OH, USA
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Ding Y, Ting JP, Liu J, Al-Azzam S, Pandya P, Afshar S. Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics. Amino Acids 2020; 52:1207-1226. [PMID: 32945974 PMCID: PMC7544725 DOI: 10.1007/s00726-020-02890-9] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 09/05/2020] [Indexed: 12/14/2022]
Abstract
With the development of modern chemistry and biology, non-proteinogenic amino acids (NPAAs) have become a powerful tool for developing peptide-based drug candidates. Drug-like properties of peptidic medicines, due to the smaller size and simpler structure compared to large proteins, can be changed fundamentally by introducing NPAAs in its sequence. While peptides composed of natural amino acids can be used as drug candidates, the majority have shown to be less stable in biological conditions. The impact of NPAA incorporation can be extremely beneficial in improving the stability, potency, permeability, and bioavailability of peptide-based therapies. Conversely, undesired effects such as toxicity or immunogenicity should also be considered. The impact of NPAAs in the development of peptide-based therapeutics is reviewed in this article. Further, numerous examples of peptides containing NPAAs are presented to highlight the ongoing development in peptide-based therapeutics.
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Affiliation(s)
- Yun Ding
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, 92121, USA
| | - Joey Paolo Ting
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, 92121, USA
| | - Jinsha Liu
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, 92121, USA
| | - Shams Al-Azzam
- Professional Scientific Services, Eurofins Lancaster Laboratories, Lancaster, PA, 17605, USA
| | - Priyanka Pandya
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, 92121, USA
| | - Sepideh Afshar
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, 92121, USA.
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Zhai J, Li L, Dong L, Dong K, Xiang S, Gui L, Zhang J, Song H, Ge Z. Simultaneous quantitative determination of liraglutide and insulin degludec in rat plasma by liquid chromatography–tandem mass spectrometry method and its application. Biomed Chromatogr 2020; 34:e4921. [DOI: 10.1002/bmc.4921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/03/2020] [Accepted: 06/10/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Jianping Zhai
- School of Chemical Engineering Tianjin University Tianjin China
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing) Beijing Institute of LifeOmics Beijing China
- Beijing United‐Power Pharma Tech Co., Ltd. Beijing China
| | - Li Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing) Beijing Institute of LifeOmics Beijing China
- Beijing United‐Power Pharma Tech Co., Ltd. Beijing China
| | - Lihou Dong
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing) Beijing Institute of LifeOmics Beijing China
| | - Kelly Dong
- Beijing United‐Power Pharma Tech Co., Ltd. Beijing China
| | - Shensi Xiang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing) Beijing Institute of LifeOmics Beijing China
| | - Luolan Gui
- School of Chemical Engineering Tianjin University Tianjin China
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing) Beijing Institute of LifeOmics Beijing China
- Beijing United‐Power Pharma Tech Co., Ltd. Beijing China
| | - Jiaying Zhang
- Beijing United‐Power Pharma Tech Co., Ltd. Beijing China
| | - Haifeng Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing) Beijing Institute of LifeOmics Beijing China
| | - Zhiqiang Ge
- School of Chemical Engineering Tianjin University Tianjin China
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49
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Lear S, Seo H, Lee C, Lei L, Amso Z, Huang D, Zou H, Zhou Z, Nguyen-Tran VTB, Shen W. Recombinant Expression and Stapling of a Novel Long-Acting GLP-1R Peptide Agonist. Molecules 2020; 25:molecules25112508. [PMID: 32481528 PMCID: PMC7321126 DOI: 10.3390/molecules25112508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/10/2020] [Accepted: 05/12/2020] [Indexed: 11/16/2022] Open
Abstract
Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step.
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50
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Wegeberg AML, Hansen CS, Farmer AD, Karmisholt JS, Drewes AM, Jakobsen PE, Brock B, Brock C. Liraglutide accelerates colonic transit in people with type 1 diabetes and polyneuropathy: A randomised, double-blind, placebo-controlled trial. United European Gastroenterol J 2020; 8:695-704. [PMID: 32390563 DOI: 10.1177/2050640620925968] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists, such as liraglutide, reduce hyperglycaemia and induce weight loss and are used as a treatment in diabetes. However, common adverse effects include nausea, loss of appetite and prolonged gastric emptying. It is not known whether these changes are centrally generated or if liraglutide alters the enteric motility. OBJECTIVE To investigate the effects of liraglutide on gastrointestinal function and symptoms. METHODS A total of 48 adults with type 1 diabetes and confirmed distal symmetric polyneuropathy were randomised to receive liraglutide 1.8 mg/day or placebo for 26 weeks. Regional transit times and motility indexes were assessed with a wireless motility capsule, whereas symptoms were evaluated using the validated gastroparesis cardinal symptom index. RESULTS Liraglutide treatment reduced large bowel transit time (31.7%, p = 0.04) and decreased motility index (6.1%, p = 0.04) compared to placebo, whereas the groups did not differ in gastric emptying or small-bowel transit times. Liraglutide increased postprandial fullness with 29% (p = 0.01). Increased small bowel transit time was associated with decreased bloating (p = 0.008). CONCLUSION Liraglutide accelerates large bowel transit and decreases motility index, which may indicate better coordination of propulsive motility. This potentially improves the function of the enteric nervous system, leading to normalised colonic function and positive effects in type 1 diabetes.
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Affiliation(s)
- Anne-Marie Langmach Wegeberg
- Mech-Sense, Department of Gastroenterology and Hepatology Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | | | - Adam D Farmer
- Mech-Sense, Department of Gastroenterology and Hepatology Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Centre for Neuroscience and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts, United Kingdom; London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.,Department of Gastroenterology, University Hospitals of North Midlands, Stoke-on-Trent, Staffordshire, United Kingdom
| | - Jesper Scott Karmisholt
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark.,Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Asbjorn M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Poul Erik Jakobsen
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark.,Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Birgitte Brock
- Steno Diabetes Center Copenhagen, Region Hovedstaden, Gentofte, Denmark.,Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Pharmacotherapy and Development, University of Copenhagen, Copenhagen, Denmark
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