|
1
|
Müller TD, Adriaenssens A, Ahrén B, Blüher M, Birkenfeld AL, Campbell JE, Coghlan MP, D'Alessio D, Deacon CF, DelPrato S, Douros JD, Drucker DJ, Figueredo Burgos NS, Flatt PR, Finan B, Gimeno RE, Gribble FM, Hayes MR, Hölscher C, Holst JJ, Knerr PJ, Knop FK, Kusminski CM, Liskiewicz A, Mabilleau G, Mowery SA, Nauck MA, Novikoff A, Reimann F, Roberts AG, Rosenkilde MM, Samms RJ, Scherer PE, Seeley RJ, Sloop KW, Wolfrum C, Wootten D, DiMarchi RD, Tschöp MH. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab 2025; 95:102118. [PMID: 40024571 PMCID: PMC11931254 DOI: 10.1016/j.molmet.2025.102118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. MAJOR CONCLUSIONS Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.
Collapse
Affiliation(s)
- Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany.
| | - Alice Adriaenssens
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Bo Ahrén
- Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
| | - Matthias Blüher
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Matthew P Coghlan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - David D'Alessio
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Carolyn F Deacon
- School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano DelPrato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | | | - Daniel J Drucker
- The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Natalie S Figueredo Burgos
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Brian Finan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Fiona M Gribble
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christian Hölscher
- Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Patrick J Knerr
- Indianapolis Biosciences Research Institute, Indianapolis, IN, USA
| | - Filip K Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christine M Kusminski
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arkadiusz Liskiewicz
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France
| | | | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany
| | - Frank Reimann
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Anna G Roberts
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Ricardo J Samms
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Philip E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kyle W Sloop
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland
| | - Denise Wootten
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | | | - Matthias H Tschöp
- Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
| |
Collapse
|
|
2
|
Zhou C, Gong B, Liu X, Hu G, Sun L. Glucose-dependent insulinotropic peptide and beyond: co-agonist innovations in the treatment of metabolic diseases. Eur J Pharmacol 2025; 999:177681. [PMID: 40306536 DOI: 10.1016/j.ejphar.2025.177681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 04/12/2025] [Accepted: 04/24/2025] [Indexed: 05/02/2025]
Abstract
Glucose-dependent insulinotropic peptide (GIP), a key incretin hormone, has emerged as a pivotal therapeutic target in metabolic disorders. Historically, its therapeutic potential in type 2 diabetes mellitus (T2DM) has been underestimated owing to GIP resistance and its limited acute effects on glycemic control and body weight regulation. However, emerging evidence has demonstrated that GIP resistance is reversible through sustained glycemic improvement, thereby restoring its physiological effectiveness. With the development of gut hormone co-agonists, the potential of GIP in the treatment of metabolic diseases has been reevaluated. The study of GIP and its co-agonists such as glucagon-like peptide-1 (GLP-1), revealed that its mechanism of action in regulating blood glucose, fat metabolism, and bone metabolism is complex and diverse. A better understanding of GIP evolution can help in designing more effective GIP-based treatment strategies. In this review, we summarize the physiological functions of GIP, systematically explores its diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects of GIP analogs.
Collapse
Affiliation(s)
- Chenxu Zhou
- College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Binbin Gong
- College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Xiyu Liu
- College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Guoqiang Hu
- Taizhou Hospital, Zhejiang University, Taizhou, 317000, China
| | - Lidan Sun
- College of Medicine, Jiaxing University, Jiaxing, 314001, China; Taizhou Hospital, Zhejiang University, Taizhou, 317000, China.
| |
Collapse
|
|
3
|
Melson E, Ashraf U, Papamargaritis D, Davies MJ. What is the pipeline for future medications for obesity? Int J Obes (Lond) 2025; 49:433-451. [PMID: 38302593 PMCID: PMC11971045 DOI: 10.1038/s41366-024-01473-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/12/2024] [Accepted: 01/15/2024] [Indexed: 02/03/2024]
Abstract
Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.
Collapse
Affiliation(s)
- Eka Melson
- Diabetes Research Centre, University of Leicester College of Life Sciences, Leicester, UK
| | - Uzma Ashraf
- Diabetes Research Centre, University of Leicester College of Life Sciences, Leicester, UK
| | - Dimitris Papamargaritis
- Diabetes Research Centre, University of Leicester College of Life Sciences, Leicester, UK.
- Leicester Diabetes Centre, Leicester General Hospital, Leicester, LE5 4PW, UK.
- Department of Diabetes and Endocrinology, Kettering General Hospital NHS Foundation Trust, Kettering, NN16 8UZ, UK.
| | - Melanie J Davies
- Diabetes Research Centre, University of Leicester College of Life Sciences, Leicester, UK
- Leicester Diabetes Centre, Leicester General Hospital, Leicester, LE5 4PW, UK
| |
Collapse
|
|
4
|
Hamza M, Papamargaritis D, Davies MJ. Tirzepatide for overweight and obesity management. Expert Opin Pharmacother 2025; 26:31-49. [PMID: 39632534 DOI: 10.1080/14656566.2024.2436595] [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: 09/27/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION Tirzepatide is a once-weekly dual agonist, acting on glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. It is approved at the same doses (5, 10 and 15 mg) for both type 2 diabetes (T2D) and chronic weight management. AREAS COVERED Following a search in PubMed, clinicaltrials.gov, conference abstracts and Lilly website, we review herein the global phase 3 SURMOUNT program on tirzepatide's safety and efficacy for chronic weight management. Additionally, we discuss findings from the regional SURMOUNT-CN and SURMOUNT-J trials (in East-Asian populations) and the phase 2 SYNERGY-NASH, phase 3 SURMOUNT-OSA and SUMMIT studies on tirzepatide's impact on obesity-related complications. We also explore the clinical implications of SURMOUNT program results, considerations for tirzepatide prescribing for overweight/obesity, ongoing research and evidence gaps. EXPERT OPINION Tirzepatide marks a new era in overweight/obesity treatment, enabling many to achieve ≥ 20% weight loss. It is well-tolerated with a safety profile similar to GLP-1 receptor agonists. Tirzepatide also results in clinically important improvements in multiple obesity-related complications including sleep apnea, metabolic-dysfunction associated steatohepatitis, heart failure with preserved ejection fraction and diabetes prevention. Ongoing trials will provide further data on tirzepatide's long-term safety, efficacy (including cardiovascular outcomes) and potential cost-effectiveness for managing overweight/obesity and/or T2D.
Collapse
Affiliation(s)
- Malak Hamza
- Diabetes Research Centre, University of Leicester, Leicester, UK
- Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Dimitris Papamargaritis
- Diabetes Research Centre, University of Leicester, Leicester, UK
- Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
- Department of Diabetes and Endocrinology, Kettering General Hospital NHS Trust, Kettering, UK
| | - Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, UK
- Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
| |
Collapse
|
|
5
|
Rabbani SA, El-Tanani M, Matalka II, Rangraze IR, Aljabali AAA, Khan MA, Tambuwala MM. Tirzepatide: unveiling a new dawn in dual-targeted diabetes and obesity management. Expert Rev Endocrinol Metab 2024; 19:487-505. [PMID: 39194153 DOI: 10.1080/17446651.2024.2395540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION Incretin-based therapies have emerged as effective treatments for type 2 diabetes (T2D) and obesity. However, not all patients achieve optimal outcomes with existing treatments, highlighting the need for more effective solutions. AREAS COVERED We present a comprehensive evaluation of Tirzepatide (TZP), a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonist, for managing obesity and T2D. We conducted a systematic search of Cochrane, PubMed, Scopus, and Web of Science databases from inception to April 2024. The focus of the review is on the development and therapeutic potential of TZP, with detailed exploration on pharmacodynamics, pharmacokinetics, clinical efficacy, and safety. Furthermore, it reviews TZP's impacts on glycemic control, weight management, and its potential cardiovascular (CV) benefits. EXPERT OPINION TZP represents a significant advancement in the dual-targeted approach to treating T2D and obesity. Its unique mechanism of action offers superior efficacy in reducing glycemic levels and body weight compared to existing therapies. New data suggesting improvements in CV outcomes indicate that TZP could set a new standard in the treatment paradigm. While long-term data on efficacy and safety are still forthcoming, current evidence positions TZP as a promising option for patients who have not reached their therapeutic goals with existing treatments.
Collapse
Affiliation(s)
- Syed Arman Rabbani
- RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Mohamed El-Tanani
- RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Ismail I Matalka
- RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
- Department of Pathology and Microbiology, Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Imran Rashid Rangraze
- Internal Medicine Department, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Alaa A A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | | |
Collapse
|
|
6
|
Tanday N, Zhu W, Tarasov AI, Flatt PR, Irwin N. [P 3]PP, a stable, long-acting pancreatic polypeptide analogue, evokes weight lowering and pancreatic beta-cell-protective effects in obesity-associated diabetes. Diabetes Obes Metab 2024; 26:4945-4957. [PMID: 39192525 DOI: 10.1111/dom.15897] [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: 06/21/2024] [Revised: 08/07/2024] [Accepted: 08/07/2024] [Indexed: 08/29/2024]
Abstract
AIM To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesity-associated diabetes. METHODS Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to high-fat-fed mice with streptozotocin-induced insulin deficiency, known as HFF/STZ mice. RESULTS Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PP-treated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucose-stimulated insulin secretion were improved in [P3]PP-treated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and beta-cell areas. Positive effects on islet architecture were linked to increased beta-cell proliferation and decreased apoptosis. Treatment intervention also decreased islet alpha-cell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PP-treated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. CONCLUSION Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes.
Collapse
Affiliation(s)
- Neil Tanday
- Diabetes Research Centre, Ulster University, Coleraine, UK
| | - Wuyun Zhu
- Diabetes Research Centre, Ulster University, Coleraine, UK
| | | | - Peter R Flatt
- Diabetes Research Centre, Ulster University, Coleraine, UK
| | - Nigel Irwin
- Diabetes Research Centre, Ulster University, Coleraine, UK
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Corrao S, Pollicino C, Maggio D, Torres A, Argano C. Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence. Front Endocrinol (Lausanne) 2024; 15:1402583. [PMID: 38978621 PMCID: PMC11228148 DOI: 10.3389/fendo.2024.1402583] [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: 03/17/2024] [Accepted: 06/07/2024] [Indexed: 07/10/2024] Open
Abstract
Obesity is a chronic, multifactorial disease in which accumulated excess body fat has a negative impact on health. Obesity continues to rise among the general population, resulting in an epidemic that shows no significant signs of decline. It is directly involved in development of cardiometabolic diseases, ischemic coronary heart disease peripheral arterial disease, heart failure, and arterial hypertension, producing global morbidity and mortality. Mainly, abdominal obesity represents a crucial factor for cardiovascular illness and also the most frequent component of metabolic syndrome. Recent evidence showed that Tirzepatide (TZP), a new drug including both Glucagon Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) receptor agonism, is effective in subjects with type 2 diabetes (T2D), lowering body weight, fat mass and glycated hemoglobin (HbA1c) also in obese or overweight adults without T2D. This review discusses the pathophysiological mechanisms and clinical aspects of TZP in treating obesity.
Collapse
Affiliation(s)
- Salvatore Corrao
- Department of Clinical Medicine, Internal Medicine Unit, National Relevance and High Specialization Hospital Trust Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico, Di Cristina, Benfratelli, Palermo, Italy
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties. Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy
| | - Chiara Pollicino
- Department of Clinical Medicine, Internal Medicine Unit, National Relevance and High Specialization Hospital Trust Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico, Di Cristina, Benfratelli, Palermo, Italy
| | - Dalila Maggio
- Department of Clinical Medicine, Internal Medicine Unit, National Relevance and High Specialization Hospital Trust Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico, Di Cristina, Benfratelli, Palermo, Italy
| | - Alessandra Torres
- Department of Clinical Medicine, Internal Medicine Unit, National Relevance and High Specialization Hospital Trust Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico, Di Cristina, Benfratelli, Palermo, Italy
| | - Christiano Argano
- Department of Clinical Medicine, Internal Medicine Unit, National Relevance and High Specialization Hospital Trust Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico, Di Cristina, Benfratelli, Palermo, Italy
| |
Collapse
|
|
9
|
Gogineni P, Melson E, Papamargaritis D, Davies M. Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now? Expert Opin Pharmacother 2024; 25:801-818. [PMID: 38753454 PMCID: PMC11195668 DOI: 10.1080/14656566.2024.2356254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/13/2024] [Indexed: 05/18/2024]
Abstract
INTRODUCTION Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. AREAS COVERED Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. EXPERT OPINION We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in ≥15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.
Collapse
Affiliation(s)
- Prathima Gogineni
- Diabetes Research Centre, University of Leicester College of Life Sciences, Leicester, UK
| | - Eka Melson
- Diabetes Research Centre, University of Leicester College of Life Sciences, Leicester, UK
| | | | - Melanie Davies
- Diabetes Research Centre, University of Leicester College of Life Sciences, Leicester, UK
| |
Collapse
|
|
10
|
Xia X, Lin Q, Zhou Z, Chen Y. An imbalanced GLP-1R/GIPR co-agonist peptide with a site-specific N-terminal PEGylation to maximize metabolic benefits. iScience 2024; 27:109377. [PMID: 38510128 PMCID: PMC10951637 DOI: 10.1016/j.isci.2024.109377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/18/2024] [Accepted: 02/27/2024] [Indexed: 03/22/2024] Open
Abstract
Glycemic and body weight control gained from GLP-1R agonists remains an unmet need for diabetes and obesity treatment, leading to the development of GLP-1R/GIPR co-agonists. An imbalance in GLP-1R/GIPR agonism may extensively maximize the glucose- and weight-lowering effects. Hence, we prepared a potent and imbalanced GLP-1R/GIPR co-agonist, and refined its action time through a site-specific N-terminal PEGylation strategy. The pharmacological efficacy of these resulting long-acting co-agonists was interrogated both in vitro and in vivo. The results showed that peptide 1 possessed potent and imbalanced receptor-stimulating potency favoring GIP activity, but its hypoglycemic action was disrupted probably resulting from its short half-life. After PEGylation to improve the pharmacokinetics, the pharmacological effects were amplified compared to native peptide 1. Among the resulting derivatives, D-5K exhibited significant glycemic, HbA1c, body-weight, and food-intake control, outperforming GLP-1R mono-agonists. Based on its excellent pharmacological profiles, D-5K may hold the great therapeutic potential for diabetes and obesity treatment.
Collapse
Affiliation(s)
- Xuan Xia
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Qianmeng Lin
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhan Zhou
- Research Center for Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| |
Collapse
|
|
11
|
Bailey CJ, Flatt PR. Duodenal enteroendocrine cells and GIP as treatment targets for obesity and type 2 diabetes. Peptides 2024; 174:171168. [PMID: 38320643 DOI: 10.1016/j.peptides.2024.171168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 02/02/2024] [Accepted: 02/02/2024] [Indexed: 02/08/2024]
Abstract
The duodenum is an important source of endocrine and paracrine signals controlling digestion and nutrient disposition, notably including the main incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Bariatric procedures that prevent nutrients from contact with the duodenal mucosa are particularly effective interventions to reduce body weight and improve glycaemic control in obesity and type 2 diabetes. These procedures take advantage of increased nutrient delivery to more distal regions of the intestine which enhances secretion of the other incretin hormone glucagon-like peptide-1 (GLP-1). Preclinical experiments have shown that either an increase or a decrease in the secretion or action of GIP can decrease body weight and blood glucose in obesity and non-insulin dependent hyperglycaemia, but clinical studies involving administration of GIP have been inconclusive. However, a synthetic dual agonist peptide (tirzepatide) that exerts agonism at receptors for GIP and GLP-1 has produced marked weight-lowering and glucose-lowering effects in people with obesity and type 2 diabetes. This appears to result from chronic biased agonism in which the novel conformation of the peptide triggers enhanced signalling by the GLP-1 receptor through reduced internalisation while reducing signalling by the GIP receptor directly or via functional antagonism through increased internalisation and degradation.
Collapse
Affiliation(s)
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA Northern Ireland, UK
| |
Collapse
|
|
12
|
Jakubowska A, le Roux CW, Viljoen A. The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor - An Update. Endocrinol Metab (Seoul) 2024; 39:12-22. [PMID: 38356208 PMCID: PMC10901658 DOI: 10.3803/enm.2024.1942] [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: 01/23/2024] [Revised: 01/29/2024] [Accepted: 01/31/2024] [Indexed: 02/16/2024] Open
Abstract
Obesity is the fifth leading risk factor for global deaths with numbers continuing to increase worldwide. In the last 20 years, the emergence of pharmacological treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. The successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, followed by the synergistic combined effect of glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists achieved remarkable weight loss and glycemic control in those with the diseases of obesity and type 2 diabetes. The multiple cardiometabolic benefits include improving glycemic control, lipid profiles, blood pressure, inflammation, and hepatic steatosis. The 2023 phase 2 double-blind, randomized controlled trial evaluating a GLP-1/GIP/glucagon receptor triagonist (retatrutide) in patients with the disease of obesity reported 24.2% weight loss at 48 weeks with 12 mg retatrutide. This review evaluates the current available evidence for GLP-1 receptor agonists, dual GLP-1/GIP receptor co-agonists with a focus on GLP-1/GIP/glucagon receptor triagonists and discusses the potential future benefits and research directions.
Collapse
Affiliation(s)
| | - Carel W. le Roux
- Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland
| | - Adie Viljoen
- Borthwick Diabetes Research Centre, Lister Hospital, Stevenage, UK
| |
Collapse
|
|
13
|
Tschöp M, Nogueiras R, Ahrén B. Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy. Diabetologia 2023; 66:1796-1808. [PMID: 37209227 PMCID: PMC10474213 DOI: 10.1007/s00125-023-05929-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/27/2023] [Indexed: 05/22/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are established pharmaceutical therapies for the treatment of type 2 diabetes and obesity. They mimic the action of GLP-1 to reduce glucose levels through stimulation of insulin secretion and inhibition of glucagon secretion. They also reduce body weight by inducing satiety through central actions. The GLP-1 receptor agonists used clinically are based on exendin-4 and native GLP-1 and are available as formulations for daily or weekly s.c. or oral administration. GLP-1 receptor agonism is also achieved by inhibitors of dipeptidyl peptidase-4 (DPP-4), which prevent the inactivation of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), thereby prolonging their raised levels after meal ingestion. Other developments in GLP-1 receptor agonism include the formation of small orally available agonists and compounds with the potential to pharmaceutically stimulate GLP-1 secretion from the gut. In addition, GLP-1/glucagon and GLP-1/GIP dual receptor agonists and GLP-1/GIP/glucagon triple receptor agonists have shown the potential to reduce blood glucose levels and body weight through their effects on islets and peripheral tissues, improving beta cell function and stimulating energy expenditure. This review summarises developments in gut hormone-based therapies and presents the future outlook for their use in type 2 diabetes and obesity.
Collapse
Affiliation(s)
- Matthias Tschöp
- Institute for Diabetes and Obesity, Helmholtz Zentrum, München, Germany
| | - Ruben Nogueiras
- Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
| |
Collapse
|
|
14
|
Abstract
Obesity is a chronic disease associated with increased morbidity and mortality. Bariatric surgery can lead to sustained long-term weight loss (WL) and improvement in multiple obesity-related complications, but it is not scalable at the population level. Over the past few years, gut hormone-based pharmacotherapies for obesity and type 2 diabetes mellitus (T2DM) have rapidly evolved, and combinations of glucagon-like peptide 1 (GLP1) with other gut hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) as dual or triple agonists are under investigation to enhance and complement the effects of GLP1 on WL and obesity-related complications. Tirzepatide, a dual agonist of GLP1 and GIP receptors, marks a new era in obesity pharmacotherapy in which a combination of gut hormones could approach the WL achieved with bariatric surgery. In this review, we discuss emerging obesity treatments with a focus on gut hormone combinations and the concept of a multimodal approach for obesity management.
Collapse
Affiliation(s)
- Eka Melson
- Diabetes Research Centre, Leicester General Hospital, University of Leicester, Leicester, UK
| | | | - Dimitris Papamargaritis
- Diabetes Research Centre, Leicester General Hospital, University of Leicester, Leicester, UK; Kettering General Hospital NHS Foundation Trust, Kettering, UK.
| |
Collapse
|
|
15
|
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.
Collapse
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
| |
Collapse
|
|
16
|
Davies I, Tan TMM. Design of novel therapeutics targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss. Expert Opin Drug Discov 2023; 18:659-669. [PMID: 37154171 DOI: 10.1080/17460441.2023.2203911] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
INTRODUCTION With obesity rates growing globally, there is a paramount need for new obesity pharmacotherapies to tackle this pandemic. AREAS COVERED This review focuses on the design of therapeutics that target the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss. The authors highlight the paradoxical observation that both GIPR agonism and antagonism appear to provide metabolic benefits when combined with glucagon-like peptide-1 receptor (GLP-1 R) agonism. The therapeutic potential of compounds that target the GIPR alongside the GLP-1 R and the glucagon receptor are discussed, and the impressive clinical findings of such compounds are reviewed. EXPERT OPINION In this area, the translation of pre-clinical findings to clinical studies appears to be particularly difficult. Well-designed physiological studies in man are required to answer the paradox highlighted above, and to support the safe future development of a combination of GLP-1 R/GIPR targeting therapies.
Collapse
Affiliation(s)
- Iona Davies
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Tricia M M Tan
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| |
Collapse
|
|
17
|
Lafferty RA, Flatt PR, Irwin N. GLP-1/GIP analogues: potential impact in the landscape of obesity pharmacotherapy. Expert Opin Pharmacother 2023; 24:587-597. [PMID: 36927378 DOI: 10.1080/14656566.2023.2192865] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
INTRODUCTION : Obesity is recognised as a major healthcare challenge. Following years of slow progress in discovery of safe, effective therapies for weight management, recent approval of the glucagon-like peptide 1 receptor (GLP-1R) mimetics, liraglutide and semaglutide, for obesity has generated considerable excitement. It is anticipated these agents will pave the way for application of tirzepatide, a highly effective glucose-dependent insulinotropic polypeptide receptor (GIPR), GLP-1R co-agonist recently approved for management of type 2 diabetes mellitus. AREAS COVERED : Following promising weight loss in obese individuals in Phase III clinical trials, liraglutide and semaglutide were approved for weight management without diabetes. Tirzepatide has attained Fast Track designation for obesity management by the US Food and Drug Association. This narrative review summarises experimental, preclinical and clinical data for these agents and related GLP-1R/GIPR co-agonists, prioritising clinical research published within the last 10 years where possible. EXPERT OPINION : GLP-1R mimetics are often discontinued within 24-months, owing to gastrointestinal side-effects, meaning long-term application of these agents in obesity is questioned. Combined GIPR/GLP-1R agonism appears to induce fewer side-effects, indicating GLP-1R/GIPR co-agonists may be more suitable for enduring obesity management. After years of debate, this GIPR-biased GLP-1R/GIPR co-agonist highlights the therapeutic promise of including GIPR modulation for diabetes and obesity therapy.
Collapse
Affiliation(s)
- Ryan A Lafferty
- Diabetes Research Centre, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - Peter R Flatt
- Diabetes Research Centre, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - Nigel Irwin
- Diabetes Research Centre, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| |
Collapse
|
|
18
|
Zaffina I, Pelle MC, Armentaro G, Giofrè F, Cassano V, Sciacqua A, Arturi F. Effect of dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist on weight loss in subjects with obesity. Front Endocrinol (Lausanne) 2023; 14:1095753. [PMID: 36909312 PMCID: PMC9992880 DOI: 10.3389/fendo.2023.1095753] [Citation(s) in RCA: 6] [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: 11/11/2022] [Accepted: 02/08/2023] [Indexed: 02/24/2023] Open
Abstract
The occurrence of obesity is an increasing issue worldwide, especially in industrialized countries. Weight loss is important both to treat obesity and to prevent the development of complications. Currently, several drugs are used to treat obesity, but their efficacy is modest. Thus, new anti-obesity treatments are needed. Recently, there has been increased interest in the development of incretins that combine body-weight-lowering and glucose-lowering effects. Therefore, a new drug that simultaneously coactivates both the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R) has been developed. Tirzepatide, the first in this class, improves glycemic control by increasing insulin sensitivity and lipid metabolism as well as by reducing body weight. Combining the activation of the two receptors, greater improvement of β-cell function offers more effective treatment of diabetes and obesity with fewer adverse effects than selective GLP-1R agonists. In the present review, we discuss the progress in the use of GIPR and GLP-1R coagonists and review literature from in vitro studies, animal studies, and human trials, highlighting the synergistic mechanisms of tirzepatide.
Collapse
Affiliation(s)
- Isabella Zaffina
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Maria Chiara Pelle
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Giuseppe Armentaro
- Geriatric Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Federica Giofrè
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Velia Cassano
- Geriatric Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Angela Sciacqua
- Geriatric Unit, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Franco Arturi
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
- Research Centre for the Prevention and Treatment of Metabolic Diseases (CR METDIS), Magna Graecia University of Catanzaro, Catanzaro, Italy
- *Correspondence: Franco Arturi,
| |
Collapse
|
|
19
|
Tall Bull S, Nuffer W, Trujillo JM. Tirzepatide: A novel, first-in-class, dual GIP/GLP-1 receptor agonist. J Diabetes Complications 2022; 36:108332. [PMID: 36375235 DOI: 10.1016/j.jdiacomp.2022.108332] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/26/2022] [Accepted: 09/29/2022] [Indexed: 11/05/2022]
Abstract
The objective of this article is to review the efficacy and safety of tirzepatide and discuss its potential role in the treatment of type 2 diabetes. Tirzepatide is a novel once-weekly dual GIP and GLP-1 receptor agonist which has been studied in the SURPASS clinical trials in doses of 5 mg, 10 mg, and 15 mg. Tirzepatide phase III clinical trials, SURPASS-1 through SURPASS-5, demonstrate that this medication is safe and effective in treating type 2 diabetes both with and without a variety of background medications versus placebo, semaglutide, insulin degludec, and insulin glargine in different patient populations. Most adverse events were gastrointestinal in nature, with a relatively low withdrawal rate in the active treatment arms. It seems likely that tirzepatide will be recommended as a preferred option in the American Diabetes Association treatment algorithm for high glucose lowering effects in patients with a compelling need for low hypoglycemia risk and weight loss. However, the positioning of tirzepatide in the treatment algorithm will ultimately be dependent on the results of the cardiovascular outcomes trial (CVOT) or other outcome-based trials. Tirzepatide is effective for treating type 2 diabetes by lowering glycated hemoglobin and contributing to significant weight loss.
Collapse
Affiliation(s)
- Shasta Tall Bull
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States of America.
| | - Wesley Nuffer
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States of America
| | - Jennifer M Trujillo
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States of America
| |
Collapse
|
|
20
|
Gvazava IG, Karimova MV, Vasiliev AV, Vorotelyak EA. Type 2 Diabetes Mellitus: Pathogenic Features and Experimental Models in Rodents. Acta Naturae 2022; 14:57-68. [PMID: 36348712 PMCID: PMC9611859 DOI: 10.32607/actanaturae.11751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/19/2022] [Indexed: 11/20/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is the most common endocrine disorder (90%) in the world; it has numerous clinical, immunological, and genetic differences from type 1 diabetes mellitus. The pathogenesis of T2DM is complex and not fully clear. To date, animal models remain the main tool by which to study the pathophysiology and therapy of T2DM. Rodents are considered the best choice among animal models, because they are characterized by a small size, short induction period, easy diabetes induction, and economic efficiency. This review summarizes data on experimental models of T2DM that are currently used, evaluates their advantages and disadvantages vis-a-vis research, and describes in detail the factors that should be taken into account when using these models. Selection of a suitable model for tackling a particular issue is not always trivial; it affects study results and their interpretation.
Collapse
Affiliation(s)
- I. G. Gvazava
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
| | - M. V. Karimova
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
| | - A. V. Vasiliev
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
- Lomonosov Moscow State University, Faculty of Biology, Moscow, 119234 Russia
| | - E. A. Vorotelyak
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
- Lomonosov Moscow State University, Faculty of Biology, Moscow, 119234 Russia
| |
Collapse
|
|
21
|
Chen T, Sun T, Bian Y, Pei Y, Feng F, Chi H, Li Y, Tang X, Sang S, Du C, Chen Y, Chen Y, Sun H. The Design and Optimization of Monomeric Multitarget Peptides for the Treatment of Multifactorial Diseases. J Med Chem 2022; 65:3685-3705. [DOI: 10.1021/acs.jmedchem.1c01456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Tingkai Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| | - Tianyu Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| | - Yaoyao Bian
- College of Acupuncture and Massage, College of Regimen and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Yuqiong Pei
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Feng Feng
- Food and Pharmaceutical Research Institute, Jiangsu Food and Pharmaceuticals Science College, Huaian 223003, People’s Republic of China
| | - Heng Chi
- Food and Pharmaceutical Research Institute, Jiangsu Food and Pharmaceuticals Science College, Huaian 223003, People’s Republic of China
| | - Yuan Li
- Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceuticals Science College, Huaian 223005, People’s Republic of China
| | - Xu Tang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Shenghu Sang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Chenxi Du
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| | - Ying Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| | - Yao Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Haopeng Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| |
Collapse
|
|
22
|
Jonik S, Marchel M, Grabowski M, Opolski G, Mazurek T. Gastrointestinal Incretins-Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) beyond Pleiotropic Physiological Effects Are Involved in Pathophysiology of Atherosclerosis and Coronary Artery Disease-State of the Art. BIOLOGY 2022; 11:biology11020288. [PMID: 35205155 PMCID: PMC8869592 DOI: 10.3390/biology11020288] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 02/06/2023]
Abstract
Simple Summary The presented manuscript contains the most current and extensive summary of the role of the most predominant gastrointestinal hormones—GIP and GLP-1 in the pathophysiology of atherosclerosis and coronary artery disease both in animals and humans. We have described GIP and GLP-1 as (1) expressed in many human tissues, (2) emphasized relationship between GIP and GLP-1 and inflammation, (3) highlighted importance of GIP and GLP-1-dependent pathways in atherosclerosis and coronary artery disease and (4) proved that GIP and GLP-1 could be used as markers of incidence, clinical course and recurrence of coronary artery disease, and related to extent and severity of atherosclerosis and myocardial ischemia. Our initial review may state a cornerstone for the future, however, there are still many unknowns and understatements on this topic. Due to the widespread growing interest for the potential use of incretins in cardiovascular diseases, we think that further research in this direction is desirable. For the future, we would like to recognize GIP and GLP-1 as widely implemented into clinical practice as new biomarkers of atherosclerosis and coronary artery disease. Abstract Coronary artery disease (CAD), which is the manifestation of atherosclerosis in coronary arteries, is the most common single cause of death and is responsible for disabilities of millions of people worldwide. Despite numerous dedicated clinical studies and an enormous effort to develop diagnostic and therapeutic methods, coronary atherosclerosis remains one of the most serious medical problems of the modern world. Hence, new markers are still being sought to identify and manage CAD optimally. Trying to face this problem, we have raised the question of the most predominant gastrointestinal hormones; glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), mainly involved in carbohydrates disorders, could be also used as new markers of incidence, clinical course, and recurrence of CAD and are related to extent and severity of atherosclerosis and myocardial ischemia. We describe GIP and GLP-1 as expressed in many animal and human tissues, known to be connected to inflammation and related to enormous noncardiac and cardiovascular (CV) diseases. In animals, GIP and GLP-1 improve endothelial function and lead to reduced atherosclerotic plaque macrophage infiltration and stabilize atherosclerotic lesions by directly blocking monocyte migration. Moreover, in humans, GIPR activation induces the pro-atherosclerotic factors ET-1 (endothelin-1) and OPN (osteopontin) but also has anti-atherosclerotic effects through secretion of NO (nitric oxide). Furthermore, four large clinical trials showed a significant reduction in composite of CV death, MI, and stroke in long-term follow-up using GLP-1 analogs for DM 2 patients: liraglutide in LEADER, semaglutide in SUSTAIN-6, dulaglutide in REWIND and albiglutide in HARMONY. However, very little is known about GIP metabolism in the acute phase of myocardial ischemia or for stable patients with CAD, which constitutes a direction for future research. This review aims to comprehensively discuss the impact of GIP and GLP-1 on atherosclerosis and CAD and its potential therapeutic implications.
Collapse
|
|
23
|
Hölscher C. Protective properties of GLP-1 and associated peptide hormones in neurodegenerative disorders. Br J Pharmacol 2022; 179:695-714. [PMID: 33900631 PMCID: PMC8820183 DOI: 10.1111/bph.15508] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes mellitus and the associated desensitisation of insulin signalling has been identified as a risk factor for progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and others. Glucagon-like peptide 1 (GLP-1) is a hormone that has growth factor-like and neuroprotective properties. Several clinical trials have been conducted, testing GLP-1 receptor agonists in patients with Alzheimer's disease, Parkinson's disease or diabetes-induced memory impairments. The trials showed clear improvements in Alzheimer's disease, Parkinson's disease and diabetic patients. Glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) is the 'sister' incretin hormone of GLP-1. GIP analogues have shown neuroprotective effects in animal models of disease and can improve on the effects of GLP-1. Novel dual GLP-1/GIP receptor agonists have been developed that can enter the brain at an enhanced rate. The improved neuroprotective effects of these drugs suggest that they are superior to single GLP-1 receptor agonists and could provide disease-modifying care for Alzheimer's disease and Parkinson's disease patients. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.
Collapse
Affiliation(s)
- Christian Hölscher
- The Second Associated Hospital, Neurology DepartmentShanxi Medical UniversityTaiyuanChina
- Academy of Chinese Medical ScienceHenan University of Chinese MedicineZhengzhouChina
| |
Collapse
|
|
24
|
Pelle MC, Provenzano M, Zaffina I, Pujia R, Giofrè F, Lucà S, Andreucci M, Sciacqua A, Arturi F. Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment. Life (Basel) 2021; 12:29. [PMID: 35054422 PMCID: PMC8779403 DOI: 10.3390/life12010029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two gut hormones, defined incretins, responsible for the amplification of insulin secretion after oral glucose intake. Unlike GLP-1, GIP has little acute effect on insulin secretion and no effect on food intake; instead it seems that the GIP may be an obesity-promoting hormone. In patients with type2 diabetes mellitus (T2DM) some studies found a downregulation of GIP receptors on pancreatic β cells caused by hyperglycemic state, but the glucagonotropic effect persisted. Agonists of the receptor for the GLP-1 have proven successful for the treatment of diabetes, since they reduce the risk for cardiovascular and renal events, but the possible application of GIP as therapy for T2DM is discussed. Moreover, the latest evidence showed a synergetic effect when GIP was combined with GLP-1 in monomolecular co-agonists. In fact, compared with the separate infusion of each hormone, the combination increased both insulin response and glucagonostatic response. In accordance with theseconsiderations, a dual GIP/GLP-1receptor agonist, i.e., Tirzepatide, known as a "twincretin" had been developed. In the pre-clinical trials, as well as Phase 1-3 clinical trials, Tirzepatideshowedpotent glucose lowering and weight loss effects within an acceptable safety.
Collapse
Affiliation(s)
- Maria Chiara Pelle
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Michele Provenzano
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.P.); (M.A.)
| | - Isabella Zaffina
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Roberta Pujia
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Federica Giofrè
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Stefania Lucà
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Michele Andreucci
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.P.); (M.A.)
| | - Angela Sciacqua
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Franco Arturi
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| |
Collapse
|
|
25
|
Mráziková L, Neprašová B, Mengr A, Popelová A, Strnadová V, Holá L, Železná B, Kuneš J, Maletínská L. Lipidized Prolactin-Releasing Peptide as a New Potential Tool to Treat Obesity and Type 2 Diabetes Mellitus: Preclinical Studies in Rodent Models. Front Pharmacol 2021; 12:779962. [PMID: 34867411 PMCID: PMC8637538 DOI: 10.3389/fphar.2021.779962] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/01/2021] [Indexed: 11/13/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.
Collapse
Affiliation(s)
- Lucia Mráziková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech
| | - Barbora Neprašová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech.,Institute of Physiology, Czech Academy of Sciences, Prague, Czech
| | - Anna Mengr
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech
| | - Andrea Popelová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech
| | - Veronika Strnadová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech
| | - Lucie Holá
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech
| | - Blanka Železná
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech
| | - Jaroslav Kuneš
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech.,Institute of Physiology, Czech Academy of Sciences, Prague, Czech
| | - Lenka Maletínská
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech
| |
Collapse
|
|
26
|
Tanday N, Flatt PR, Irwin N. Amplifying the antidiabetic actions of glucagon-like peptide-1: Potential benefits of new adjunct therapies. Diabet Med 2021; 38:e14699. [PMID: 34562330 DOI: 10.1111/dme.14699] [Citation(s) in RCA: 8] [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: 07/05/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022]
Abstract
Clinically approved for the treatment of diabetes and obesity, glucagon-like peptide-1 (GLP-1) receptor agonists display prominent glucose- and weight-lowering effects as well as positive cardioprotective and neuroprotective actions. Despite these benefits, bariatric surgery remains superior in producing robust and sustained weight loss alongside improvements in metabolic control with possible diabetes remission. The current review considers the potential for adjunct therapies to augment the therapeutic actions of GLP-1 receptor agonists. In this regard, several gut-derived hormones also, modulated by bariatric surgery, display additive properties when combined with GLP-1 receptor agonists in both preclinical and clinical studies. In addition, glucocorticoids and oestrogen have shown promise in augmenting the biological actions of GLP-1 in animal models. Additionally, GLP-1 efficacy can also be enhanced by use of compounds that prolong GLP-1 receptor coupling to potentiate downstream receptor signalling. Taken together, therapies that activate GLP-1 receptor signalling, in combination with various other cell signalling pathways, show potential for treating type 2 diabetes and obesity with superiority over GLP-1 receptor agonist therapy alone.
Collapse
Affiliation(s)
- Neil Tanday
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Coleraine, UK
| | - Peter R Flatt
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Coleraine, UK
| | - Nigel Irwin
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Coleraine, UK
| |
Collapse
|
|
27
|
Zhang M, Yan W, Yu Y, Cheng J, Yi X, Guo T, Liu N, Shang J, Wang Z, Hu H, Chen L. Liraglutide ameliorates diabetes-associated cognitive dysfunction via rescuing autophagic flux. J Pharmacol Sci 2021; 147:234-244. [PMID: 34507632 DOI: 10.1016/j.jphs.2021.07.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/28/2021] [Accepted: 07/15/2021] [Indexed: 01/16/2023] Open
Abstract
The incidence of diabetes-associated cognitive dysfunction is increasing. However, few clinical interventions are available to prevent the disorder. Several researches have shown that liraglutide, as a glucagon-like peptide-1 analog, has protective effects on various neurodegenerative diseases, but its roles in diabetic cognitive dysfunction are rarely reported. This study aims to investigate the protective effects of liraglutide on diabetic cognitive dysfunction and its underlying mechanisms. In vivo, the effects of liraglutide treatment were investigated in a mouse model of type 2 diabetes mellitus (T2DM). In vitro, we investigated the effects of liraglutide on the high-glucose-induced rat primary neurons. The results showed that liraglutide reduced the escape latency and increased the time in effective area in the Morris water maze test, improved the damage of hippocampal and synaptic ultrastructure, and decreased the accumulation of amyloid β protein in hippocampus of T2DM mice. Furthermore, liraglutide increased the ratio of microtubule-associated protein light 1 chain Ⅱ/Ⅰ, the expression of Beclin1 protein and Lysosome-associated membrane protein 2 in vivo and vitro. Additionally, Bafilomycin A1 which can inhibit the fusion of autophagosome and lysosome partially abolished the effects of liraglutide. These findings indicate liraglutide ameliorates diabetes-associated cognitive dysfunction by rescuing autophagic flux.
Collapse
Affiliation(s)
- Meng Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Wenhui Yan
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Ye Yu
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Jie Cheng
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Xinyao Yi
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Tingli Guo
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Na Liu
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Jia Shang
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Zhuanzhuan Wang
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Hao Hu
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Lina Chen
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China.
| |
Collapse
|
|
28
|
Craig SL, Irwin N, Gault VA. Xenin and Related Peptides: Potential Therapeutic Role in Diabetes and Related Metabolic Disorders. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2021; 14:11795514211043868. [PMID: 34588834 PMCID: PMC8474313 DOI: 10.1177/11795514211043868] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/09/2021] [Indexed: 11/16/2022]
Abstract
Xenin bioactivity and its role in normal physiology has been investigated by several research groups since its discovery in 1992. The 25 amino acid peptide hormone is secreted from the same enteroendocrine K-cells as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), with early studies highlighting the biological significance of xenin in the gastrointestinal tract, along with effects on satiety. Recently there has been more focus directed towards the role of xenin in insulin secretion and potential for diabetes therapies, especially through its ability to potentiate the insulinotropic actions of GIP as well as utilisation in dual/triple acting gut hormone therapeutic approaches. Currently, there is a lack of clinically approved therapies aimed at restoring GIP bioactivity in type 2 diabetes mellitus, thus xenin could hold real promise as a diabetes therapy. The biological actions of xenin, including its ability to augment insulin secretion, induce satiety effects, as well as restoring GIP sensitivity, earmark this peptide as an attractive antidiabetic candidate. This minireview will focus on the multiple biological actions of xenin, together with its proposed mechanism of action and potential benefits for the treatment of metabolic diseases such as diabetes.
Collapse
Affiliation(s)
- Sarah L Craig
- Faculty of Life and Health Sciences, School of Biomedical Sciences, Ulster University, UK
| | - Nigel Irwin
- Faculty of Life and Health Sciences, School of Biomedical Sciences, Ulster University, UK
| | - Victor A Gault
- Faculty of Life and Health Sciences, School of Biomedical Sciences, Ulster University, UK
| |
Collapse
|
|
29
|
Bethea M, Bozadjieva-Kramer N, Sandoval DA. Preproglucagon Products and Their Respective Roles Regulating Insulin Secretion. Endocrinology 2021; 162:6329397. [PMID: 34318874 PMCID: PMC8375443 DOI: 10.1210/endocr/bqab150] [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: 05/24/2021] [Indexed: 11/19/2022]
Abstract
Historically, intracellular function and metabolic adaptation within the α-cell has been understudied, with most of the attention being placed on the insulin-producing β-cells due to their role in the pathophysiology of type 2 diabetes mellitus. However, there is a growing interest in understanding the function of other endocrine cell types within the islet and their paracrine role in regulating insulin secretion. For example, there is greater appreciation for α-cell products and their contributions to overall glucose homeostasis. Several recent studies have addressed a paracrine role for α-cell-derived glucagon-like peptide-1 (GLP-1) in regulating glucose homeostasis and responses to metabolic stress. Further, other studies have demonstrated the ability of glucagon to impact insulin secretion by acting through the GLP-1 receptor. These studies challenge the central dogma surrounding α-cell biology describing glucagon's primary role in glucose counterregulation to one where glucagon is critical in regulating both hyper- and hypoglycemic responses. Herein, this review will update the current understanding of the role of glucagon and α-cell-derived GLP-1, placing emphasis on their roles in regulating glucose homeostasis, insulin secretion, and β-cell mass.
Collapse
Affiliation(s)
- Maigen Bethea
- Department of Pediatrics, Nutrition Section, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | - Darleen A Sandoval
- Department of Pediatrics, Nutrition Section, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Correspondence: Darleen A. Sandoval, PhD, University of Colorado Anschut, Division of Endocrinology, Metabolism, and Diabetes,12801 E 17th Ave. Research Complex 1 South 7th Floor, Aurora, CO 80045, USA. E-mail:
| |
Collapse
|
|
30
|
Bhagavathula AS, Vidyasagar K, Tesfaye W. Efficacy and Safety of Tirzepatide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Phase II/III Trials. Pharmaceuticals (Basel) 2021; 14:991. [PMID: 34681215 PMCID: PMC8537322 DOI: 10.3390/ph14100991] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/17/2022] Open
Abstract
Tirzepatide is a novel once-a-week dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, currently under trial to assess glycemic efficacy and safety in people with type 2 diabetes. A systematic review and meta-analysis were conducted to investigate the efficacy of tirzepatide on glycated hemoglobin (HbA1c, %), fasting serum glucose (mg/dL), and body weight (kg) in patients with uncontrolled type 2 diabetes (HbA1c > 7.0%). Mean changes for efficacy and proportions (safety) with corresponding 95% confidence intervals (CIs) were used to provide pooled estimates. A total of four randomized controlled trials, comprising 2783 patients of whom 69.4% (n = 1934) were treated with 5 mg (n = 646), 10 mg (n = 641), or 15 mg (n = 647) of tirzepatide, were compared to the placebo (n = 192) or the selective GLP-1 receptor agonist (n = 523). The pooled analysis showed that tirzepatide treatment resulted in a greater lowering of the HbA1c (-1.94%, 95% CI: -2.02 to -1.87), fasting serum glucose (-54.72 mg/dL, 95% CI: -62.05 to -47.39), and body weight (-8.47, 95% CI: -9.66 to -7.27). We also found that improvement in the HbA1c levels was still maintained at weeks 26 and 40 from the long-term trials. As for safety, only 3% experienced hypoglycemia, and 4% (95% CI: 2 to 6) experienced serious adverse events, while the discontinuation of therapy percentage was 7% (95% CI: 5 to 8). Tirzepatide significantly improved glycemic control and body weight and had an acceptable safety profile, indicating that it is an effective therapeutic option for glucose-lowering in patients with type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Akshaya Srikanth Bhagavathula
- Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University, 50115 Hradec Králové, Czech Republic
| | - Kota Vidyasagar
- University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506009, India;
| | - Wubshet Tesfaye
- Health Research Institute, University of Canberra, Canberra, ACT 2617, Australia;
| |
Collapse
|
|
31
|
Lafferty RA, O’Harte FPM, Irwin N, Gault VA, Flatt PR. Proglucagon-Derived Peptides as Therapeutics. Front Endocrinol (Lausanne) 2021; 12:689678. [PMID: 34093449 PMCID: PMC8171296 DOI: 10.3389/fendo.2021.689678] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
Collapse
Affiliation(s)
| | | | | | - Victor A. Gault
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | | |
Collapse
|
|
32
|
Coulter-Parkhill A, McClean S, Gault VA, Irwin N. Therapeutic Potential of Peptides Derived from Animal Venoms: Current Views and Emerging Drugs for Diabetes. Clin Med Insights Endocrinol Diabetes 2021; 14:11795514211006071. [PMID: 34621137 PMCID: PMC8491154 DOI: 10.1177/11795514211006071] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/10/2021] [Indexed: 12/13/2022] Open
Abstract
The therapeutic potential of venom-derived drugs is evident today. Currently, several significant drugs are FDA approved for human use that descend directly from animal venom products, with others having undergone, or progressing through, clinical trials. In addition, there is growing awareness of the important cosmeceutical application of venom-derived products. The success of venom-derived compounds is linked to their increased bioactivity, specificity and stability when compared to synthetically engineered compounds. This review highlights advancements in venom-derived compounds for the treatment of diabetes and related disorders. Exendin-4, originating from the saliva of Gila monster lizard, represents proof-of-concept for this drug discovery pathway in diabetes. More recent evidence emphasises the potential of venom-derived compounds from bees, cone snails, sea anemones, scorpions, snakes and spiders to effectively manage glycaemic control. Such compounds could represent exciting exploitable scaffolds for future drug discovery in diabetes, as well as providing tools to allow for a better understanding of cell signalling pathways linked to insulin secretion and metabolism.
Collapse
Affiliation(s)
| | | | - Victor A Gault
- Diabetes Research Group, Ulster University, Coleraine, UK
| | - Nigel Irwin
- Diabetes Research Group, Ulster University, Coleraine, UK
| |
Collapse
|
|
33
|
Lu VB, Gribble FM, Reimann F. Nutrient-Induced Cellular Mechanisms of Gut Hormone Secretion. Nutrients 2021; 13:nu13030883. [PMID: 33803183 PMCID: PMC8000029 DOI: 10.3390/nu13030883] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/27/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.
Collapse
|
|
34
|
Tanday N, English A, Lafferty RA, Flatt PR, Irwin N. Benefits of Sustained Upregulated Unimolecular GLP-1 and CCK Receptor Signalling in Obesity-Diabetes. Front Endocrinol (Lausanne) 2021; 12:674704. [PMID: 34054734 PMCID: PMC8160446 DOI: 10.3389/fendo.2021.674704] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/29/2021] [Indexed: 12/11/2022] Open
Abstract
Combined activation of GLP-1 and CCK1 receptors has potential to synergistically augment the appetite-suppressive and glucose homeostatic actions of the individual parent peptides. In the current study, pancreatic beta-cell benefits of combined GLP-1 and CCK1 receptor upregulation were established, before characterising bioactivity and antidiabetic efficacy of an acylated dual-acting GLP-1/CCK hybrid peptide, namely [Lys12Pal]Ex-4/CCK. Both exendin-4 and CCK exhibited (p<0.001) proliferative and anti-apoptotic effects in BRIN BD11 beta-cells. Proliferative benefits were significantly (p<0.01) augmented by combined peptide treatment when compared to either parent peptide alone. These effects were linked to increases (p<0.001) in GLUT2 and glucokinase beta-cell gene expression, with decreased (p<0.05-p<0.001) expression of NFκB and BAX. [Lys12Pal]Ex-4/CCK exhibited prominent insulinotropic actions in vitro, coupled with beneficial (p<0.001) satiety and glucose homeostatic effects in the mice, with bioactivity evident 24 h after administration. Following twice daily injection of [Lys12Pal]Ex-4/CCK for 28 days in diabetic high fat fed (HFF) mice with streptozotocin (STZ)-induced compromised beta-cells, there were clear reductions (p<0.05-p<0.001) in energy intake and body weight. Circulating glucose was returned to lean control concentrations, with associated increases (p<0.001) in plasma and pancreatic insulin levels. Glucose tolerance and insulin secretory responsiveness were significantly (p<0.05-p<0.001) improved by hybrid peptide therapy. In keeping with this, evaluation of pancreatic histology revealed restoration of normal islet alpha- to beta-cell ratios and reduction (p<0.01) in centralised islet glucagon staining. Improvements in pancreatic islet morphology were associated with increased (p<0.05) proliferation and reduced (p<0.001) apoptosis of beta-cells. Together, these data highlight the effectiveness of sustained dual GLP-1 and CCK1 receptor activation by [Lys12Pal]Ex-4/CCK for the treatment of obesity-related diabetes.
Collapse
MESH Headings
- Animals
- Biomarkers/blood
- Blood Glucose/analysis
- Body Weight
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diet, High-Fat
- Exenatide/pharmacology
- Glucagon-Like Peptide 1/genetics
- Glucagon-Like Peptide 1/metabolism
- Hypoglycemic Agents/pharmacology
- Insulin Secretion
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Insulin-Secreting Cells/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Obesity/physiopathology
- Peptide Fragments/pharmacology
- Receptors, Cholecystokinin/genetics
- Receptors, Cholecystokinin/metabolism
- Up-Regulation
Collapse
|
|
35
|
Pappritz K, Klein O, Dong F, Hamdani N, Kovacs A, O'Flynn L, Elliman S, O'Brien T, Tschöpe C, Van Linthout S. MALDI-IMS as a Tool to Determine the Myocardial Response to Syndecan-2-Selected Mesenchymal Stromal Cell Application in an Experimental Model of Diabetic Cardiomyopathy. Proteomics Clin Appl 2021; 15:e2000050. [PMID: 33068073 DOI: 10.1002/prca.202000050] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 10/12/2020] [Indexed: 01/08/2023]
Abstract
PURPOSE Mesenchymal stromal cells (MSC) are an attractive tool for treatment of diabetic cardiomyopathy. Syndecan-2/CD362 has been identified as a functional marker for MSC isolation. Imaging mass spectrometry (IMS) allows for the characterization of therapeutic responses in the left ventricle. This study aims to investigate whether IMS can assess the therapeutic effect of CD362+ -selected MSC on early onset experimental diabetic cardiomyopathy. EXPERIMENTAL DESIGN 1 × 106 wild type (WT), CD362- , or CD362+ MSC are intravenously injected into db/db mice. Four weeks later, mice are hemodynamically characterized and subsequently sacrificed for IMS combined with bottom-up mass spectrometry, and isoform and phosphorylation analyses of cardiac titin. RESULTS Overall alterations of the cardiac proteome signatures, especially titin, are observed in db/db compared to control mice. Interestingly, only CD362+ MSC can overcome the reduced titin intensity distribution and shifts the isoform ratio toward the more compliant N2BA form. In contrast, WT and CD362- MSCs improve all-titin phosphorylation and protein kinase G activity, which is reflected in an improvement in diastolic performance. CONCLUSIONS AND CLINICAL RELEVANCE IMS enables the characterization of differences in titin intensity distribution following MSC application. However, further analysis of titin phosphorylation is needed to allow for the assessment of the therapeutic efficacy of MSC.
Collapse
Affiliation(s)
- Kathleen Pappritz
- Berlin-Brandenburg Center for Regenerative Therapies and Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, 13353 and 10178, Germany
- German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, 13347, Germany
| | - Oliver Klein
- Berlin-Brandenburg Center for Regenerative Therapies and Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, 13353 and 10178, Germany
- German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, 13347, Germany
| | - Fengquan Dong
- Berlin-Brandenburg Center for Regenerative Therapies and Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, 13353 and 10178, Germany
| | - Nazha Hamdani
- Department of Physiology, Institute of Physiology, Ruhr University Bochum, Bochum, 44780, Germany
| | - Arpad Kovacs
- Department of Physiology, Institute of Physiology, Ruhr University Bochum, Bochum, 44780, Germany
| | - Lisa O'Flynn
- Orbsen Therapeutics, National University of Ireland (NUIG), Galway, H91 TK33, Ireland
| | - Steve Elliman
- Orbsen Therapeutics, National University of Ireland (NUIG), Galway, H91 TK33, Ireland
| | - Timothy O'Brien
- Regenerative Medicine Institute and Department of Medicine, NUIG, Galway, H91 TK33, Ireland
| | - Carsten Tschöpe
- Berlin-Brandenburg Center for Regenerative Therapies and Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, 13353 and 10178, Germany
- German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, 13347, Germany
- Department of Cardiology, Charité - Universitätsmedizin Berlin, CVK, Berlin, 13353, Germany
| | - Sophie Van Linthout
- Berlin-Brandenburg Center for Regenerative Therapies and Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, 13353 and 10178, Germany
- German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, 13347, Germany
| |
Collapse
|
|
36
|
Pandey S, Dvorakova MC. Future Perspective of Diabetic Animal Models. Endocr Metab Immune Disord Drug Targets 2020; 20:25-38. [PMID: 31241444 PMCID: PMC7360914 DOI: 10.2174/1871530319666190626143832] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/06/2019] [Accepted: 04/17/2019] [Indexed: 12/15/2022]
Abstract
Objective The need of today’s research is to develop successful and reliable diabetic animal models for understanding the disease susceptibility and pathogenesis. Enormous success of animal models had already been acclaimed for identifying key genetic and environmental factors like Idd loci and effects of microorganisms including the gut microbiota. Furthermore, animal models had also helped in identifying many therapeutic targets and strategies for immune-intervention. In spite of a quite success, we have acknowledged that many of the discovered immunotherapies are working on animals and did not have a significant impact on human. Number of animal models were developed in the past to accelerate drug discovery pipeline. However, due to poor initial screening and assessment on inequivalent animal models, the percentage of drug candidates who succeeded during clinical trials was very low. Therefore, it is essential to bridge this gap between pre-clinical research and clinical trial by validating the existing animal models for consistency. Results and Conclusion In this review, we have discussed and evaluated the significance of animal models on behalf of published data on PUBMED. Amongst the most popular diabetic animal models, we have selected six animal models (e.g. BioBreeding rat, “LEW IDDM rat”, “Nonobese Diabetic (NOD) mouse”, “STZ RAT”, “LEPR Mouse” and “Zucker Diabetic Fatty (ZDF) rat” and ranked them as per their published literature on PUBMED. Moreover, the vision and brief imagination for developing an advanced and robust diabetic model of 21st century was discussed with the theme of one mice-one human concept including organs-on-chips.
Collapse
Affiliation(s)
- Shashank Pandey
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Magdalena C Dvorakova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Department of Physiology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| |
Collapse
|
|
37
|
Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol Metab 2020; 46:101090. [PMID: 32987188 PMCID: PMC8085566 DOI: 10.1016/j.molmet.2020.101090] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/13/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022] Open
Abstract
Background Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved to treat type 2 diabetes and obesity. They elicit robust improvements in glycemic control and weight loss, combined with cardioprotection in individuals at risk of or with pre-existing cardiovascular disease. These attributes make GLP-1 a preferred partner for next-generation therapies exhibiting improved efficacy yet retaining safety to treat diabetes, obesity, non-alcoholic steatohepatitis, and related cardiometabolic disorders. The available clinical data demonstrate that the best GLP-1R agonists are not yet competitive with bariatric surgery, emphasizing the need to further improve the efficacy of current medical therapy. Scope of review In this article, we discuss data highlighting the physiological and pharmacological attributes of potential peptide and non-peptide partners, exemplified by amylin, glucose-dependent insulinotropic polypeptide (GIP), and steroid hormones. We review the progress, limitations, and future considerations for translating findings from preclinical experiments to competitive efficacy and safety in humans with type 2 diabetes and obesity. Major conclusions Multiple co-agonist combinations exhibit promising clinical efficacy, notably tirzepatide and investigational amylin combinations. Simultaneously, increasing doses of GLP-1R agonists such as semaglutide produces substantial weight loss, raising the bar for the development of new unimolecular co-agonists. Collectively, the available data suggest that new co-agonists with robust efficacy should prove superior to GLP-1R agonists alone to treat metabolic disorders.
GLP-1 is a preferred partner for co-agonist development. Co-agonist combinations must exhibit improved weight loss beyond GLP-1 alone. Unimolecular coagonists must exhibit retained or improved cardioprotection. Obesity represents an optimal condition for the development of new GLP-1 co-agonists.
Collapse
Affiliation(s)
- Laurie L Baggio
- Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada
| | - Daniel J Drucker
- Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada.
| |
Collapse
|
|
38
|
Liu C, Zou Y, Qian H. GLP-1R agonists for the treatment of obesity: a patent review (2015-present). Expert Opin Ther Pat 2020; 30:781-794. [PMID: 32799587 DOI: 10.1080/13543776.2020.1811851] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Glucagon-like peptide-1 (GLP-1) is an endogenous peptide which is secreted by enteroendocrine L cells, GLP-1 receptor agonists (GLP-1 RAs) can exhibit glucoregulation by stimulating insulin release, promote satiety, delay gastric emptying, and reduce energy intake. Liraglutide is the only GLP-1 RA approved for the treatment of obesity. The phase III clinical study of semaglutide has completed and the result showed significant weight loss effect. GLP-1 RAs have been proven to be safe and effective in clinical trials, they are considered to be promising anti-obesity drugs. AREAS COVERED This review provides an overview of recently published patents describing modified GLP-1 RAs, multi-agonists in the treatment or prevention of obesity from January 2015 to April 2020. Moreover, small molecule GLP-1 RAs, recombinant fusion proteins, combination of GLP-1 RAs with other drugs and the preparation of GLP-1 RAs are also covered. EXPERT OPINION Currently, research on anti-obesity effect of modified GLP-1 RAs has grown significantly, liraglutide accounts for approximately 56% of the global obesity drug market. Long-acting analogues and multifunctional peptides showed good weight loss activity. As more and more clinical trials are carried out, we believe that GLP-1 RAs will occupy an important position in the market of obesity treatment.
Collapse
Affiliation(s)
- Chunxia Liu
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, PR, China
| | - Yuxing Zou
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, PR, China
| | - Hai Qian
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, PR, China.,Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University , Nanjing, PR, China
| |
Collapse
|
|
39
|
Moffett RC, Docherty NG, le Roux CW. The altered enteroendocrine reportoire following roux-en-Y-gastric bypass as an effector of weight loss and improved glycaemic control. Appetite 2020; 156:104807. [PMID: 32871202 DOI: 10.1016/j.appet.2020.104807] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 02/08/2023]
Abstract
The alarming rise in obesity and relative lack of pharmacotherapies to treat, what is becoming a global epidemic, has necessitated that an increasing number of bariatric procedures be performed. Several surgical techniques have been developed during the last 50 years and the advent of laparoscopic surgery has increased the safety and efficacy of these procedures. Bariatric surgery is by a substantial margin, the most efficacious means of achieving sustained weight loss maintenance in patients with obesity. Roux-en-Y gastric bypass surgery (RYGB) elicits the most favourable metabolic outcomes with attendant benefits for type 2 diabetes and, cardiovascular disease as well as endocrine disorders and cancers in females. RYGB is the most extensively studied bariatric procedure regarding mechanism of action. In this review we catalogue the multiple alterations in secretion of gut hormones (ghrelin, obestatin, cholecystokinin, GLP-1, PYY, GIP, oxyntomodulin, glicentin and GLP-2) occurring after RYGB and summarise evidence indicating that these changes play a role in the reduction of food intake and improvements in glucose homeostasis.
Collapse
Affiliation(s)
- R Charlotte Moffett
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
| | - Neil G Docherty
- Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Ireland; Department of Gastrosurgical Research and Education, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Carel W le Roux
- Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Ireland; Investigative Science, Imperial College London, UK
| |
Collapse
|
|
40
|
Hölscher C. Brain insulin resistance: role in neurodegenerative disease and potential for targeting. Expert Opin Investig Drugs 2020; 29:333-348. [PMID: 32175781 DOI: 10.1080/13543784.2020.1738383] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Introduction: This review evaluates the novel strategy of treating Alzheimer's and Parkinson's disease (AD and PD) withdrugs that initially have been developed to treat type 2 diabetes. As insulin signalling has been found to be de-sensitized in the brains of patients, drugs that can re-sensitize insulin signalling have been tested to evaluate if this strategy can alter disease progression.Areas covered: The review will give an overview of preclinical and clinical tests in AD and PD of drugs activating insulin receptors, glucagon-like peptide -1 (GLP-1) receptors, and glucose-dependent insulinotropic polypeptide (GIP) receptors.Expert opinion: Insulin, GLP-1 and GIP receptor agonists have shown good effects in preclinical studies. First clinical trials in MCI/AD patients have shown that insulin can improve on key pathological symptoms of AD such as memory impairment, brain activity, neuronal energy utilization, and inflammation markers. A GLP-1 receptor agonist has shown disease-modifying effects in PD patients, and first pilot studies have shown encouraging effects of a GLP-1 receptor agonist in AD patients. Novel dual GLP-1/GIP receptor agonists that cross the blood brain barrier show superior neuroprotective effects compared to single GLP-1 or GIP receptor agonists, and show great promise as novel treatments of AD and PD.
Collapse
Affiliation(s)
- Christian Hölscher
- Second Hospital, Neurology Department, Shanxi Medical University, Taiyuan, Shanxi, PR China.,Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China
| |
Collapse
|
|
41
|
Zhang ZQ, Hölscher C. GIP has neuroprotective effects in Alzheimer and Parkinson's disease models. Peptides 2020; 125:170184. [PMID: 31705913 DOI: 10.1016/j.peptides.2019.170184] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 12/17/2022]
Abstract
Glucose-dependent Insulinotropic polypeptide (GIP) is a peptide hormone of the incretin family. It has growth factor properties and can re-activate energy utilization. In progressive neurodegenerative disorders such as Alzheimer's and Parkinson's disease, energy utilization is much reduced, and GIP has the potential to reverse this. Furthermore, GIP can reduce the inflammation response in the brain and reduce levels of pro-inflammatory cytokines. Tests in animal models of Alzheimer's and Parkinson's disease show good neuroprotective effects. In Parkinson's disease models, motor activity is normalized, dopaminergic neurons are protected, synapse numbers and dopamine levels are maintained. Levels of growth factors that are essential for neuronal and synaptic function are increased and alpha-synuclein levels are reduced. The chronic inflammation response and mitochondrial damage is reduced. In Alzheimer's disease models, memory is rescued, synapse numbers and synaptic plasticity in the hippocampus is normalized, amyloid plaque load and the chronic inflammation is reduced. Similar protective effects have been previously reported with analogues of glucagon-like peptide 1 (GLP-1), the sister incretin hormone. First clinical trials show good protective effects in both diseases. Recently, novel dual GLP-1/GIP receptor agonists have been developed. The ability to cross the blood-brain barrier (BBB) is key to their neuroprotective effects. We have developed two dual GLP-1/GIP receptor agonist that have cell penetrating sequences added for better BBB penetration. In direct comparisons, these dual agonists show improved neuroprotection in a mouse model of Parkinson's disease. Therefore, such novel multiple receptor agonists hold great promise as potential treatments for Alzheimer's and Parkinson's disease.
Collapse
Affiliation(s)
- Zhen Qiang Zhang
- Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China
| | - Christian Hölscher
- Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China.
| |
Collapse
|
|
42
|
Bergmann NC, Gasbjerg LS, Heimbürger SM, Krogh LSL, Dela F, Hartmann B, Holst JJ, Jessen L, Christensen MB, Vilsbøll T, Lund A, Knop FK. No Acute Effects of Exogenous Glucose-Dependent Insulinotropic Polypeptide on Energy Intake, Appetite, or Energy Expenditure When Added to Treatment With a Long-Acting Glucagon-Like Peptide 1 Receptor Agonist in Men With Type 2 Diabetes. Diabetes Care 2020; 43:588-596. [PMID: 31949084 DOI: 10.2337/dc19-0578] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 12/18/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Dual incretin receptor agonists in clinical development have shown reductions in body weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes, but the impact of glucose-dependent insulinotropic polypeptide (GIP) receptor activation remains unclear. Here, we evaluated the effects of high-dose exogenous GIP on energy intake, energy expenditure, plasma glucose, and glucose-regulating hormones in patients with type 2 diabetes treated with a long-acting glucagon-like peptide 1 receptor (GLP-1R) agonist. RESEARCH DESIGN AND METHODS In a randomized, double-blind design, men with type 2 diabetes (n = 22, mean ± SEM HbA1c 6.8 ± 0.1% [51 ± 1.5 mmol/mol]) treated with metformin and long-acting GLP-1R agonists were subjected to two 5-h continuous infusions (separated by a washout period of ≥3 days): one with GIP (6 pmol/kg/min) and another with saline (placebo). After 60 min of infusion, a liquid mixed-meal test was performed, and after 270 min of infusion, an ad libitum meal was served for evaluation of energy intake (primary end point). RESULTS Energy intake was similar during GIP and placebo infusion (648 ± 74 kcal vs. 594 ± 55 kcal, respectively; P = 0.480), as were appetite measures and energy expenditure. Plasma glucagon and glucose were higher during GIP infusion compared with placebo infusion (P = 0.026 and P = 0.017) as assessed by area under the curve. CONCLUSIONS In patients with type 2 diabetes, GIP infusion on top of treatment with metformin and a long-acting GLP-1R agonist did not affect energy intake, appetite, or energy expenditure but increased plasma glucose compared with placebo. These results indicate no acute beneficial effects of combining GIP and GLP-1.
Collapse
Affiliation(s)
- Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Zealand Pharma A/S, Glostrup, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sebastian M Heimbürger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Liva S L Krogh
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Flemming Dela
- Xlab, Center for Healthy Ageing, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Geriatrics, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Asger Lund
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark .,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Steno Diabetes Center Copenhagen, Gentofte, Denmark
| |
Collapse
|
|
43
|
Thondam SK, Cuthbertson DJ, Wilding JPH. The influence of Glucose-dependent Insulinotropic Polypeptide (GIP) on human adipose tissue and fat metabolism: Implications for obesity, type 2 diabetes and Non-Alcoholic Fatty Liver Disease (NAFLD). Peptides 2020; 125:170208. [PMID: 31759125 DOI: 10.1016/j.peptides.2019.170208] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/16/2019] [Accepted: 11/19/2019] [Indexed: 12/25/2022]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide (GLP-1) are the two incretin hormones secreted by the enteroendocrine system in response to nutrient ingestion. Compared with GLP-1, GIP is less well studied as a hormone or as a potential pharmacological treatment. Beyond its insulinotropic effects in the pancreas, GIP has important biological actions in many other tissues but its role in dietary fat metabolism and lipid storage in adipose tissue has been most studied. It is still unclear if such effects of GIP on adipose tissue/fat metabolism are protective or deleterious in the long term. Antagonising GIP actions through genetic and chemical disruption in mice models prevented diet induced obesity and improved insulin sensitivity. Whilst such effects of GIP antagonism are yet to be evaluated in humans, recent studies using combined GIP and GLP-1 agonists have shown weight reduction and improved glycaemic control in people with type 2 diabetes (T2D). Therapeutic manipulation of GIP physiology is intriguing in that both agonists and antagonists of GIP are being investigated to explore their potential weight-reducing and other metabolic benefits in people with obesity, T2D and non-alcoholic fatty liver disease (NAFLD). This review will discuss the physiological effects of GIP on fat metabolism in human adipose and other non-adipose tissues such as liver, pancreas, skeletal muscle and heart, describe where the actions of GIP may contribute to the pathophysiology of obesity, T2D and NAFLD and finally describe the therapeutic implications of GIP antagonism and agonism in these conditions.
Collapse
Affiliation(s)
- Sravan K Thondam
- Department of Diabetes and Endocrinology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Daniel J Cuthbertson
- Department of Diabetes and Endocrinology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom; Obesity and Endocrinology Research Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom
| | - John P H Wilding
- Department of Diabetes and Endocrinology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom; Obesity and Endocrinology Research Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
| |
Collapse
|
|
44
|
Bailey CJ. GIP analogues and the treatment of obesity-diabetes. Peptides 2020; 125:170202. [PMID: 31756366 DOI: 10.1016/j.peptides.2019.170202] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/09/2019] [Accepted: 11/11/2019] [Indexed: 12/18/2022]
Abstract
The potential application of glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide, GIP) in the management of obesity and type 2 diabetes has been controversial. Initial interest in the therapeutic use of GIP was dampened by evidence that its insulinotropic activity was reduced in type 2 diabetes and by reports that it increased glucagon secretion and adipose deposition in non-diabetic individuals. Also, attention was diverted away from GIP by the successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, and a therapeutic strategy for GIP became uncertain when evidence emerged that both inhibition and enhancement of GIP action could prevent or reverse obese non-insulin dependent forms of diabetes in rodents. Species differences in GIP receptor responsiveness complicated the extrapolation of evidence from rodents to humans, but initial clinical studies are investigating the effect of a GIP antagonist in non-diabetic individuals. A therapeutic role for GIP agonists was reconsidered when clinical studies noted that the insulinotropic effect of GIP was increased if near-normal glycaemia was re-established, and GIP was found to have little effect on glucagon secretion or adipose deposition in obese type 2 diabetes patients. This encouraged the development of designer peptides that act as GIP receptor agonists, including chimeric peptides that mimic the incretin partnership of GIP with GLP-1, where the two agents exert complementary and often additive effects to improve glycaemic control and facilitate weight loss. Polyagonist peptides that exert agonism at GIP, GLP-1 and glucagon receptors are also under investigation as potential treatments for obese type 2 diabetes.
Collapse
Affiliation(s)
- Clifford J Bailey
- School of Life and Health Sciences, Aston University, B4 7ET, Birmingham, UK.
| |
Collapse
|
|
45
|
Knerr PJ, Mowery SA, Finan B, Perez-Tilve D, Tschöp MH, DiMarchi RD. Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates. Peptides 2020; 125:170225. [PMID: 31786282 DOI: 10.1016/j.peptides.2019.170225] [Citation(s) in RCA: 20] [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: 10/22/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
The continued global growth in the prevalence of obesity coupled with the limited number of efficacious and safe treatment options elevates the importance of innovative pharmaceutical approaches. Combinatorial strategies that harness the metabolic benefits of multiple hormonal mechanisms have emerged at the preclinical and more recently clinical stages of drug development. A priority has been anti-obesity unimolecular peptides that function as balanced, high potency poly-agonists at two or all the cellular receptors for the endocrine hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon. This report reviews recent progress in this area, with emphasis on what the initial clinical results demonstrate and what remains to be addressed.
Collapse
Affiliation(s)
- Patrick J Knerr
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | | | - Brian Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | - Diego Perez-Tilve
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Garching, Germany
| | - Richard D DiMarchi
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA.
| |
Collapse
|
|
46
|
Hasib A. Multiagonist Unimolecular Peptides for Obesity and Type 2 Diabetes: Current Advances and Future Directions. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2020; 13:1179551420905844. [PMID: 32110131 PMCID: PMC7025423 DOI: 10.1177/1179551420905844] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 01/16/2020] [Indexed: 12/18/2022]
Abstract
The ever-increasing prevalence of obesity and Type 2 diabetes has necessitated the development of newer and more effective approaches for achieving efficient glycemic control and weight loss. Conventional treatment methods often result in weight gain, further deteriorating the already impaired metabolic control in people with obesity/Type 2 diabetes. Alleviation of obesity and diabetes achieved after bariatric surgeries highlight the therapeutic importance of gut-brain axis and entails development of more patient-friendly approaches replicating the positive metabolic effects of bariatric surgery. Given the potential involvement of several gut hormones in the success of bariatric surgery, the therapeutic importance of synergistic interaction between these hormones for improved metabolism cannot be ignored. Many unimolecular multiagonist peptides are in preclinical and clinical trials as they maximize the combinatorial metabolic efficacy by concurrent activation of multiple gut hormone receptors. This review summarizes the ongoing developments of multiagonist peptides as novel therapeutic approaches against obesity-diabetes.
Collapse
Affiliation(s)
- Annie Hasib
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, UK
| |
Collapse
|
|
47
|
Antidiabetic effects and sustained metabolic benefits of sub-chronic co-administration of exendin-4/gastrin and xenin-8-Gln in high fat fed mice. Eur J Pharmacol 2019; 865:172733. [PMID: 31614140 DOI: 10.1016/j.ejphar.2019.172733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/09/2019] [Accepted: 10/11/2019] [Indexed: 11/20/2022]
Abstract
The present study has examined the antidiabetic effects of 21 days co-administration of xenin-8-Gln with the dual-acting fusion peptide, exendin-4/gastrin, as well as persistence of beneficial metabolic benefits, in high fat fed (HFF) mice. Xenin-8-Gln, exendin-4 and gastrin represent compounds that activate receptors of the gut-derived hormones, xenin, glucagon-like peptide-1 (GLP-1) and gastrin, respectively. Twice-daily administration of exendin-4/gastrin, xenin-8-Gln or a combination of both peptides significantly reduced circulating glucose, HbA1c and cumulative energy intake. Combination therapy with xenin-8-Gln and exendin-4/gastrin increased circulating insulin. All HFF mice treated with exendin-4/gastrin presented with body weight similar to lean control mice on day 21. Each treatment improved glucose tolerance and the glucose-lowering actions of glucose dependent insulinotropic polypeptide (GIP), as well as augmenting glucose- and GIP-induced insulin secretion, with benefits being most prominent in the combination group. Administration of exendin-4/gastrin alone, and in combination with xenin-8-Gln, increased pancreatic insulin content and improved the insulin sensitivity index. Pancreatic beta-cell area was significantly increased, and alpha cell area decreased, by all treatments, with the combination group also displaying enhanced overall islet area. Notably, metabolic benefits were generally retained in all groups of HFF mice, and especially in the combination group, following discontinuation of the treatment regimens for 21 days. This was associated with maintenance of increased islet and beta-cell areas. Together, these data confirm the antidiabetic effects of co-activation of GLP-1, gastrin and xenin cell signalling pathways, and highlight the sustainable benefits this type of treatment paradigm can offer in T2DM.
Collapse
|
|
48
|
Prolactin-Releasing Peptide: Physiological and Pharmacological Properties. Int J Mol Sci 2019; 20:ijms20215297. [PMID: 31653061 PMCID: PMC6862262 DOI: 10.3390/ijms20215297] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/21/2019] [Accepted: 10/23/2019] [Indexed: 12/18/2022] Open
Abstract
Prolactin-releasing peptide (PrRP) belongs to the large RF-amide neuropeptide family with a conserved Arg-Phe-amide motif at the C-terminus. PrRP plays a main role in the regulation of food intake and energy expenditure. This review focuses not only on the physiological functions of PrRP, but also on its pharmacological properties and the actions of its G-protein coupled receptor, GPR10. Special attention is paid to structure-activity relationship studies on PrRP and its analogs as well as to their effect on different physiological functions, mainly their anorexigenic and neuroprotective features and the regulation of the cardiovascular system, pain, and stress. Additionally, the therapeutic potential of this peptide and its analogs is explored.
Collapse
|
|
49
|
Capcarova M, Kalafova A, Schwarzova M, Schneidgenova M, Svik K, Prnova MS, Slovak L, Kovacik A, Lory V, Zorad S, Brindza J. Cornelian cherry fruit improves glycaemia and manifestations of diabetes in obese Zucker diabetic fatty rats. Res Vet Sci 2019; 126:118-123. [PMID: 31446268 DOI: 10.1016/j.rvsc.2019.08.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 08/06/2019] [Accepted: 08/12/2019] [Indexed: 01/05/2023]
Abstract
Cornelian cherry (Cornus mas L.) was in the past frequently used in Slovak Republic; meanwhile fell into oblivion despite the fact that it is known as antidiabetic supplement. However, there is no research investigated its effect on animal model of Diabetes mellitus (DM) 2 type as it is Zucker diabetic fatty (ZDF) rats. Thus, the aim of this study was to determine the effect of C. mas fruit given orally on the development of DM symptoms in ZDF rats. In the experiment male ZDF rats (fa/fa) and their age-matched non-diabetic lean controls (fa/+) were used aged 12 weeks. Male ZDF rats were administered C. mas in two doses (500 and 1000 mg/kg body weight) using a gastric gavage for 10 weeks. One group of diabetic animals served as positive control and received only distilled water. We found significant decrease of glucose level after oral administration of C. mas in dose of 1000 mg/kg bw in pre-diabetic state of animals (until 7th week of the experiment) and significant restriction of water intake in both C. mas groups against the diabetic control. We presume that the higher dose of Cornelian cherry could be beneficial and helpful in prevention of diabetic symptoms when consumed regularly in young animals.
Collapse
Affiliation(s)
- Marcela Capcarova
- Department of Animal Physiology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovak Republic.
| | - Anna Kalafova
- Department of Animal Physiology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovak Republic
| | - Marianna Schwarzova
- Department of Human Nutrition, Faculty of Agrobiology and Food Resources, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovak Republic
| | - Monika Schneidgenova
- Department of Animal Physiology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovak Republic
| | - Karol Svik
- Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Science, Bratislava, Slovak Republic
| | - Marta Soltesova Prnova
- Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Science, Bratislava, Slovak Republic
| | - Lukas Slovak
- Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Science, Bratislava, Slovak Republic
| | - Anton Kovacik
- Department of Animal Physiology, Faculty of Biotechnology and Food Sciences, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovak Republic
| | - Viktoria Lory
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Science, Bratislava, Slovak Republic
| | - Stefan Zorad
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Science, Bratislava, Slovak Republic
| | - Jan Brindza
- Department of Genetics and Plant Breeding, Faculty of Agrobiology and Food Resources, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovak Republic; Institute of Biodiversity Conservation and Biosafety, Slovak University of Agriculture in Nitra, 949 76 Nitra, Slovak Republic
| |
Collapse
|
|
50
|
Mathiesen DS, Bagger JI, Bergmann NC, Lund A, Christensen MB, Vilsbøll T, Knop FK. The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion-A Review. Int J Mol Sci 2019; 20:E4092. [PMID: 31443356 PMCID: PMC6747202 DOI: 10.3390/ijms20174092] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 08/16/2019] [Accepted: 08/20/2019] [Indexed: 02/07/2023] Open
Abstract
The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.
Collapse
Affiliation(s)
- David S Mathiesen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
| | - Jonatan I Bagger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark
| | - Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
| | - Asger Lund
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark.
- Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
| |
Collapse
|