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Zhou Q, Li G, Hang K, Li J, Yang D, Wang MW. Weight Loss Blockbuster Development: A Role for Unimolecular Polypharmacology. Annu Rev Pharmacol Toxicol 2025; 65:191-213. [PMID: 39259982 DOI: 10.1146/annurev-pharmtox-061324-011832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Obesity and type 2 diabetes mellitus (T2DM) impact more than 2.5 billion adults worldwide, necessitating innovative therapeutic approaches. Unimolecular polypharmacology, which involves designing single molecules to target multiple receptors or pathways simultaneously, has revolutionized treatment strategies. Blockbuster drugs such as tirzepatide and retatrutide have shown unprecedented success in managing obesity and T2DM, demonstrating superior efficacy compared to conventional single agonists. Tirzepatide, in particular, has garnered tremendous attention for its remarkable effectiveness in promoting weight loss and improving glycemic control, while offering additional cardiovascular and renal benefits. Despite their promises, such therapeutic agents also face challenges that include gastrointestinal side effects, patient compliance issues, and body weight rebound after cessation of the treatment. Nonetheless, the development of these therapies marks a significant leap forward, underscoring the transformative potential of unimolecular polypharmacology in addressing metabolic diseases and paving the way for future innovations in personalized medicine.
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Affiliation(s)
- Qingtong Zhou
- Research Center for Deepsea Bioresources, Sanya, Hainan, China
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Guanyi Li
- School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
- Research Center for Deepsea Bioresources, Sanya, Hainan, China
| | - Kaini Hang
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jie Li
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Dehua Yang
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Chemical Biology and The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;
- Research Center for Deepsea Bioresources, Sanya, Hainan, China
| | - Ming-Wei Wang
- Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, China
- Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan
- State Key Laboratory of Chemical Biology and The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Research Center for Deepsea Bioresources, Sanya, Hainan, China
- Translational Research Center for Structural Biology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Mohammad Karim A. Principles and Biomedical Applications of Self-Assembled Peptides: Potential Treatment of Type 2 Diabetes Mellitus. Pharmaceutics 2024; 16:1442. [PMID: 39598565 PMCID: PMC11597675 DOI: 10.3390/pharmaceutics16111442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 11/29/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder worldwide. There have been tremendous efforts to find a safe and prolonged effective therapy for its treatment. Peptide hormones, from certain organisms in the human body, as the pharmaceutical agents, have shown outstanding profiles of efficacy and safety in plasma glucose regulation. Their therapeutic promises have undergone intensive investigations via examining their physicochemical and pharmacokinetic properties. Their major drawback is their short half-life in vivo. To address this challenge, researchers have recently started to apply the state-of-the-art molecular self-assembly on peptide hormones to form nanofibrillar structures, as a smart nanotherapeutic drug delivery technique, to tremendously enhance their prolonged bioactivity in vivo. This revolutionary therapeutic approach would significantly improve patient compliance. First, this review provides a comprehensive summary on the pathophysiology of T2DM, various efforts to treat this chronic disorder, and the limitations and drawbacks of these treatment approaches. Next, this review lays out detailed insights on various aspects of peptide self-assembly: adverse effects, potential applications in nanobiotechnology, thermodynamics and kinetics of the process, as well as the molecular structures of the self-assembled configurations. Furthermore, this review elucidates the recent efforts on applying reversible human-derived peptide self-assembly to generate highly organized smart nanostructured drug formulations known as nanofibrils to regulate and prolong the bioactivity of the human gut hormone peptides in vivo to treat T2DM. Finally, this review highlights the future research directions to advance the knowledge on the state-of-the-art peptide self-assembly process to apply the revolutionary smart nanotherapeutics for treatment of chronic disorders such as T2DM with highly improved patient compliance.
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Affiliation(s)
- Alireza Mohammad Karim
- Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J. J. Thomson Avenue, Cambridge CB3 0FF, UK
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3
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Sangwung P, Ho JD, Siddall T, Lin J, Tomas A, Jones B, Sloop KW. Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease. Am J Physiol Endocrinol Metab 2024; 327:E600-E615. [PMID: 38984948 PMCID: PMC11559640 DOI: 10.1152/ajpendo.00371.2023] [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: 11/08/2023] [Revised: 06/14/2024] [Accepted: 07/01/2024] [Indexed: 07/11/2024]
Abstract
The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via an N-terminal extracellular domain that forms a hydrophobic ligand-binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogs of several class B1 ligands for therapeutic use. Among the most accepted of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multifunctional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of polypharmacologic ligands. Furthermore, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complexes with either native ligands or multifunctional agonists are provided, supporting the pharmacological basis of such therapeutic agents.
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Affiliation(s)
- Panjamaporn Sangwung
- Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States
| | - Joseph D Ho
- Department of Structural Biology, Lilly Biotechnology Center, San Diego, California, United States
| | - Tessa Siddall
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Jerry Lin
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Ben Jones
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Kyle W Sloop
- Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States
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Forst T, De Block C, Del Prato S, Armani S, Frias J, Lautenbach A, Ludvik B, Marinez M, Mathieu C, Müller TD, Schnell O. The role of incretin receptor agonists in the treatment of obesity. Diabetes Obes Metab 2024; 26:4178-4196. [PMID: 39072877 DOI: 10.1111/dom.15796] [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: 05/03/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/30/2024]
Abstract
INTRODRODUCTION Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon-like peptide-1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co-agonists. METHODS The objective of this narrative review was to summarize the available data on approved and emerging incretin-based agents for the treatment of obesity. RESULTS In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction-associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation. CONCLUSIONS Many dual and triple co-agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin-based therapies; however, data are promising, and further results are eagerly awaited.
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Affiliation(s)
- Thomas Forst
- CRS Clinical Research Services GmbH, Mannheim, Germany
| | | | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science," Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Sara Armani
- CRS Clinical Research Services GmbH, Mannheim, Germany
| | - Juan Frias
- Biomea Fusion, Redwood City, California, USA
| | - Anne Lautenbach
- University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bernhard Ludvik
- Landstrasse Clinic and Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
| | | | | | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Walther-Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Oliver Schnell
- Forschergruppe Diabetes e.V. at the Helmholtz Center Munich, Munich, Germany
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Nicze M, Dec A, Borówka M, Krzyżak D, Bołdys A, Bułdak Ł, Okopień B. Molecular Mechanisms behind Obesity and Their Potential Exploitation in Current and Future Therapy. Int J Mol Sci 2024; 25:8202. [PMID: 39125772 PMCID: PMC11311839 DOI: 10.3390/ijms25158202] [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: 06/28/2024] [Revised: 07/22/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Obesity is a chronic disease caused primarily by the imbalance between the amount of calories supplied to the body and energy expenditure. Not only does it deteriorate the quality of life, but most importantly it increases the risk of cardiovascular diseases and the development of type 2 diabetes mellitus, leading to reduced life expectancy. In this review, we would like to present the molecular pathomechanisms underlying obesity, which constitute the target points for the action of anti-obesity medications. These include the central nervous system, brain-gut-microbiome axis, gastrointestinal motility, and energy expenditure. A significant part of this article is dedicated to incretin-based drugs such as GLP-1 receptor agonists (e.g., liraglutide and semaglutide), as well as the brand new dual GLP-1 and GIP receptor agonist tirzepatide, all of which have become "block-buster" drugs due to their effectiveness in reducing body weight and beneficial effects on the patient's metabolic profile. Finally, this review article highlights newly designed molecules with the potential for future obesity management that are the subject of ongoing clinical trials.
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Affiliation(s)
- Michał Nicze
- Department of Internal Medicine and Clinical Pharmacology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Medyków 18, 40-752 Katowice, Poland (A.B.); (B.O.)
| | | | | | | | | | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Medyków 18, 40-752 Katowice, Poland (A.B.); (B.O.)
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Bauri R, Bele S, Edelli J, Reddy NC, Kurukuti S, Devasia T, Ibrahim A, Rai V, Mitra P. Reduced incretin receptor trafficking upon activation enhances glycemic control and reverses obesity in diet-induced obese mice. Am J Physiol Cell Physiol 2024; 327:C74-C96. [PMID: 38738303 DOI: 10.1152/ajpcell.00474.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 05/14/2024]
Abstract
Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP. The peptide I-M-150847 is a partial agonist of GLP-1R and GIPR; however, the receptors, upon activation by I-M-150847, undergo reduced internalization that promotes agonist-mediated iterative cAMP signaling and augments glucose-stimulated insulin exocytosis in pancreatic β cells. Chronic administration of I-M-150847 improved glycemic control, enhanced insulin sensitivity, and provided profound weight loss in diet-induced obese (DIO) mice. Our results demonstrated that despite being a partial agonist, I-M-150847, by reducing the receptor internalization upon activation, enhanced the incretin effect and reversed obesity.NEW & NOTEWORTHY Replacement of the tryptophan cage (Trp-cage) with the C-terminal oxyntomodulin undecapeptide along with the tyrosine substitution at the amino terminus converts the selective glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 to a novel GLP-1R and GIPR dual agonist I-M-150847. Reduced internalization of incretin receptors upon activation by the GLP-1R and GIPR dual agonist I-M-150847 promotes iterative receptor signaling that enhances the incretin effect and reverses obesity.
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Affiliation(s)
- Rathin Bauri
- Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, India
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Shilpak Bele
- Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, India
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Jhansi Edelli
- Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, India
| | - Neelesh C Reddy
- Department of Chemistry, Indian Institute of Science Education and Research, Bhopal, India
| | | | - Tom Devasia
- Department of Cardiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Ahamed Ibrahim
- Division of Lipid Chemistry, National Institute of Nutrition Hyderabad, Hyderabad, India
| | - Vishal Rai
- Department of Chemistry, Indian Institute of Science Education and Research, Bhopal, India
| | - Prasenjit Mitra
- Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, India
- Institute of Transformative Molecular medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
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7
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Li X, Petrov MS. Dietary Fibre for the Prevention of Post-Pancreatitis Diabetes Mellitus: A Review of the Literature and Future Research Directions. Nutrients 2024; 16:435. [PMID: 38337719 PMCID: PMC10857198 DOI: 10.3390/nu16030435] [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: 12/12/2023] [Revised: 01/30/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
Post-pancreatitis diabetes mellitus-the most common sequela of pancreatitis-leads to poorer glycaemic control compared with type 2 diabetes. Because post-pancreatitis diabetes mellitus is an exemplar of secondary diabetes (with a clear underlying cause), much post-pancreatitis diabetes mellitus is preventable or treatable early. Earlier literature established the important role of dietary fibre in reducing plasma glucose in individuals with type 2 diabetes. The present review benchmarks available evidence on the role of habitual dietary fibre intake in pancreatitis and post-pancreatitis diabetes mellitus. It also paves the way for future research on the use of dietary fibre in the post-pancreatitis setting.
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Affiliation(s)
| | - Maxim S. Petrov
- School of Medicine, University of Auckland, Auckland 1023, New Zealand
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8
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Prajapati RN, Bhushan B, Singh K, Chopra H, Kumar S, Agrawal M, Pathak D, Chanchal DK, Laxmikant. Recent Advances in Pharmaceutical Design: Unleashing the Potential of Novel Therapeutics. Curr Pharm Biotechnol 2024; 25:2060-2077. [PMID: 38288793 DOI: 10.2174/0113892010275850240102105033] [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: 09/29/2023] [Revised: 12/01/2023] [Accepted: 12/11/2023] [Indexed: 09/10/2024]
Abstract
Pharmaceutical design has made significant advancements in recent years, leading to the development of novel therapeutics with unprecedented efficacy and safety profiles. This review highlights the potential of these innovations to revolutionize healthcare and improve patient outcomes. The application of cutting-edge technologies like artificial intelligence, machine learning, and data mining in drug discovery and design has made it easier to find potential drug candidates. Combining big data and omics has led to the discovery of new therapeutic targets and personalized medicine strategies. Nanoparticles, liposomes, and microneedles are examples of advanced drug delivery systems that allow precise control over drug release, better bioavailability, and targeted delivery to specific tissues or cells. This improves the effectiveness of the treatment while reducing side effects. Stimuli-responsive materials and smart drug delivery systems enable drugs to be released on demand when specific internal or external signals are sent. Biologics and gene therapies are promising approaches in pharmaceutical design, offering high specificity and potency for treating various diseases like cancer, autoimmune disorders, and infectious diseases. Gene therapies hold tremendous potential for correcting genetic abnormalities, with recent breakthroughs demonstrating successful outcomes in inherited disorders and certain types of cancer. Advancements in nanotechnology and nanomedicine have paved the way for innovative diagnostic tools and therapeutics, such as nanoparticle-based imaging agents, targeted drug delivery systems, gene editing technologies, and regenerative medicine strategies. Finally, the review emphasizes the importance of regulatory considerations, ethical challenges, and future directions in pharmaceutical design. Regulatory agencies are adapting to the rapid advancements in the field, ensuring the safety and efficacy of novel therapeutics while fostering innovation. Ethical considerations regarding the use of emerging technologies, patient privacy, and access to advanced therapies also require careful attention.
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Affiliation(s)
- Ram Narayan Prajapati
- Department of Pharmaceutics, Institute of Pharmacy, Bundelkhand University, Jhansi-284128 (UP) India
| | - Bharat Bhushan
- Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura Uttar Pradesh, India
| | - Kuldeep Singh
- Department of Pharmacology, Rajiv Academy for Pharmacy, Mathura Uttar Pradesh India
| | - Himansu Chopra
- Department of Pharmaceutics, Rajiv Academy for Pharmacy, Mathura Uttar Pradesh, India
| | - Shivendra Kumar
- Department of Pharmacology, Rajiv Academy for Pharmacy, Mathura Uttar Pradesh India
| | - Mehak Agrawal
- Department of Pharmaceutics, Rajiv Academy for Pharmacy, Mathura Uttar Pradesh, India
| | - Devender Pathak
- Department of Chemistry, Rajiv Academy for Pharmacy, Mathura Uttar Pradesh, India
| | - Dilip Kumar Chanchal
- Department of Pharmacognosy, Smt. Vidyawati College of Pharmacy, Jhansi, Uttar Pradesh, India
| | - Laxmikant
- Department of Chemistry, Agra Public Pharmacy College, Artoni Agra, Uttar Pradesh, India
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9
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Pocai A. G protein-coupled receptors and obesity. Front Endocrinol (Lausanne) 2023; 14:1301017. [PMID: 38161982 PMCID: PMC10757641 DOI: 10.3389/fendo.2023.1301017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/29/2023] [Indexed: 01/03/2024] Open
Abstract
G protein-coupled receptors (GPCRs) have emerged as important drug targets for various chronic diseases, including obesity and diabetes. Obesity is a complex chronic disease that requires long term management predisposing to type 2 diabetes, heart disease, and some cancers. The therapeutic landscape for GPCR as targets of anti-obesity medications has undergone significant changes with the approval of semaglutide, the first peptide glucagon like peptide 1 receptor agonist (GLP-1RA) achieving double digit weight loss (≥10%) and cardiovascular benefits. The enhanced weight loss, with the expected beneficial effect on obesity-related complications and reduction of major adverse cardiovascular events (MACE), has propelled the commercial opportunity for the obesity market leading to new players entering the space. Significant progress has been made on approaches targeting GPCRs such as single peptides that simultaneously activate GIP and/or GCGR in addition to GLP1, oral tablet formulation of GLP-1, small molecules nonpeptidic oral GLP1R and fixed-dose combination as well as add-on therapy for patients already treated with a GLP-1 agonist.
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Affiliation(s)
- Alessandro Pocai
- Cardiovascular and Metabolic Disease, Johnson & Johnson Innovative Medicine Research & Development, Spring House, PA, United States
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10
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Li Y, Zhou Q, Dai A, Zhao F, Chang R, Ying T, Wu B, Yang D, Wang MW, Cong Z. Structural analysis of the dual agonism at GLP-1R and GCGR. Proc Natl Acad Sci U S A 2023; 120:e2303696120. [PMID: 37549266 PMCID: PMC10438375 DOI: 10.1073/pnas.2303696120] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 06/15/2023] [Indexed: 08/09/2023] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy. To study the underlying molecular mechanisms, we determined high-resolution cryo-electron microscopy structures of GLP-1R or GCGR in complex with heterotrimeric Gs protein and three GLP-1R/GCGR dual agonists including peptide 15, MEDI0382 (cotadutide) and SAR425899 with variable activating profiles at GLP-1R versus GCGR. Compared with related structures reported previously and supported by our published pharmacological data, key residues responsible for ligand recognition and dual agonism were identified. Analyses of peptide conformational features revealed a difference in side chain orientations within the first three residues, indicating that distinct engagements in the deep binding pocket are required to achieve receptor selectivity. The middle region recognizes extracellular loop 1 (ECL1), ECL2, and the top of transmembrane helix 1 (TM1) resulting in specific conformational changes of both ligand and receptor, especially the dual agonists reshaped ECL1 conformation of GLP-1R relative to that of GCGR, suggesting an important role of ECL1 interaction in executing dual agonism. Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously.
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Affiliation(s)
- Yang Li
- Department of Medical Microbiology and Parasitology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
| | - Qingtong Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
| | - Antao Dai
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
| | - Fenghui Zhao
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
| | - Rulue Chang
- School of Pharmacy, Fudan University, Shanghai201203, China
| | - Tianlei Ying
- Department of Medical Microbiology and Parasitology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
| | - Beili Wu
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
| | - Dehua Yang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- Research Center for Deepsea Bioresources, Sanya, Hainan572025, China
| | - Ming-Wei Wang
- Department of Medical Microbiology and Parasitology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
- Research Center for Deepsea Bioresources, Sanya, Hainan572025, China
- Department of Chemistry, School of Science, The University of Tokyo, Tokyo113-0033, Japan
- School of Pharmacy, Hainan Medical College, Haikou570228, China
| | - Zhaotong Cong
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
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11
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Vishnoi S, Bhattacharya S, Walsh EM, Okoh GI, Thompson D. Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors. J Chem Inf Model 2023; 63:4934-4947. [PMID: 37523325 PMCID: PMC10428222 DOI: 10.1021/acs.jcim.3c00752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Indexed: 08/02/2023]
Abstract
Peptides are sustainable alternatives to conventional therapeutics for G protein-coupled receptor (GPCR) linked disorders, promising biocompatible and tailorable next-generation therapeutics for metabolic disorders including type-2 diabetes, as agonists of the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). However, single agonist peptides activating GLP-1R to stimulate insulin secretion also suppress obesity-linked glucagon release. Hence, bioactive peptides cotargeting GCGR and GLP-1R may remediate the blood glucose and fatty acid metabolism imbalance, tackling both diabetes and obesity to supersede current monoagonist therapy. Here, we design and model optimized peptide sequences starting from peptide sequences derived from earlier phage-displayed library screening, identifying those with predicted molecular binding profiles for dual agonism of GCGR and GLP-1R. We derive design rules from extensive molecular dynamics simulations based on peptide-receptor binding. Our newly designed coagonist peptide exhibits improved predicted coupled binding affinity for GCGR and GLP-1R relative to endogenous ligands and could in the future be tested experimentally, which may provide superior glycemic and weight loss control.
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Affiliation(s)
- Shubham Vishnoi
- Department
of Physics, Bernal Institute, University
of Limerick, Limerick V94T9PX, Ireland
| | - Shayon Bhattacharya
- Department
of Physics, Bernal Institute, University
of Limerick, Limerick V94T9PX, Ireland
| | | | | | - Damien Thompson
- Department
of Physics, Bernal Institute, University
of Limerick, Limerick V94T9PX, Ireland
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12
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Liarakos AL, Koliaki C. Novel Dual Incretin Receptor Agonists in the Spectrum of Metabolic Diseases with a Focus on Tirzepatide: Real Game-Changers or Great Expectations? A Narrative Review. Biomedicines 2023; 11:1875. [PMID: 37509514 PMCID: PMC10377278 DOI: 10.3390/biomedicines11071875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/24/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023] Open
Abstract
The prevalence of metabolic diseases including type 2 diabetes (T2D), obesity and non-alcoholic fatty liver disease (NAFLD) increases globally. This highlights an unmet need for identifying optimal therapies for the management of these conditions. Tirzepatide is a novel dual incretin receptor agonist (twincretin) that activates both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. The aim of this narrative review was to examine the impact of novel twincretins, focusing on tirzepatide, on the management of a wide spectrum of metabolic diseases. Data from preclinical and clinical trials have shown that twincretins significantly reduce blood glucose levels in T2D, and tirzepatide is the first agent of this class that has been approved for the management of T2D. Additionally, the beneficial impact of tirzepatide on weight reduction has been corroborated in several studies, showing that this agent can achieve substantial and sustained weight loss in obese patients with or without T2D. Data also suggest that tirzepatide could be a promising drug for hepatic steatosis reduction in individuals with NAFLD. The remarkable effects of tirzepatide on glycaemic control, weight loss and liver-related outcomes have posed new research questions that are likely to lead to further advancements in the treatment of T2D, obesity and related metabolic disorders.
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Affiliation(s)
| | - Chrysi Koliaki
- First Propaedeutic Department of Internal Medicine and Diabetes Center, Laiko General Hospital, Medical Faculty, National Kapodistrian University of Athens, 11527 Athens, Greece
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13
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Zhihong Y, Chen W, Qianqian Z, Lidan S, Qiang Z, Jing H, Wenxi W, Bhawal R. Emerging roles of oxyntomodulin-based glucagon-like peptide-1/glucagon co-agonist analogs in diabetes and obesity. Peptides 2023; 162:170955. [PMID: 36669563 DOI: 10.1016/j.peptides.2023.170955] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 01/13/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023]
Abstract
Oxyntomodulin (OXM) is an endogenous peptide hormone secreted from the intestines following nutrient ingestion that activates both glucagon-like peptide-1 (GLP-1) and glucagon receptors. OXM is known to exert various effects, including improvement in glucose tolerance, promotion of energy expenditure, acceleration of liver lipolysis, inhibition of food intake, delay of gastric emptying, neuroprotection, and pain relief. The antidiabetic and antiobesity properties have led to the development of biologically active and enzymatically stable OXM-based analogs with proposed therapeutic promise for metabolic diseases. Structural modification of OXM was ongoing to enhance its potency and prolong half-life, and several GLP-1/glucagon dual receptor agonist-based therapies are being explored in clinical trials for the treatment of type 2 diabetes mellitus and its complications. In the present article, we provide a brief overview of the physiology of OXM, focusing on its structural-activity relationship and ongoing clinical development.
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Affiliation(s)
- Yao Zhihong
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, China; College of Pharmacy, Zhejiang University of Technology, Hangzhou 310000, China
| | - Wang Chen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, China
| | - Zhu Qianqian
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, China
| | - Sun Lidan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, China.
| | - Zhou Qiang
- The First Hospital of Jiaxing & The Affiliated Hospital of Jiaxing University, Jiaxing 314001, China.
| | - Han Jing
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, China
| | - Wang Wenxi
- The First Hospital of Jiaxing & The Affiliated Hospital of Jiaxing University, Jiaxing 314001, China; College of Pharmacy, Zhejiang University of Technology, Hangzhou 310000, China
| | - Ruchika Bhawal
- Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA
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14
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Bakaj I, Pocai A. Metabolism-based approaches for autosomal dominant polycystic kidney disease. Front Mol Biosci 2023; 10:1126055. [PMID: 36876046 PMCID: PMC9980902 DOI: 10.3389/fmolb.2023.1126055] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) leads to end stage kidney disease (ESKD) through the development and expansion of multiple cysts throughout the kidney parenchyma. An increase in cyclic adenosine monophosphate (cAMP) plays an important role in generating and maintaining fluid-filled cysts because cAMP activates protein kinase A (PKA) and stimulates epithelial chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). A vasopressin V2 receptor antagonist, Tolvaptan, was recently approved for the treatment of ADPKD patients at high risk of progression. However additional treatments are urgently needed due to the poor tolerability, the unfavorable safety profile, and the high cost of Tolvaptan. In ADPKD kidneys, alterations of multiple metabolic pathways termed metabolic reprogramming has been consistently reported to support the growth of rapidly proliferating cystic cells. Published data suggest that upregulated mTOR and c-Myc repress oxidative metabolism while enhancing glycolytic flux and lactic acid production. mTOR and c-Myc are activated by PKA/MEK/ERK signaling so it is possible that cAMPK/PKA signaling will be upstream regulators of metabolic reprogramming. Novel therapeutics opportunities targeting metabolic reprogramming may avoid or minimize the side effects that are dose limiting in the clinic and improve on the efficacy observed in human ADPKD with Tolvaptan.
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Affiliation(s)
- Ivona Bakaj
- Cardiovascular and Metabolism, Janssen Research and Development, Spring House, PA, United States
| | - Alessandro Pocai
- Cardiovascular and Metabolism, Janssen Research and Development, Spring House, PA, United States
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15
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Factors Affecting the Circulating Levels of Oxyntomodulin in Health and After Acute Pancreatitis. Pancreas 2022; 51:774-783. [PMID: 36395403 DOI: 10.1097/mpa.0000000000002114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVES To investigate the factors associated with the circulating levels of oxyntomodulin in healthy individuals and individuals after an episode of acute pancreatitis (AP). METHODS Blood samples were collected from all participants after an overnight fast and analyzed for 28 biomarkers. Participants also underwent comprehensive body composition analysis on a 3-T magnetic resonance imaging scanner. Regression analyses were done to investigate the associations between oxyntomodulin and the studied factors. RESULTS The study included 105 individuals who had a primary diagnosis of AP and 58 healthy individuals. Peptide YY (B coefficient, 0.094; 95% confidence interval [95% CI], 0.164-0.123), pancreatic polypeptide (0.048; 95% CI, 0.030-0.066), and leptin (0.394; 95% CI, 0.128-0.661) had significant associations with oxyntomodulin in healthy individuals. Peptide YY was the most prominent factor associated with oxyntomodulin, explaining 60% of its variance in health. Cholecystokinin (0.014; 95% CI, 0.010-0.018), amylin (-0.107; 95% CI, -0.192 to -0.021), and glycated hemoglobin (-0.761; 95% CI, -1.249 to -0.273) had significant associations with oxyntomodulin in individuals after AP. Cholecystokinin was the most prominent factor associated with oxyntomodulin, explaining 44% of its variance after AP. CONCLUSIONS Factors affecting the circulating levels of oxyntomodulin are different in health and after AP. These insights will enable the determination of populations that benefit from oxyntomodulin therapeutics in the future.
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16
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Pang J, Feng JN, Ling W, Jin T. The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs—Therapeutic potential exploration in lung injury. Acta Pharm Sin B 2022; 12:4040-4055. [PMID: 36386481 PMCID: PMC9643154 DOI: 10.1016/j.apsb.2022.06.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/25/2022] [Accepted: 06/01/2022] [Indexed: 12/02/2022] Open
Abstract
Since 2005, GLP-1 receptor (GLP-1R) agonists (GLP-1RAs) have been developed as therapeutic agents for type 2 diabetes (T2D). GLP-1R is not only expressed in pancreatic islets but also other organs, especially the lung. However, controversy on extra-pancreatic GLP-1R expression still needs to be further resolved, utilizing different tools including the use of more reliable GLP-1R antibodies in immune-staining and co-immune-staining. Extra-pancreatic expression of GLP-1R has triggered extensive investigations on extra-pancreatic functions of GLP-1RAs, aiming to repurpose them into therapeutic agents for other disorders. Extensive studies have demonstrated promising anti-inflammatory features of GLP-1RAs. Whether those features are directly mediated by GLP-1R expressed in immune cells also remains controversial. Following a brief review on GLP-1 as an incretin hormone and the development of GLP-1RAs as therapeutic agents for T2D, we have summarized our current understanding of the anti-inflammatory features of GLP-1RAs and commented on the controversy on extra-pancreatic GLP-1R expression. The main part of this review is a literature discussion on GLP-1RA utilization in animal models with chronic airway diseases and acute lung injuries, including studies on the combined use of mesenchymal stem cell (MSC) based therapy. This is followed by a brief summary.
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17
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Martinou E, Stefanova I, Iosif E, Angelidi AM. Neurohormonal Changes in the Gut-Brain Axis and Underlying Neuroendocrine Mechanisms following Bariatric Surgery. Int J Mol Sci 2022; 23:3339. [PMID: 35328759 PMCID: PMC8954280 DOI: 10.3390/ijms23063339] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 02/05/2023] Open
Abstract
Obesity is a complex, multifactorial disease that is a major public health issue worldwide. Currently approved anti-obesity medications and lifestyle interventions lack the efficacy and durability needed to combat obesity, especially in individuals with more severe forms or coexisting metabolic disorders, such as poorly controlled type 2 diabetes. Bariatric surgery is considered an effective therapeutic modality with sustained weight loss and metabolic benefits. Numerous genetic and environmental factors have been associated with the pathogenesis of obesity, while cumulative evidence has highlighted the gut-brain axis as a complex bidirectional communication axis that plays a crucial role in energy homeostasis. This has led to increased research on the roles of neuroendocrine signaling pathways and various gastrointestinal peptides as key mediators of the beneficial effects following weight-loss surgery. The accumulate evidence suggests that the development of gut-peptide-based agents can mimic the effects of bariatric surgery and thus is a highly promising treatment strategy that could be explored in future research. This article aims to elucidate the potential underlying neuroendocrine mechanisms of the gut-brain axis and comprehensively review the observed changes of gut hormones associated with bariatric surgery. Moreover, the emerging role of post-bariatric gut microbiota modulation is briefly discussed.
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Affiliation(s)
- Eirini Martinou
- Department of Upper Gastrointestinal Surgery, Frimley Health NHS Foundation Trust, Camberley GU16 7UJ, UK;
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Irena Stefanova
- Department of General Surgery, Frimley Health NHS Foundation Trust, Camberley GU16 7UJ, UK;
| | - Evangelia Iosif
- Department of General Surgery, Royal Surrey County Hospital, Guildford GU2 7XX, UK;
| | - Angeliki M. Angelidi
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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18
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Yang GZ, Gao QC, Li WR, Cai HY, Zhao HM, Wang JJ, Zhao XR, Wang JX, Wu MN, Zhang J, Hölscher C, Qi JS, Wang ZJ. (D-Ser2) oxyntomodulin recovers hippocampal synaptic structure and theta rhythm in Alzheimer's disease transgenic mice. Neural Regen Res 2022; 17:2072-2078. [PMID: 35142699 PMCID: PMC8848598 DOI: 10.4103/1673-5374.335168] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
In our previous studies, we have shown that (D-Ser2) oxyntomodulin (Oxm), a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide, protects hippocampal neurons against Aβ1–42 -induced cytotoxicity, and stabilizes the calcium homeostasis and mitochondrial membrane potential of hippocampal neurons. Additionally, we have demonstrated that (D-Ser2) Oxm improves cognitive decline and reduces the deposition of amyloid-beta in Alzheimer's disease model mice. However, the protective mechanism remains unclear. In this study, we showed that 2 weeks of intraperitoneal administration of (D-Ser2) Oxm ameliorated the working memory and fear memory impairments of 9-month-old 3×Tg Alzheimer's disease model mice. In addition, electrophysiological data recorded by a wireless multichannel neural recording system implanted in the hippocampal CA1 region showed that (D-Ser2) Oxm increased the power of the theta rhythm. In addition, (D-Ser2) Oxm treatment greatly increased the expression level of synaptic-associated proteins SYP and PSD-95 and increased the number of dendritic spines in 3×Tg Alzheimer's disease model mice. These findings suggest that (D-Ser2) Oxm improves the cognitive function of Alzheimer's disease transgenic mice by recovering hippocampal synaptic function and theta rhythm.
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Affiliation(s)
- Guang-Zhao Yang
- Department of Cardiovascular Medicine, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Qi-Chao Gao
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
| | - Wei-Ran Li
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
| | - Hong-Yan Cai
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Hui-Min Zhao
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
| | - Jian-Ji Wang
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
| | - Xin-Rui Zhao
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
| | - Jia-Xin Wang
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
| | - Mei-Na Wu
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
| | - Jun Zhang
- Functional Laboratory Center, Shanxi Medical University, Taiyuan, Shanxi Province, China
| | - Christian Hölscher
- Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China
| | - Jin-Shun Qi
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
| | - Zhao-Jun Wang
- Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China
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19
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Shao L, Chen Y, Zhang S, Zhang Z, Cao Y, Yang D, Wang MW. Modulating effects of RAMPs on signaling profiles of the glucagon receptor family. Acta Pharm Sin B 2022; 12:637-650. [PMID: 35256936 PMCID: PMC8897147 DOI: 10.1016/j.apsb.2021.07.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/04/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Receptor activity-modulating proteins (RAMPs) are accessory molecules that form complexes with specific G protein-coupled receptors (GPCRs) and modulate their functions. It is established that RAMP interacts with the glucagon receptor family of GPCRs but the underlying mechanism is poorly understood. In this study, we used a bioluminescence resonance energy transfer (BRET) approach to comprehensively investigate such interactions. In conjunction with cAMP accumulation, Gαq activation and β-arrestin1/2 recruitment assays, we not only verified the GPCR–RAMP pairs previously reported, but also identified new patterns of GPCR–RAMP interaction. While RAMP1 was able to modify the three signaling events elicited by both glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), and RAMP2 mainly affected β-arrestin1/2 recruitment by GCGR, GLP-1R and glucagon-like peptide-2 receptor, RAMP3 showed a widespread negative impact on all the family members except for growth hormone-releasing hormone receptor covering the three pathways. Our results suggest that RAMP modulates both G protein dependent and independent signal transduction among the glucagon receptor family members in a receptor-specific manner. Mapping such interactions provides new insights into the role of RAMP in ligand recognition and receptor activation.
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Key Words
- AMY, amylin
- Allosteric modulation
- BRET, bioluminescence resonance energy transfer
- Bmax, maximum measured BRET value
- CGRP, calcitonin gene-related peptide
- CLR, calcitonin-like receptor
- EC50, half maximal effective concentration
- ECD, extracellular domain
- Emax, maximal response
- G protein-coupled receptor
- GCGR, glucagon receptor
- GHRHR, hormone-releasing hormone receptor
- GIPR, gastric inhibitory polypeptide receptor or glucose-dependent insulinotropic polypeptide
- GLP-1R, glucagon-like peptide-1 receptor
- GLP-2R, glucagon-like peptide-2 receptor
- GPCRs, G protein-coupled receptors
- GPCR–RAMP interaction
- Glucagon receptor family
- Ligand selectivity
- RAMP, receptor activity-modulating protein
- Receptor activity-modulating protein
- Receptor pharmacology
- Rluc, Renilla luciferase
- SBA, suspension bead array
- SCTR, secretin receptor
- SV, splice variant
- Signaling
- TMD, transmembrane domain
- VPAC2R, vasoactive intestinal polypeptide 2 receptor
- cAMP, cyclic adenosine monophosphate
- pEC50, negative logarithm of EC50
- β2-AR, β2-adrenergic receptor
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Affiliation(s)
- Lijun Shao
- The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yan Chen
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Shikai Zhang
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Zhihui Zhang
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yongbing Cao
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Dehua Yang
- The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Corresponding authors.
| | - Ming-Wei Wang
- The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Pharmacy, Fudan University, Shanghai 201203, China
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Corresponding authors.
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20
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Di Mauro A, Tuccinardi D, Watanabe M, Del Toro R, Monte L, Giorgino R, Rampa L, Rossini G, Kyanvash S, Soare A, Rosati M, Piccoli A, Napoli N, Fioriti E, Pozzilli P, Khazrai YM, Manfrini S. The Mediterranean diet increases glucagon-like peptide 1 and oxyntomodulin compared with a vegetarian diet in patients with type 2 diabetes: A randomized controlled cross-over trial. Diabetes Metab Res Rev 2021; 37:e3406. [PMID: 32926502 DOI: 10.1002/dmrr.3406] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/30/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022]
Abstract
AIM To compare a Mediterranean diet (MED) with a high-fibre vegetarian diet (HFV) in terms of hunger-satiety perception through post-prandial assessment of appetite-related hormones glucagon-like peptide 1 (GLP-1) and oxyntomodulin, as well as self-rated visual analogue scale (VAS) quantification, in overweight/obese subjects with type 2 diabetes (T2D). MATERIALS AND METHODS Twelve T2D subjects (Male to female ratio = 7:5), mean age 63 ± 8.5 years, were enrolled in a randomized, controlled, crossover study. Participants consumed an MED meal as well as an isocaloric meal rich in complex carbohydrate as well as an isocaloric MED meal in two different visits with a 1-week washout period between the two visits. Appetite ratings, glucose/insulin, and gastrointestinal hormone concentrations were measured at fasting and every 30' until 210' following meal consumption. RESULTS GLP-1 and oxyntomodulin levels were significantly higher following MED meal compared with HFV meals (210' area under the curve, p < 0.022 and p < 0.023, respectively). Both MED and HFV meal resulted in a biphasic pattern of GLP-1 and oxyntomodulin, although MED meal was related to a delayed, significantly higher second GLP-1 peak at 150' compared with that of HFV meal (p < 0.05). MED meal was related to lower glucose profile compared with HFV meal (p < 0.039), whereas we did not observe significant changes in terms of self-reported VAS scores and insulin trend. CONCLUSIONS In T2D overweight/obese subjects, an MED meal is more effective than a HFV meal in terms of post-prandial plasma glucose homoeostasis and GLP-1 and oxyntomodulin release. These changes were not confirmed by VAS appetite self-assessment over a 210' period.
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Affiliation(s)
- Antonio Di Mauro
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Dario Tuccinardi
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Mikiko Watanabe
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - Rossella Del Toro
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Lavinia Monte
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Riccardo Giorgino
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Lorenzo Rampa
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Giovanni Rossini
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Shadi Kyanvash
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Andreea Soare
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Milena Rosati
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Alessandra Piccoli
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Nicoli Napoli
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
- Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, Missouri, USA
| | - Elvira Fioriti
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Paolo Pozzilli
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
- Centre of Immunobiology, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Yeganeh M Khazrai
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Silvia Manfrini
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
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21
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Jepsen MM, Christensen MB. Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. Expert Opin Emerg Drugs 2021; 26:231-243. [PMID: 34176426 DOI: 10.1080/14728214.2021.1947240] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Introduction: Obesity is a growing threat to public health, increasing risks of numerous diseases and mortality, and impairing quality of life. If current trends continue, more than 1.1 billion individuals will have obesity in 2030, corresponding to almost 2.5 times the number of adults currently living with diabetes. There is a strong interest in developing obesity treatments based on glucagon-like peptide-1 (GLP-1) agonism, which have proved to limit morbidity and mortality in type 2 diabetes.Areas covered: This review provides an overview of current compounds containing GLP-1 receptor agonism in clinical development for obesity, with mono-activity at the GLP-1 receptor (PF-0688296, glutazumab, semaglutide) or engaging one or more other endogenous hormonal systems involved in energy balance and metabolism, including glucagon, oxyntomodulin, glucose-dependent inhibitory peptide and amylin (CT-868, CT-388, AMG 133, tirzepatide, NNC9204-1177, JNJ-54,728,518, SAR425899, pegapamodutide, MK8521, cotadutide, efinopegdutide, BI-456,906, cagrilintide + semaglutide 2,4 mg, HM15211, NNC9204-1706).Expert opinion: Many novel compounds employing GLP-1 receptor agonism are in clinical development. Semaglutide is farthest in clinical development and will presumably become a benchmark for this class of novel anti-obesity compounds.
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Affiliation(s)
- Mathies M Jepsen
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
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22
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Abstract
OBJECTIVE New-onset diabetes is an important sequela of acute pancreatitis, but there are no biomarkers to differentiate it from the much more common type 2 diabetes. The objective was to investigate whether postprandial circulating levels of gut hormones can serve this purpose. METHODS This was a case-control study nested into a prospective longitudinal cohort study that included 42 insulin-naive cases with new-onset prediabetes/diabetes after acute pancreatitis (NODAP) and prediabetes/diabetes followed by acute pancreatitis (T2D-AP), sex matched with 21 healthy controls. All individuals underwent a standardized mixed-meal test, and blood samples were assayed for gut hormones (glucose-dependent insulinotropic peptide, glucagon-like peptide-1, oxyntomodulin, and peptide YY). Analysis of variance and linear regression analysis were conducted in unadjusted and adjusted models (accounting for age, homeostatic model assessment of β-cell function, and magnetic resonance imaging-derived body fat composition). RESULTS Oxyntomodulin levels were significantly lower in NODAP compared with T2D-AP and healthy controls (P = 0.027 and P = 0.001, respectively, in the most adjusted model). Glucagon-like peptide-1 and peptide YY were significantly lower in NODAP compared with T2D-AP (P = 0.001 and P = 0.014, respectively, in the most adjusted model) but not compared with healthy controls (P = 1.000 and P = 0.265, respectively, in the most adjusted model). Glucose-dependent insulinotropic peptide levels were not significantly different between NODAP and T2D-AP. DISCUSSION Oxyntomodulin is a promising biomarker to guide the differential diagnosis of new-onset diabetes after acute pancreatitis. However, external validation studies are warranted before it can be recommended for routine use in clinical practice.
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23
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Kinna S, Ouberaï MM, Sonzini S, Gomes Dos Santos AL, Welland ME. Thermo-Responsive self-assembly of a dual glucagon-like peptide and glucagon receptor agonist. Int J Pharm 2021; 604:120719. [PMID: 34015379 DOI: 10.1016/j.ijpharm.2021.120719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/13/2021] [Accepted: 05/13/2021] [Indexed: 01/02/2023]
Abstract
The human peptide hormone Oxyntomodulin (Oxm) is known to induce satiety, increase energy expenditure, and control blood glucose in humans, making it a promising candidate for treatment of obesity and/or type 2 diabetes mellitus. However, a pharmaceutical exploitation has thus far been impeded by fast in vivo clearance and the molecule's sensitivity to half-life extending structural modifications. We recently showed that Oxm self-assembles into amyloid-like nanofibrils that continuously release active, soluble Oxm in a peptide-deprived environment. S.c. injected Oxm nanofibrils extended plasma exposure from a few hours to five days in rodents, compared to s.c. applied soluble Oxm. Here we show that Oxm fibril elongation kinetics and thermodynamics display a uniquely low temperature optimum compared to previously reported amyloid-like peptide and protein assemblies. Elongation rate is optimal at room temperature, with association rates 2-3 times higher at 25 °C than at ≥37 °C or ≤20 °C. We deduce from a combination of Cryo electron microscopy and spectroscopic methods that Oxm fibrils have a double-layered, triangular cross-section composed of arch-shaped monomers. We suggest a thermodynamic model that links the necessary molecular rearrangements during fibrillation and peptide release to the unique temperature effects in Oxm self-assembly and disassembly.
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Affiliation(s)
- Sonja Kinna
- Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB30FF, UK
| | - Myriam M Ouberaï
- Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB30FF, UK.
| | - Silvia Sonzini
- Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca, Granta Park, Cambridge CB21 6GH, UK
| | - Ana L Gomes Dos Santos
- Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca, Granta Park, Cambridge CB21 6GH, UK.
| | - Mark E Welland
- Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca, Granta Park, Cambridge CB21 6GH, UK
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24
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Karavashkina TA, Balbotkina EV, Marina AS, Kutina AV. Role of Proglucagon Peptides in Osmoregulation. Bull Exp Biol Med 2021; 170:618-622. [PMID: 33788103 DOI: 10.1007/s10517-021-05118-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Indexed: 11/29/2022]
Abstract
Glucagon-like peptide-1 (GLP-1), a product of partial proteolysis of proglucagon, is involved not only in regulation of carbohydrates, but also in water-salt metabolism. The study examined the role of proglucagon derivatives GLP-1, GLP-2, and oxyntomodulin in rat osmoregulation. Of them, only blood plasma GLP-1 increased in response to water load (20 ml/kg). Administration of glucose (1.5 g/kg) elevated GLP-1 and oxyntomodulin but did not change the level of GLP-2. GLP-1 accelerated excretion of excess water during hyperhydration, whereas GLP-2 decreased this parameter. No physiological effects of oxyntomodulin in the kidneys were revealed. Probably, the blood levels of proglucagon derivatives are independently regulated for each peptide. In contrast to GLP-2 and oxyntomodulin, GLP-1 is involved in osmoregulation.
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Affiliation(s)
- T A Karavashkina
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - E V Balbotkina
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - A S Marina
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - A V Kutina
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
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25
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Do Gut Hormones Contribute to Weight Loss and Glycaemic Outcomes after Bariatric Surgery? Nutrients 2021; 13:nu13030762. [PMID: 33652862 PMCID: PMC7996890 DOI: 10.3390/nu13030762] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/18/2021] [Accepted: 02/20/2021] [Indexed: 02/07/2023] Open
Abstract
Bariatric surgery is an effective intervention for management of obesity through treating dysregulated appetite and achieving long-term weight loss maintenance. Moreover, significant changes in glucose homeostasis are observed after bariatric surgery including, in some cases, type 2 diabetes remission from the early postoperative period and postprandial hypoglycaemia. Levels of a number of gut hormones are dramatically increased from the early period after Roux-en-Y gastric bypass and sleeve gastrectomy—the two most commonly performed bariatric procedures—and they have been suggested as important mediators of the observed changes in eating behaviour and glucose homeostasis postoperatively. In this review, we summarise the current evidence from human studies on the alterations of gut hormones after bariatric surgery and their impact on clinical outcomes postoperatively. Studies which assess the role of gut hormones after bariatric surgery on food intake, hunger, satiety and glucose homeostasis through octreotide use (a non-specific inhibitor of gut hormone secretion) as well as with exendin 9–39 (a specific glucagon-like peptide-1 receptor antagonist) are reviewed. The potential use of gut hormones as biomarkers of successful outcomes of bariatric surgery is also evaluated.
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26
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Guimarães M, Pereira SS, Monteiro MP. From Entero-Endocrine Cell Biology to Surgical Interventional Therapies for Type 2 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1307:273-297. [PMID: 32016913 DOI: 10.1007/5584_2020_480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The physiological roles of the enteroendocrine system in relation to energy and glucose homeostasis regulation have been extensively studied in the past few decades. Considerable advances were made that enabled to disclose the potential use of gastro-intestinal (GI) hormones to target obesity and type 2 diabetes (T2D). The recognition of the clinical relevance of these discoveries has led the pharmaceutical industry to design several hormone analogues to either to mitigate physiological defects or target pharmacologically T2D.Amongst several advances, a major breakthrough in the field was the unexpected observation that enteroendocrine system modulation to T2D target could be achieved by surgically induced anatomical rearrangement of the GI tract. These findings resulted from the widespread use of bariatric surgery procedures for obesity treatment, which despite initially devised to induce weight loss by limiting the systemic availably of nutrients, are now well recognized to influence GI hormone dynamics in a manner that is highly dependent on the type of anatomical rearrangement produced.This chapter will focus on enteroendocrine system related mechanisms leading to improved glycemic control in T2D after bariatric surgery interventions.
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Affiliation(s)
- Marta Guimarães
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal.,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Department of General Surgery, Centro Hospitalar de Entre o Douro e Vouga, Santa Maria da Feira, Portugal
| | - Sofia S Pereira
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal.,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Mariana P Monteiro
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal. .,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
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27
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Campbell KL, Haspel N, Gath C, Kurniatash N, Nouduri Akkiraju I, Stuffers N, Vadher U. Protein hormone fragmentation in intercellular signaling: hormones as nested information systems. Biol Reprod 2021; 104:887-901. [PMID: 33403392 DOI: 10.1093/biolre/ioaa234] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/21/2020] [Accepted: 01/04/2021] [Indexed: 11/14/2022] Open
Abstract
This study explores the hypothesis that protein hormones are nested information systems in which initial products of gene transcription, and their subsequent protein fragments, before and after secretion and initial target cell action, play additional physiological regulatory roles. The study produced four tools and key results: (1) a problem approach that proceeds, with examples and suggestions for in vivo organismal functional tests for peptide-protein interactions, from proteolytic breakdown prediction to models of hormone fragment modulation of protein-protein binding motifs in unrelated proteins; (2) a catalog of 461 known soluble human protein hormones and their predicted fragmentation patterns; (3) an analysis of the predicted proteolytic patterns of the canonical protein hormone transcripts demonstrating near-universal persistence of 9 ± 7 peptides of 8 ± 8 amino acids even after cleavage with 24 proteases from four protease classes; and (4) a coincidence analysis of the predicted proteolysis locations and the 1939 exon junctions within the transcripts that shows an excess (P < 0.001) of predicted proteolysis within 10 residues, especially at the exonal junction (P < 0.01). It appears all protein hormone transcripts generate multiple fragments the size of peptide hormones or protein-protein binding domains that may alter intracellular or extracellular functions by acting as modulators of metabolic enzymes, transduction factors, protein binding proteins, or hormone receptors. High proteolytic frequency at exonal junctions suggests proteolysis has evolved, as a complement to gene exon fusion, to extract structures or functions within single exons or protein segments to simplify the genome by discarding archaic one-exon genes.
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Affiliation(s)
- Kenneth L Campbell
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA
| | - Nurit Haspel
- Department of Computer Sciences, University of Massachusetts Boston, Boston, MA, USA
| | - Cassandra Gath
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA
| | - Nuzulul Kurniatash
- Department of Computer Sciences, University of Massachusetts Boston, Boston, MA, USA
| | | | - Naomi Stuffers
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA
| | - Uma Vadher
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA
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28
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Lee SP, Qi J, Xu G, Rankin MM, Littrell J, Xu JZ, Bakaj I, Pocai A. GRK Inhibition Potentiates Glucagon-Like Peptide-1 Action. Front Endocrinol (Lausanne) 2021; 12:652628. [PMID: 34054727 PMCID: PMC8160450 DOI: 10.3389/fendo.2021.652628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/09/2021] [Indexed: 12/11/2022] Open
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.
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Affiliation(s)
- Seunghun P. Lee
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - Jenson Qi
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - Guozhang Xu
- Discovery Sciences, Janssen Research & Development, Spring House, PA, United States
| | - Matthew M. Rankin
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - James Littrell
- Discovery Sciences, Janssen Research & Development, Spring House, PA, United States
| | - June Zhi Xu
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - Ivona Bakaj
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
| | - Alessandro Pocai
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, United States
- *Correspondence: Alessandro Pocai,
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29
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Shah A, Dodson WC, Kris-Etherton PM, Kunselman AR, Stetter CM, Gnatuk CL, Estes SJ, Allison KC, Sarwer DB, Sluss PM, Coutifaris C, Dokras A, Legro RS. Effects of Oral Contraception and Lifestyle Modification on Incretins and TGF-ß Superfamily Hormones in PCOS. J Clin Endocrinol Metab 2021; 106:108-119. [PMID: 32968804 PMCID: PMC7765645 DOI: 10.1210/clinem/dgaa682] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 09/21/2020] [Indexed: 01/11/2023]
Abstract
OBJECTIVE To examine the effects of common treatments for polycystic ovary syndrome (PCOS) on a panel of hormones (reproductive/metabolic). DESIGN Secondary analysis of blood from a randomized controlled trial of three 16-week preconception interventions designed to improve PCOS-related abnormalities: continuous oral contraceptive pills (OCPs, N = 34 subjects), intensive lifestyle modification (Lifestyle, N = 31), or a combination of both (Combined, N = 29). MATERIALS AND METHODS Post-treatment levels of activin A and B, inhibin B, and follistatin (FST), as well as Insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 2 (IGFBP-2), glucagon, glucagon-like peptide 1 (GLP-1) and 2, and oxyntomodulin were compared to baseline, and the change from baseline in these parameters were correlated with outcomes. RESULTS Oral contraceptive pill use was associated with a significant suppression in activin A, inhibin A, and anti-mullerian hormone (AMH), but a significant increase in FST. IGF-1, IGFBP-2, glucagon, and GLP-2 levels were significantly decreased. Oxyntomodulin was profoundly suppressed by OCPs (ratio of geometric means: 0.09, 95% confidence interval [CI]: 0.05, 0.18, P < 0.001). None of the analytes were significantly affected by Lifestyle, whereas the effects of Combined were similar to OCPs alone, although attenuated. Oxyntomodulin was significantly positively associated with the change in total ovarian volume (rs = 0.27; 95% CI: 0.03, 0.48; P = 0.03) and insulin sensitivity index (rs = 0.48; 95% CI: 0.27, 0.64; P < 0.001), and it was inversely correlated with change in area under the curve (AUC) glucose [rs = -0.38; 95% CI: -0.57, -0.16; P = 0.001]. None of the hormonal changes were associated with live birth, only Activin A was associated with ovulation (risk ratio per 1 ng/mL increase in change in Activin A: 6.0 [2.2, 16.2]; P < 0.001). CONCLUSIONS In women with PCOS, OCPs (and not Lifestyle) affect a wide variety of reproductive/metabolic hormones, but their treatment response does not correlate with live birth.
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Affiliation(s)
- Aesha Shah
- Department of Obstetrics and GynecologyPenn State College of Medicine, Hershey, PA
| | - William C Dodson
- Department of Public Health SciencesPenn State College of Medicine, Hershey, PA
| | | | - Allen R Kunselman
- Department of Public Health SciencesPenn State College of Medicine, Hershey, PA
| | - Christy M Stetter
- Department of Public Health SciencesPenn State College of Medicine, Hershey, PA
| | - Carol L Gnatuk
- Department of Obstetrics and GynecologyPenn State College of Medicine, Hershey, PA
| | - Stephanie J Estes
- Department of Obstetrics and GynecologyPenn State College of Medicine, Hershey, PA
| | - Kelly C Allison
- Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - David B Sarwer
- Center for Obesity Research and Education, College of Public Health, Temple University, Philadelphia, PA
| | - Patrick M Sluss
- Penn State College of Health and Human Development, University Park, PA
- Department of Pathology, Massachusetts General Hospital, Boston, MA TX
| | - Christos Coutifaris
- Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Anuja Dokras
- Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Richard S Legro
- Department of Obstetrics and GynecologyPenn State College of Medicine, Hershey, PA
- Department of Public Health SciencesPenn State College of Medicine, Hershey, PA
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30
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Acosta-Montalvo A, Saponaro C, Kerr-Conte J, Prehn JHM, Pattou F, Bonner C. Proglucagon-Derived Peptides Expression and Secretion in Rat Insulinoma INS-1 Cells. Front Cell Dev Biol 2020; 8:590763. [PMID: 33240888 PMCID: PMC7683504 DOI: 10.3389/fcell.2020.590763] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 10/20/2020] [Indexed: 11/26/2022] Open
Abstract
Rat insulinoma INS-1 cells are widely used to study insulin secretory mechanisms. Studies have shown that a population of INS-1 cells are bi-hormonal, co-expressing insulin, and proglucagon proteins. They coined this population as immature cells since they co-secrete proglucagon-derived peptides from the same secretory vesicles similar to that of insulin. Since proglucagon encodes multiple peptides including glucagon, glucagon-like-peptide-1 (GLP-1), GLP-2, oxyntomodulin, and glicentin, their specific expression and secretion are technically challenging. In this study, we aimed to focus on glucagon expression which shares the same amino acid sequence with glicentin and proglucagon. Validation of the anti-glucagon antibody (Abcam) by Western blotting techniques revealed that the antibody detects proglucagon (≈ 20 kDa), glicentin (≈ 9 kDa), and glucagon (≈ 3 kDa) in INS-1 cells and primary islets, all of which were absent in the kidney cell line (HEK293). Using the validated anti-glucagon antibody, we showed by immunofluorescence imaging that a population of INS-1 cells co-express insulin and proglucagon-derived proteins. Furthermore, we found that chronic treatment of INS-1 cells with high-glucose decreases insulin and glucagon content, and also reduces the percentage of bi-hormonal cells. In line with insulin secretion, we found glucagon and glicentin secretion to be induced in a glucose-dependent manner. We conclude that INS-1 cells are a useful model to study glucose-stimulated insulin secretion, but not that of glucagon or glicentin. Our study suggests Western blotting technique as an important tool for researchers to study proglucagon-derived peptides expression and regulation in primary islets in response to various metabolic stimuli.
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Affiliation(s)
- Ana Acosta-Montalvo
- INSERM, U1190, Lille, France.,European Genomic Institute for Diabetes, Lille, France.,University of Lille, Lille, France
| | - Chiara Saponaro
- INSERM, U1190, Lille, France.,European Genomic Institute for Diabetes, Lille, France.,University of Lille, Lille, France
| | - Julie Kerr-Conte
- INSERM, U1190, Lille, France.,European Genomic Institute for Diabetes, Lille, France.,University of Lille, Lille, France
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - François Pattou
- INSERM, U1190, Lille, France.,European Genomic Institute for Diabetes, Lille, France.,University of Lille, Lille, France.,Chirurgie Endocrinienne et Métabolique, CHU Lille, Lille, France
| | - Caroline Bonner
- INSERM, U1190, Lille, France.,European Genomic Institute for Diabetes, Lille, France.,University of Lille, Lille, France.,Institut Pasteur de Lille, Lille, France
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31
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Ma T, Huo S, Xu B, Li F, Wang P, Liu Y, Lei H. A novel long-acting oxyntomodulin analogue eliminates diabetes and obesity in mice. Eur J Med Chem 2020; 203:112496. [PMID: 32682196 DOI: 10.1016/j.ejmech.2020.112496] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/14/2020] [Accepted: 05/26/2020] [Indexed: 12/21/2022]
Abstract
Oxyntomodulin (OXM) was identified as a glucagon (GCG) receptor (GCGR) and glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) dual agonist to suppress appetite, increase energy expenditure, and induce body weight loss in obese humans. However, the activities of native OXM to activate GCGR and GLP-1R in vitro were much weaker than the natural ligands. To address this gap, structural modifications were adopted and novel OXM analogues were obtained through chimeric peptide sequence design. One specific analogue with enhanced and balanced GCGR/GLP-1R activations was chemically conjugated with polyethylene glycol (PEG) to achieve sustained release in vivo. This PEGylated analogue was further explored pharmacologically in db/db and diet-induced obese (DIO) mice models. Chronic weekly administration significantly induced hypoglycemic effects and body weight loss with dose dependency, along with normalized adiposity, lipid metabolism, and liver steatosis. Based on its profiles in vitro and in vivo, the analogue has the great potential to develop as a novel anti-diabetic and/or anti-obese candidate. As observed more insulin stimulation and improved insulin resistance, it may be also explored for the treatment of nonalcoholic steatohepatitis (NASH) in the future.
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Affiliation(s)
- Tao Ma
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Fangshan District, Beijing, 102488, PR China.
| | - Su Huo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Fangshan District, Beijing, 102488, PR China
| | - Bing Xu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Fangshan District, Beijing, 102488, PR China
| | - Feifei Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Fangshan District, Beijing, 102488, PR China
| | - Penglong Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Fangshan District, Beijing, 102488, PR China
| | - Yonggang Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Fangshan District, Beijing, 102488, PR China
| | - Haimin Lei
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Fangshan District, Beijing, 102488, PR China
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32
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Tsilingiris D, Liatis S, Dalamaga M, Kokkinos A. The Fight Against Obesity Escalates: New Drugs on the Horizon and Metabolic Implications. Curr Obes Rep 2020; 9:136-149. [PMID: 32388792 DOI: 10.1007/s13679-020-00378-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW There is currently a steep rise in the global prevalence of obesity. Pharmaceutical therapy is a valuable component of conservative obesity therapy. Herein, medications currently in the phase of preclinical or clinical testing are reviewed, along with an overview of the mechanisms that regulate energy intake and expenditure. In addition, the current and potential future directions of obesity drug therapy are discussed. RECENT FINDINGS Although the current arsenal of obesity pharmacotherapy is limited, a considerable number of agents that exert their actions through a variety of pharmacodynamic targets and mechanisms are in the pipeline. This expansion shapes a potential near future of obesity conservative management, characterized by tailored combined therapeutic regimens, targeting not only weight loss but also improved overall health outcomes. The progress regarding the elucidation of the mechanisms which regulate the bodily energy equilibrium has led to medications which mimic hormonal adaptations that follow bariatric surgery, in the quest for a "Medical bypass." These, combined with agents which could increase energy expenditure, point to a brilliant future in the conservative treatment of obesity.
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Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 17 Ag. Thoma Street, 11527, Athens, Greece
| | - Stavros Liatis
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 17 Ag. Thoma Street, 11527, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 17 Ag. Thoma Street, 11527, Athens, Greece.
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33
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Artasensi A, Pedretti A, Vistoli G, Fumagalli L. Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs. Molecules 2020; 25:E1987. [PMID: 32340373 PMCID: PMC7221535 DOI: 10.3390/molecules25081987] [Citation(s) in RCA: 242] [Impact Index Per Article: 48.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90-95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed.
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Affiliation(s)
| | | | | | - Laura Fumagalli
- Dipartimento di Scienze Farmaceutiche, University Degli Studi di Milano, 20133 Milano, Italy; (A.A.); (A.P.); (G.V.)
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Pei Z, Zhou D, Yan J, Wang S, Yang X, Pei Z. Design and characterization of novel oxyntomodulin derivatives with potent dual GLP-1/glucagon receptor activation and prolonged antidiabetic effects. Life Sci 2020; 253:117651. [PMID: 32304764 DOI: 10.1016/j.lfs.2020.117651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 11/18/2022]
Abstract
AIMS To investigate the combination of dimerization and PEGylation to enhance the receptor activation and in vivo stability of Oxyntomodulin (OXM). MAIN METHODS All LDM peptides were produced by using standard method of solid phase synthesis. The in vitro effects of LDM peptides were assessed by glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GcgR) binding test and Proteolytic stability test. Subsequently, saline, Liraglutide and three doses of LDM-3 treated groups were subjected to the evaluation of aute and long-term efficacy. KEY FINDINGS Five long-acting OXM conjugates, termed LDM-1 to LDM-5, were designed using cysteine (Cys)-specific modification reaction including the activated PEG, bisMal-NH2, and OXM-Cys, and all prepared with high purity. LDM-3 exhibited greater GLP-1R and GcgR activation and ameliorative serum stability. In addition, LDM-3 was identified with enhanced insulinotropic and glycemic abilities in the gene knockout mice. The prolonged glucose-lowering effects of the LDM-3 were proved by hypoglycemic duration test and multiple oral glucose tolerance tests (OGTTs) in the diet-induced obesity (DIO) mice. Furthermore, the pharmacokinetic tests in Sprague Dawley (SD) rat and cynomolgus monkey exhibited the lifespans of LDM-3 at 90 nmol·kg-1 were 101.5 h and 119.4 h, respectively. Nevertheless, consecutive 8-week administration of LDM-3 improved the cumulative body weight gain, food intake, % HbA1c, glucose tolerance and the pancreatic of the obese mice. SIGNIFICANCE LDM-3, as a dual GLP-1R and GcgR agonist, holds potential to be developed as a promising therapeutic candidate for both diabetes and obesity.
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Affiliation(s)
- Zengyang Pei
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China; Hangzhou RunChongGuiMei Bio-tech Co., Ltd., Xiao Shan, Hangzhou 310058, PR China.
| | - Degang Zhou
- National Research Center for Veterinary Medicine, Road Cuiwei, High-Tech District, Luoyang 471003, PR China
| | - Jie Yan
- Suzhou Xishan Zhongke Drug R&D Co., Ltd., Wuzhong Avenue, Suzhou 215000, PR China
| | - Shenghao Wang
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Xu Yang
- Hangzhou RunChongGuiMei Bio-tech Co., Ltd., Xiao Shan, Hangzhou 310058, PR China
| | - Zengju Pei
- Hangzhou RunChongGuiMei Bio-tech Co., Ltd., Xiao Shan, Hangzhou 310058, PR China
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Gimeno RE, Briere DA, Seeley RJ. Leveraging the Gut to Treat Metabolic Disease. Cell Metab 2020; 31:679-698. [PMID: 32187525 PMCID: PMC7184629 DOI: 10.1016/j.cmet.2020.02.014] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/23/2019] [Accepted: 02/20/2020] [Indexed: 02/07/2023]
Abstract
25 years ago, the future of treating obesity and diabetes focused on end organs known to be involved in energy balance and glucose regulation, including the brain, muscle, adipose tissue, and pancreas. Today, the most effective therapies are focused around the gut. This includes surgical options, such as vertical sleeve gastrectomy and Roux-en-Y gastric bypass, that can produce sustained weight loss and diabetes remission but also extends to pharmacological treatments that simulate or amplify various signals that come from the gut. The purpose of this Review is to discuss the wealth of approaches currently under development that seek to further leverage the gut as a source of novel therapeutic opportunities with the hope that we can achieve the effects of surgical interventions with less invasive and more scalable solutions.
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Affiliation(s)
- Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46225, USA
| | - Daniel A Briere
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46225, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
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Yang PY, Zou H, Amso Z, Lee C, Huang D, Woods AK, Nguyen-Tran VTB, Schultz PG, Shen W. New Generation Oxyntomodulin Peptides with Improved Pharmacokinetic Profiles Exhibit Weight Reducing and Anti-Steatotic Properties in Mice. Bioconjug Chem 2020; 31:1167-1176. [DOI: 10.1021/acs.bioconjchem.0c00093] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Peng-Yu Yang
- Calibr at The Scripps Research Institute, La Jolla, California 92037, United States
- Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States
| | - Huafei Zou
- Calibr at The Scripps Research Institute, La Jolla, California 92037, United States
| | - Zaid Amso
- Calibr at The Scripps Research Institute, La Jolla, California 92037, United States
| | - Candy Lee
- Calibr at The Scripps Research Institute, La Jolla, California 92037, United States
| | - David Huang
- Calibr at The Scripps Research Institute, La Jolla, California 92037, United States
| | - Ashley K. Woods
- Calibr at The Scripps Research Institute, La Jolla, California 92037, United States
| | | | - Peter G. Schultz
- Calibr at The Scripps Research Institute, La Jolla, California 92037, United States
- Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States
| | - Weijun Shen
- Calibr at The Scripps Research Institute, La Jolla, California 92037, United States
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Alexiadou K, Cuenco J, Howard J, Wewer Albrechtsen NJ, Ilesanmi I, Kamocka A, Tharakan G, Behary P, Bech PR, Ahmed AR, Purkayastha S, Wheller R, Fleuret M, Holst JJ, Bloom SR, Khoo B, Tan TMM. Proglucagon peptide secretion profiles in type 2 diabetes before and after bariatric surgery: 1-year prospective study. BMJ Open Diabetes Res Care 2020; 8:8/1/e001076. [PMID: 32209584 PMCID: PMC7103850 DOI: 10.1136/bmjdrc-2019-001076] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 01/20/2020] [Accepted: 02/07/2020] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Hyperglucagonemia is a key pathophysiological driver of type 2 diabetes. Although Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for diabetes, it is presently unclear how surgery alters glucagon physiology. The aim of this study was to characterize the behavior of proglucagon-derived peptide (glucagon, glucagon-like peptide-1 (GLP-1), oxyntomodulin, glicentin) secretion after RYGB surgery. RESEARCH DESIGN AND METHODS Prospective study of 19 patients with obesity and pre-diabetes/diabetes undergoing RYGB. We assessed the glucose, insulin, GLP-1, glucose-dependent insulinotropic peptide (GIP), oxyntomodulin, glicentin and glucagon responses to a mixed-meal test (MMT) before and 1, 3 and 12 months after surgery. Glucagon was measured using a Mercodia glucagon ELISA using the 'Alternative' improved specificity protocol, which was validated against a reference liquid chromatography combined with mass spectrometry method. RESULTS After RYGB, there were early improvements in fasting glucose and glucose tolerance and the insulin response to MMT was accelerated and amplified, in parallel to significant increases in postprandial GLP-1, oxyntomodulin and glicentin secretion. There was a significant decrease in fasting glucagon levels at the later time points of 3 and 12 months after surgery. Glucagon was secreted in response to the MMT preoperatively and postoperatively in all patients and there was no significant change in this postprandial secretion. There was no significant change in GIP secretion. CONCLUSIONS There is a clear difference in the dynamics of secretion of proglucagon peptides after RYGB. The reduction in fasting glucagon secretion may be one of the mechanisms driving later improvements in glycemia after RYGB. TRIAL REGISTRATION NUMBER NCT01945840.
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Affiliation(s)
- Kleopatra Alexiadou
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Joyceline Cuenco
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - James Howard
- Drug Development Solutions, LGC Bioscience, Fordham, Cambridgeshire, UK
| | - Nicolai Jacob Wewer Albrechtsen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
- NNF Center for Protein Research, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - Ibiyemi Ilesanmi
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Anna Kamocka
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - George Tharakan
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Preeshila Behary
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Paul R Bech
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Ahmed R Ahmed
- Department of Surgery and Cancer, Imperial College London, London, UK
| | | | - Robert Wheller
- Drug Development Solutions, LGC Bioscience, Fordham, Cambridgeshire, UK
| | - Matthieu Fleuret
- Drug Development Solutions, LGC Bioscience, Fordham, Cambridgeshire, UK
| | - Jens Juul Holst
- Department of Biomedical Sciences and the NNF Center for Basic Metabolic Research, University of Copenhagen Panum Institute, Copenhagen, Denmark
| | - Stephen R Bloom
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Bernard Khoo
- Division of Medicine, University College London, London, UK
| | - Tricia M-M Tan
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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Sarnobat D, Moffett RC, Gault VA, Tanday N, Reimann F, Gribble FM, Flatt PR, Irwin N. Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic Glu CreERT2;ROSA26-eYFP mice. Peptides 2020; 125:170205. [PMID: 31738969 PMCID: PMC7212078 DOI: 10.1016/j.peptides.2019.170205] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/08/2019] [Accepted: 11/13/2019] [Indexed: 02/08/2023]
Abstract
Enzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancreatic effects are associated with alpha- to beta-cell transdifferentiation. Twice-daily administration of (D-Ala2)GIP, xenin-25[Lys13PAL] or (D-Ser2)-Oxm[Lys38PAL] for 10 days to streptozotocin (STZ)-induced diabetic mice did not affect body weight, food intake or blood glucose levels, but (D-Ser2)-Oxm[Lys38PAL] reduced (P < 0.05 to P < 0.001) fluid intake and circulating glucagon. (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] also augmented (P < 0.05 and P < 0.01, respectively) pancreatic insulin content. Detrimental changes of pancreatic morphology induced by STZ in GluCreERT2;ROSA26-eYFP mice were partially reversed by all treatment interventions. This was associated with reduced (P < 0.05) apoptosis and increased (P < 0.05 to P < 0.01) proliferation of beta-cells, alongside opposing effects on alpha-cells, with (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] being particularly effective in this regard. Alpha-cell lineage tracing revealed that induction of diabetes was accompanied by increased (P < 0.01) transdifferentiation of glucagon positive alpha-cells to insulin positive beta-cells. This islet cell transitioning process was augmented (P < 0.01 and P < 0.001, respectively) by (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL]. (D-Ser2)-Oxm[Lys38PAL] also significantly (P < 0.05) promoted loss of alpha-cell identity in favour of other endocrine islet cells. These data highlight intra-islet benefits of (D-Ala2)GIP, xenin-25[Lys13PAL] and (D-Ser2)-Oxm[Lys38PAL] in diabetes with beta-cell loss induced by STZ. The effects appear to be independent of glycaemic change, and associated with alpha- to beta-cell transdifferentiation for the GIP and Oxm analogues.
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Affiliation(s)
- Dipak Sarnobat
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - R Charlotte Moffett
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - Victor A Gault
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - Neil Tanday
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - Frank Reimann
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Fiona M Gribble
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Peter R Flatt
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - Nigel Irwin
- SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK.
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Wang ZJ, Han YF, Zhao F, Yang GZ, Yuan L, Cai HY, Yang JT, Holscher C, Qi JS, Wu MN. A dual GLP-1 and Gcg receptor agonist rescues spatial memory and synaptic plasticity in APP/PS1 transgenic mice. Horm Behav 2020; 118:104640. [PMID: 31765661 DOI: 10.1016/j.yhbeh.2019.104640] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 11/16/2019] [Accepted: 11/16/2019] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Aβ1-42-induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Aβ plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3β levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Aβ and normalization of PI3K/AKT/GSK3β cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD.
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Affiliation(s)
- Zhao-Jun Wang
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China
| | - Yu-Fei Han
- Guangzhou Kingmed Diagnostics, Guangzhou, PR China
| | - Fang Zhao
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China
| | - Guang-Zhao Yang
- Department of Cardiovascular Medicine, The First Hospital of Shanxi Medical University, Taiyuan, PR China
| | - Li Yuan
- Department of Physiology, Changzhi Medical College, Changzhi, PR China
| | - Hong-Yan Cai
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, PR China
| | - Jun-Ting Yang
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China
| | - Christian Holscher
- Neuroscience research group, Henan university of Chinese medicine, Zhengzhou, PR China
| | - Jin-Shun Qi
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China.
| | - Mei-Na Wu
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, PR China.
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Cai X, Li C, Zhou J, Dai Y, Avraham Y, Sun L, Liu C, Tong J, Wang Y, Bi X, He L, Huang W, Qian H. Novel glucagon- and OXM-based peptides acting through glucagon and GLP-1 receptors with body weight reduction and anti-diabetic properties. Bioorg Chem 2020; 95:103538. [DOI: 10.1016/j.bioorg.2019.103538] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 12/05/2019] [Accepted: 12/21/2019] [Indexed: 12/31/2022]
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Kokkinos A, Tsilingiris D, le Roux CW, Rubino F, Mantzoros CS. Will medications that mimic gut hormones or target their receptors eventually replace bariatric surgery? Metabolism 2019; 100:153960. [PMID: 31412266 DOI: 10.1016/j.metabol.2019.153960] [Citation(s) in RCA: 18] [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: 06/13/2019] [Revised: 07/31/2019] [Accepted: 08/05/2019] [Indexed: 02/07/2023]
Abstract
Bariatric surgery is currently the most effective therapeutic modality through which sustained beneficial effects on weight loss and metabolic improvement are achieved. During recent years, indications for bariatric surgery have been expanded to include cases of poorly controlled type 2 (T2DM) diabetes mellitus in lesser extremes of body weight. A spectrum of the beneficial effects of surgery is attributed to robust changes of postprandial gut peptide responses that are observed post operatively. Consolidated knowledge regarding gut peptide physiology as well as emerging new evidence shedding light on the mode of action of previously overlooked gut hormones provide appealing potential obesity and T2DM therapeutic perspectives. The accumulation of evidence from the effect of exogenous administration of native gut peptides alone or in combinations to humans as well as the development of mimetic agents exerting agonistic effects on combinations of gut hormone receptors pave the way for future integrated gut peptide-based treatments, which may mimic the effects of bariatric surgery.
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Affiliation(s)
- Alexander Kokkinos
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.
| | - Dimitrios Tsilingiris
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Carel W le Roux
- Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland
| | - Francesco Rubino
- Department of Metabolic and Bariatric Surgery, Diabetes and Nutritional Science Division, King's College Hospital, London, United Kingdom
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, USA
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Lundqvist MH, Almby K, Abrahamsson N, Eriksson JW. Is the Brain a Key Player in Glucose Regulation and Development of Type 2 Diabetes? Front Physiol 2019; 10:457. [PMID: 31133864 PMCID: PMC6524713 DOI: 10.3389/fphys.2019.00457] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 04/01/2019] [Indexed: 01/08/2023] Open
Abstract
Ever since Claude Bernards discovery in the mid 19th-century that a lesion in the floor of the third ventricle in dogs led to altered systemic glucose levels, a role of the CNS in whole-body glucose regulation has been acknowledged. However, this finding was later overshadowed by the isolation of pancreatic hormones in the 20th century. Since then, the understanding of glucose homeostasis and pathology has primarily evolved around peripheral mechanism. Due to scientific advances over these last few decades, however, increasing attention has been given to the possibility of the brain as a key player in glucose regulation and the pathogenesis of metabolic disorders such as type 2 diabetes. Studies of animals have enabled detailed neuroanatomical mapping of CNS structures involved in glucose regulation and key neuronal circuits and intracellular pathways have been identified. Furthermore, the development of neuroimaging techniques has provided methods to measure changes of activity in specific CNS regions upon diverse metabolic challenges in humans. In this narrative review, we discuss the available evidence on the topic. We conclude that there is much evidence in favor of active CNS involvement in glucose homeostasis but the relative importance of central vs. peripheral mechanisms remains to be elucidated. An increased understanding of this field may lead to new CNS-focusing pharmacologic strategies in the treatment of type 2 diabetes.
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Affiliation(s)
| | - Kristina Almby
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Jan W Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, Einig C, Keil S, Haack T, Wagner M, Bossart M, Larsen PJ. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials. Diabetes Obes Metab 2019; 21:120-128. [PMID: 30091218 DOI: 10.1111/dom.13494] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 07/27/2018] [Accepted: 08/05/2018] [Indexed: 12/11/2022]
Abstract
AIMS To evaluate the safety, pharmacokinetics and pharmacodynamics of SAR425899, a novel polypeptide, active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCR), in healthy volunteers and in overweight/obese patients with type 2 diabetes (T2D). METHODS Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (body mass index [BMI] 25-30 kg/m2 ; n = 32) received single-ascending doses (0.01-0.1 mg) of SAR425899 or placebo. In the second, a multiple-ascending-dose trial (NCT02411825), healthy normal- to overweight volunteers (BMI 20-30 kg/m2 ; n = 40) and overweight/obese patients with T2D (BMI 28-42 kg/m2 ; n = 36) received daily doses of SAR425899 or placebo over 21 or 28 days, respectively. RESULTS The most frequently reported adverse events were gastrointestinal; gastrointestinal side effects were less pronounced in patients with T2D compared with healthy volunteers. SAR425899 significantly reduced levels of fasting plasma glucose (P < 0.05 vs. placebo) and glycated haemoglobin (P < 0.001 versus placebo) in patients with T2D. Additionally, SAR425899 led to reductions in body weight, with a maximal reduction of 5.32 kg in healthy volunteers and 5.46 kg in patients with T2D (P < 0.001 vs. placebo) at end of treatment. CONCLUSIONS SAR425899 was well tolerated and led to favourable glycaemic effects in patients with T2D and weight reduction in both healthy volunteers and patients. Whether dual GLP-1R/GCR agonism represents a treatment method that is superior to pure GLP-1R agonists for obesity and diabetes treatment remains to be confirmed.
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Affiliation(s)
| | | | - Frank Wagner
- Charité Research Organisation GmbH, Berlin, Germany
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Patel VJ, Joharapurkar AA, Kshirsagar SG, Sutariya BK, Patel MS, Bahekar RH, Jain MR. Activation of GLP-1 and Glucagon Receptors Regulates Bile Homeostasis Independent of Thyroid Hormone. Curr Mol Pharmacol 2019; 12:139-146. [PMID: 30747091 DOI: 10.2174/1874467212666190212112402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 01/04/2019] [Accepted: 01/19/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism. METHODS We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH). RESULTS Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH. CONCLUSION Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.
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Affiliation(s)
- Vishal J Patel
- Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India
| | - Amit A Joharapurkar
- Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India
| | - Samadhan G Kshirsagar
- Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India
| | - Brijesh K Sutariya
- Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India
| | - Maulik S Patel
- Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India
| | - Rajesh H Bahekar
- Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India
| | - Mukul R Jain
- Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India
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45
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Graham GV, Conlon JM, Abdel-Wahab YH, Flatt PR. Glucagon-related peptides from phylogenetically ancient fish reveal new approaches to the development of dual GCGR and GLP1R agonists for type 2 diabetes therapy. Peptides 2018; 110:19-29. [PMID: 30391422 DOI: 10.1016/j.peptides.2018.10.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/29/2018] [Accepted: 10/30/2018] [Indexed: 12/11/2022]
Abstract
The insulinotropic and antihyperglycaemic properties of glucagons from the sea lamprey (Petromyzontiformes), paddlefish (Acipenseriformes) and trout (Teleostei) and oxyntomodulin from dogfish (Elasmobranchii) and ratfish (Holocephali) were compared with those of human glucagon and GLP-1 in mammalian test systems. All fish peptides produced concentration-dependent stimulation of insulin release from BRIN-BD11 rat and 1.1 B4 human clonal β-cells and isolated mouse islets. Paddlefish glucagon was the most potent and effective peptide. The insulinotropic activity of paddlefish glucagon was significantly (P < 0.01) decreased after incubating BRIN-BD11 cells with the GLP1R antagonist, exendin-4(9-39) and the GCGR antagonist [des-His1,Pro4, Glu9] glucagon amide but GIPR antagonist, GIP(6-30)Cex-K40[palmitate] was without effect. Paddlefish and lamprey glucagons and dogfish oxyntomodulin (10 nmol L-1) produced significant (P < 0.01) increases in cAMP concentration in Chinese hamster lung (CHL) cells transfected with GLP1R and human embryonic kidney (HEK293) cells transfected with GCGR. The insulinotropic activity of paddlefish glucagon was attenuated in CRISPR/Cas9-engineered GLP1R knock-out INS-1 cells but not in GIPR knock-out cells. Intraperitoneal administration of all fish peptides, except ratfish oxyntomodulin, to mice together with a glucose load produced significant (P < 0.05) decreases in plasma glucose concentrations and paddlefish glucagon produced a greater release of insulin compared with GLP-1. Paddlefish glucagon shares the sequences Glu15-Glu16 and Glu24-Trp25-Leu26-Lys27-Asn28-Gly29 with the potent GLP1R agonist, exendin-4 so may be regarded as a naturally occurring, dual-agonist hybrid peptide that may serve as a template design of new drugs for type 2 diabetes therapy.
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Affiliation(s)
- Galyna V Graham
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK
| | - J Michael Conlon
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK.
| | - Yasser H Abdel-Wahab
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK
| | - Peter R Flatt
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK
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Fothergill LJ, Ringuet MT, Sioras E, Hunne B, Fazio Coles TE, Martins PR, Furness JB. Cellular and sub-cellular localisation of oxyntomodulin-like immunoreactivity in enteroendocrine cells of human, mouse, pig and rat. Cell Tissue Res 2018; 375:359-369. [DOI: 10.1007/s00441-018-2921-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 09/05/2018] [Indexed: 11/29/2022]
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Elvert R, Herling AW, Bossart M, Weiss T, Zhang B, Wenski P, Wandschneider J, Kleutsch S, Butty U, Kannt A, Wagner M, Haack T, Evers A, Dudda A, Lorenz M, Keil S, Larsen PJ. Running on mixed fuel-dual agonistic approach of GLP-1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non-human primates. Diabetes Obes Metab 2018; 20:1836-1851. [PMID: 29938884 PMCID: PMC6055720 DOI: 10.1111/dom.13212] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 12/11/2017] [Accepted: 12/25/2017] [Indexed: 12/17/2022]
Abstract
AIM We performed acute and chronic studies in healthy and diet-induced obese animals using mouse-specific or monkey-specific dual GLP-1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP-1R agonist liraglutide was used as comparator. METHODS The mouse-specific dual agonist and liraglutide were tested in lean wild type, GLP-1R knockout and diet-induced obese mice at different doses. A chronic study was performed in DIO mice to investigate the effect on body weight, food consumption and total energy expenditure (TEE) in obese and diabetic monkeys with a focus on body weight and energy intake. RESULTS The mouse-specific dual agonist and liraglutide similarly affected glycaemic control. A higher loss in body weight was measured in dual agonist-treated obese mice. The dual agonist significantly enhanced plasma glucose excursion in overnight fed GLP-1R-/- mice, probably reflecting a potent GCGR agonist activity. It increased TEE and enhanced fat and carbohydrate oxidation, while liraglutide produced no effect on TEE. In obese and diabetic monkeys, treatment with the monkey-specific dual agonist reduced total energy intake to 60%-70% of baseline TEI during chronic treatment. A decrease in body weight and significant improvement in glucose tolerance was observed. CONCLUSIONS In DIO mice and non-human primates, dual agonists elicited robust glycaemic control, similar to the marketed GLP-1R agonist, while eliciting greater effects on body weight. Results from DIO mice suggest that the increase in TEE is caused not only by increased fat oxidation but also by an increase in carbohydrate oxidation.
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MESH Headings
- Animals
- Animals, Outbred Strains
- Appetite Depressants/administration & dosage
- Appetite Depressants/adverse effects
- Appetite Depressants/therapeutic use
- Body Weight/drug effects
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Diet, High-Fat/adverse effects
- Dose-Response Relationship, Drug
- Drug Therapy, Combination/adverse effects
- Energy Intake/drug effects
- Energy Metabolism/drug effects
- Female
- Glucagon-Like Peptide-1 Receptor/agonists
- Glucagon-Like Peptide-1 Receptor/genetics
- Glucagon-Like Peptide-1 Receptor/metabolism
- Hyperglycemia/prevention & control
- Hypoglycemic Agents/administration & dosage
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/therapeutic use
- Insulin Secretion/drug effects
- Macaca fascicularis
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Obesity/blood
- Obesity/drug therapy
- Obesity/etiology
- Obesity/metabolism
- Random Allocation
- Receptors, Glucagon/agonists
- Receptors, Glucagon/metabolism
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Affiliation(s)
- Ralf Elvert
- Sanofi‐Aventis Deutschland GmbHFrankfurtGermany
| | | | | | - Tilo Weiss
- Sanofi‐Aventis Deutschland GmbHFrankfurtGermany
| | | | | | | | | | - Uwe Butty
- Sanofi‐Aventis Deutschland GmbHFrankfurtGermany
| | - Aimo Kannt
- Sanofi‐Aventis Deutschland GmbHFrankfurtGermany
- Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
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Shankar SS, Shankar RR, Mixson LA, Miller DL, Pramanik B, O'Dowd AK, Williams DM, Frederick CB, Beals CR, Stoch SA, Steinberg HO, Kelley DE. Native Oxyntomodulin Has Significant Glucoregulatory Effects Independent of Weight Loss in Obese Humans With and Without Type 2 Diabetes. Diabetes 2018; 67:1105-1112. [PMID: 29545266 DOI: 10.2337/db17-1331] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 03/06/2018] [Indexed: 12/20/2022]
Abstract
Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of β-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.
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Rives ML, Rady B, Swanson N, Zhao S, Qi J, Arnoult E, Bakaj I, Mancini A, Breton B, Lee SP, Player MR, Pocai A. GPR40-Mediated G α12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets. Mol Pharmacol 2018; 93:581-591. [PMID: 29572336 DOI: 10.1124/mol.117.111369] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 03/20/2018] [Indexed: 12/25/2022] Open
Abstract
GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models. Full agonists bind to a distinct binding site, suggesting conformational plasticity and a potential for biased agonism. Indeed, it has been suggested that alternative pharmacology may be required for meaningful efficacy. In this study, we described the discovery and characterization of Compound A, a newly identified GPR40 allosteric full agonist highly efficacious in human islets at potentiating glucose-stimulated insulin secretion. We compared Compound A-induced GPR40 activity to that induced by both fasiglifam and AM-1638, another allosteric full agonist previously reported to be highly efficacious in preclinical models, at a panel of G proteins. Compound A was a full agonist at both the Gαq and Gαi2 pathways, and in contrast to fasiglifam Compound A also induced Gα12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The Gα12/Gα13-mediated signaling pathway has been linked to protein kinase D activation as well as actin remodeling, well known to contribute to the release of insulin vesicles. Our data suggest that the pharmacology of GPR40 is complex and that Gα12/Gα13-mediated signaling, which may contribute to GPR40 agonists therapeutic efficacy, is a specific property of GPR40 allosteric full agonists.
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Affiliation(s)
- Marie-Laure Rives
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Brian Rady
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Nadia Swanson
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Shuyuan Zhao
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Jenson Qi
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Eric Arnoult
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Ivona Bakaj
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Arturo Mancini
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Billy Breton
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - S Paul Lee
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Mark R Player
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
| | - Alessandro Pocai
- Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)
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50
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Cheang JY, Moyle PM. Glucagon-Like Peptide-1 (GLP-1)-Based Therapeutics: Current Status and Future Opportunities beyond Type 2 Diabetes. ChemMedChem 2018; 13:662-671. [PMID: 29430842 DOI: 10.1002/cmdc.201700781] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 02/07/2018] [Indexed: 12/21/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells following food intake, and plays an important role in glucose homeostasis due to its stimulation of glucose-dependent insulin secretion. Further, GLP-1 is also associated with protective effects on pancreatic β-cells and the cardiovascular system, decreased appetite, and weight loss, making GLP-1 derivatives an exciting treatment for type 2 diabetes and obesity. Despite these benefits, wild-type GLP-1 exhibits a short circulation time due to its poor metabolic stability and rapid renal clearance, and must be administered by injection, making it a poor therapeutic agent. Many strategies have been used to improve the circulation time of GLP-1 (e.g., mutations, unnatural amino acids, depot formulations, use of exendin-4 sequences, and fusions with high-molecular-weight proteins or polymers), with its therapeutic utility further improved by adding agonist activity for gastric inhibitory peptide and glucagon receptors. This minireview focuses on strategies that have been used to improve the pharmacokinetics of GLP-1 and provides an overview of GLP-1-based therapeutics in the pipeline.
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Affiliation(s)
- Jia Ying Cheang
- School of Pharmacy, The University of Queensland, Woolloongabba, 4102, QLD, Australia
| | - Peter M Moyle
- School of Pharmacy, The University of Queensland, Woolloongabba, 4102, QLD, Australia
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