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Holst JJ, Rosenkilde MM. Oxyntomodulin - past, present and future. Peptides 2025; 188:171393. [PMID: 40187415 DOI: 10.1016/j.peptides.2025.171393] [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: 02/17/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/07/2025]
Abstract
Almost since its discovery, glucagon was suspected to be formed in the gastrointestinal tract, and the L-cells were shown to contain glucagon-like immunoreactivity. This was due to the presence of two peptides that both contained the full glucagon sequence:glicentin of 69 amino acids and oxyntomodulin of 37 amino acids. While glicentin is a part of the glucagon precursor, proglucagon, and probably is inactive, oxyntomodulin, a fragment of glicentin, interacts although weakly with the glucagon as well as the GLP-1 receptor. However, in agreement with these activities, oxyntomodulin inhibited appetite and food intake in humans and inspired development of long acting, potent glucagon-GLP-1 co-agonists. Several such co-agonists are currently in clinical development and show promise because they combine GLP-1 like activities with those of glucagon agonism: additive weight loss and a stimulation of hepatic lipid metabolism with unique effectiveness on hepatic steatosis. They may therefore be effective in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).
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Affiliation(s)
- Jens Juul Holst
- The NovoNordisk Foundation Center for Basic Metabolic Research, Denmark; Department of Biomedical Sciences, the Panum institute, University of Copenhagen, Denmark.
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, the Panum institute, University of Copenhagen, Denmark.
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2
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Morad-Abbasi R, Zare-Shahne F, Naeini F, Saidpour A, Etesam F, Hosseinzadeh-Attar MJ. Effects of bariatric surgeries on Binge eating disorders, Food addiction, and eating behaviors: A comprehensive systematic review of RCTs. Clin Nutr ESPEN 2025; 67:222-232. [PMID: 40112924 DOI: 10.1016/j.clnesp.2025.03.016] [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: 01/05/2025] [Revised: 02/26/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
Different types of bariatric surgery have emerged as a major and most effective treatment for obesity. With the rapid growth of bariatric surgery in this decade, it is crucial to understand the postoperative outcomes, especially eating-related outcomes, such as non-preexisting eating disorders, food addiction, emotional eating, and eating behaviors. This systematic review of RCTs seeks to evaluate the impact of various bariatric surgery procedures on eating behaviors, eating disorders, and food addiction to better understand their post-operative effects and guide future clinical practice. Following the 2015 PRISMA guidelines, a systematic review was conducted using PubMed/Medline, Scopus, and WOS databases through May 2024. After assessing 1158 full-text articles, 14 studies were selected based on the established criteria. Based on the obtained results, bariatric surgery significantly improved eating behaviors and weight concerns among patients. Eating behavior was assessed by various questionnaires, such as TFEQ and PFS, across different types of bariatric surgeries, including RYGB, SG, LSG, DJBL, and LAGB. While some studies found varying degrees of improvements across different surgical procedures, the general trend suggests that bariatric surgery can lead to significant improvements in eating behaviors. In conclusion, bariatric surgery appears to influence eating behaviors, food addiction, and binge eating disorders by altering the gut microbiota, gut hormones, and brain regions associated with appetite. However, there is no significant difference in these outcomes among different types of surgery.
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Affiliation(s)
- Reyhaneh Morad-Abbasi
- Department of Cellular and Molecular, School of Nutritional Sciences and Dietetics, Tehran University of Medical Science, Tehran, Iran
| | - Fatemeh Zare-Shahne
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Naeini
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Science, Tehran, Iran.
| | - Atoosa Saidpour
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farnaz Etesam
- Psychosomatic Medicine Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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3
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Mohammad Karim A. Principles and Biomedical Applications of Self-Assembled Peptides: Potential Treatment of Type 2 Diabetes Mellitus. Pharmaceutics 2024; 16:1442. [PMID: 39598565 PMCID: PMC11597675 DOI: 10.3390/pharmaceutics16111442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 11/29/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder worldwide. There have been tremendous efforts to find a safe and prolonged effective therapy for its treatment. Peptide hormones, from certain organisms in the human body, as the pharmaceutical agents, have shown outstanding profiles of efficacy and safety in plasma glucose regulation. Their therapeutic promises have undergone intensive investigations via examining their physicochemical and pharmacokinetic properties. Their major drawback is their short half-life in vivo. To address this challenge, researchers have recently started to apply the state-of-the-art molecular self-assembly on peptide hormones to form nanofibrillar structures, as a smart nanotherapeutic drug delivery technique, to tremendously enhance their prolonged bioactivity in vivo. This revolutionary therapeutic approach would significantly improve patient compliance. First, this review provides a comprehensive summary on the pathophysiology of T2DM, various efforts to treat this chronic disorder, and the limitations and drawbacks of these treatment approaches. Next, this review lays out detailed insights on various aspects of peptide self-assembly: adverse effects, potential applications in nanobiotechnology, thermodynamics and kinetics of the process, as well as the molecular structures of the self-assembled configurations. Furthermore, this review elucidates the recent efforts on applying reversible human-derived peptide self-assembly to generate highly organized smart nanostructured drug formulations known as nanofibrils to regulate and prolong the bioactivity of the human gut hormone peptides in vivo to treat T2DM. Finally, this review highlights the future research directions to advance the knowledge on the state-of-the-art peptide self-assembly process to apply the revolutionary smart nanotherapeutics for treatment of chronic disorders such as T2DM with highly improved patient compliance.
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Affiliation(s)
- Alireza Mohammad Karim
- Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J. J. Thomson Avenue, Cambridge CB3 0FF, UK
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4
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Kueh MTW, Chong MC, Miras AD, le Roux CW. Oxyntomodulin physiology and its therapeutic development in obesity and associated complications. J Physiol 2024. [PMID: 39495024 DOI: 10.1113/jp287407] [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: 07/29/2024] [Accepted: 10/08/2024] [Indexed: 11/05/2024] Open
Abstract
Incretins, such as glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), have advanced the treatment landscape of obesity to a new pinnacle. As opposed to singular incretin effects, oxyntomodulin (OXM) activates glucagon receptors (GCGR) and glucagon-like peptide-1 receptors (GLP1R), demonstrating a more dynamic range of effects that are more likely to align with evolving 'health gains' goals in obesity care. Here, we will review the molecular insights from their inception to recent developments and challenges. This review will discuss the physiological actions of OXM, primarily appetite regulation, energy expenditure, and glucose homeostasis. Finally, we will shed light on the development of OXM-based therapies for obesity and associated complications, and outline important considerations for more translational efforts.
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Affiliation(s)
- Martin T W Kueh
- UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
- Royal College of Surgeons in Ireland and University College Dublin Malaysia Campus, Malaysia
| | | | | | - Carel W le Roux
- Diabetes Complications Research Centre, University College Dublin, Ireland
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5
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Forst T, De Block C, Del Prato S, Armani S, Frias J, Lautenbach A, Ludvik B, Marinez M, Mathieu C, Müller TD, Schnell O. The role of incretin receptor agonists in the treatment of obesity. Diabetes Obes Metab 2024; 26:4178-4196. [PMID: 39072877 DOI: 10.1111/dom.15796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/30/2024]
Abstract
INTRODRODUCTION Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon-like peptide-1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co-agonists. METHODS The objective of this narrative review was to summarize the available data on approved and emerging incretin-based agents for the treatment of obesity. RESULTS In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction-associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation. CONCLUSIONS Many dual and triple co-agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin-based therapies; however, data are promising, and further results are eagerly awaited.
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Affiliation(s)
- Thomas Forst
- CRS Clinical Research Services GmbH, Mannheim, Germany
| | | | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science," Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Sara Armani
- CRS Clinical Research Services GmbH, Mannheim, Germany
| | - Juan Frias
- Biomea Fusion, Redwood City, California, USA
| | - Anne Lautenbach
- University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bernhard Ludvik
- Landstrasse Clinic and Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
| | | | | | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Walther-Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Oliver Schnell
- Forschergruppe Diabetes e.V. at the Helmholtz Center Munich, Munich, Germany
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Lytvyak E, Zarrinpar A, Ore CD, Lee E, Yazdani-Boset K, Horgan S, Grunvald E. Stronger control of eating 3 months after sleeve gastrectomy predicts successful weight loss outcomes at one year. OBESITY PILLARS 2024; 11:100111. [PMID: 38770521 PMCID: PMC11103426 DOI: 10.1016/j.obpill.2024.100111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 05/22/2024]
Abstract
Background Weight loss response to sleeve gastrectomy (SG) is variable and predicting the effectiveness of surgery is challenging and elusive. The aim of our study was to assess and quantify the association between eating control and weight loss outcomes and identify the control of eating (CoE) attributes during the early postoperative period that might predict good vs. poor response to SG at one year. Methods A prospective longitudinal cohort study using the Control of Eating Questionnaire (CoEQ) was designed as a series before and at 3-, 6-, and 12-months post-SG. Primary outcomes were changes in CoE attributes and percent of total weight loss (%TWL) 12-months post-surgery. Subjects were categorized based on %TWL as good (GR, ≥25 %) or poor responders (PR, <25 %). A receiver operating characteristic and logistic regression analyses were performed. Results We included 41 participants (80.5% females, 51.2% Hispanic, mean age 41.7±10.6, median baseline body mass index (BMI) 43.6 kg/m2 [range 35.2-66.3]) who completed the CoEQ at all four timepoints. The "Difficulty to control eating" score at 3 months revealed the highest area under the curve (AUC) (AUC 0.711; 95%CI 0.524-0.898; p=0.032). In a trade-off between a high Youden index and high sensitivity, the "Difficulty to control eating" score of 7 at 3 months was identified as the optimal cut-off for distinguishing between GRs and PRs. Score ≤7 at 3 months was strongly independently associated with a successful weight loss target of 25%TWL at one-year post-SG (Relative Risk 4.43; 95%CI 1.06-18.54; p=0.042). Conclusion "Difficulty to control eating" score at 3 months post-SG is an independent early predictor of optimal response (achieving a successful TWL target of ≥25 % at one-year post-SG). Our results support the utility of this easy-to-administer validated tool for predicting the effectiveness of SG and may assist in identifying individuals with suboptimal response early and helping them with interventions to attain optimal weight loss targets.
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Affiliation(s)
- Ellina Lytvyak
- Division of Preventive Medicine, Department of Medicine, University of Alberta, 5-30 University Terrace, 8303 112 Street, Edmonton, Alberta, T6G 2T4, Canada
| | - Amir Zarrinpar
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Cecilia Dalle Ore
- School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Euyhyun Lee
- Altman Clinical and Translational Research Institute, University of California San Diego, La Jolla, CA, USA
| | | | - Santiago Horgan
- Bariatric and Metabolic Institute, Division of Minimally Invasive Surgery, University of California San Diego, 4303 La Jolla Village Drive, Suite 2110, San Diego, CA, 92122, USA
| | - Eduardo Grunvald
- School of Medicine, University of California San Diego, La Jolla, CA, USA
- Division of General Internal Medicine, University of California San Diego, La Jolla, CA, USA
- Bariatric and Metabolic Institute, Division of Minimally Invasive Surgery, University of California San Diego, 4303 La Jolla Village Drive, Suite 2110, San Diego, CA, 92122, USA
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Golubic R, Kennet J, Parker V, Robertson D, Luo D, Hansen L, Jermutus L, Ambery P, Ryaboshapkina M, Surakala M, Laker RC, Venables M, Koulman A, Park A, Evans M. Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity. Diabetes Obes Metab 2024; 26:2634-2644. [PMID: 38562018 DOI: 10.1111/dom.15579] [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: 12/15/2023] [Revised: 03/14/2024] [Accepted: 03/17/2024] [Indexed: 04/04/2024]
Abstract
AIMS To establish which components of energy balance mediate the clinically significant weight loss demonstrated with use of cotadutide, a glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist, in early-phase studies. MATERIALS AND METHODS We conducted a phase 2a, single-centre, randomized, placebo-controlled trial in overweight and obese adults with type 2 diabetes. Following a 16-day single-blind placebo run-in, participants were randomized 2:1 to double-blind 42-day subcutaneous treatment with cotadutide (100-300 μg daily) or placebo. The primary outcome was percentage weight change. Secondary outcomes included change in energy intake (EI) and energy expenditure (EE). RESULTS A total of 12 participants (63%) in the cotadutide group and seven (78%) in the placebo group completed the study. The mean (90% confidence interval [CI]) weight change was -4.0% (-4.9%, -3.1%) and -1.4% (-2.7%, -0.1%) for the cotadutide and placebo groups, respectively (p = 0.011). EI was lower with cotadutide versus placebo (-41.3% [-66.7, -15.9]; p = 0.011). Difference in EE (per kJ/kg lean body mass) for cotadutide versus placebo was 1.0% (90% CI -8.4, 10.4; p = 0.784), assessed by doubly labelled water, and -6.5% (90% CI -9.3, -3.7; p < 0.001), assessed by indirect calorimetry. CONCLUSION Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE.
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Affiliation(s)
- Rajna Golubic
- Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
- Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Jane Kennet
- Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Victoria Parker
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Darren Robertson
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Dan Luo
- Statistics, Biometrics Oncology, Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Lars Hansen
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Lutz Jermutus
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Phil Ambery
- Late Clinical Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Maria Ryaboshapkina
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | | | - Rhianna C Laker
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | | | - Albert Koulman
- MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Adrian Park
- Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Mark Evans
- Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
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8
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McFarlin BE, Duffin KL, Konkar A. Incretin and glucagon receptor polypharmacology in chronic kidney disease. Am J Physiol Endocrinol Metab 2024; 326:E747-E766. [PMID: 38477666 PMCID: PMC11551006 DOI: 10.1152/ajpendo.00374.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/10/2024] [Indexed: 03/14/2024]
Abstract
Chronic kidney disease is a debilitating condition associated with significant morbidity and mortality. In recent years, the kidney effects of incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), have garnered substantial interest in the management of type 2 diabetes and obesity. This review delves into the intricate interactions between the kidney, GLP-1RAs, and glucagon, shedding light on their mechanisms of action and potential kidney benefits. Both GLP-1 and glucagon, known for their opposing roles in regulating glucose homeostasis, improve systemic risk factors affecting the kidney, including adiposity, inflammation, oxidative stress, and endothelial function. Additionally, these hormones and their pharmaceutical mimetics may have a direct impact on the kidney. Clinical studies have provided evidence that incretins, including those incorporating glucagon receptor agonism, are likely to exhibit improved kidney outcomes. Although further research is necessary, receptor polypharmacology holds promise for preserving kidney function through eliciting vasodilatory effects, influencing volume and electrolyte handling, and improving systemic risk factors.
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Affiliation(s)
- Brandon E McFarlin
- Lilly Research Laboratories, Lilly Corporate CenterIndianapolisIndianaUnited States
| | - Kevin L Duffin
- Lilly Research Laboratories, Lilly Corporate CenterIndianapolisIndianaUnited States
| | - Anish Konkar
- Lilly Research Laboratories, Lilly Corporate CenterIndianapolisIndianaUnited States
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9
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Camilleri M, Acosta A. Newer pharmacological interventions directed at gut hormones for obesity. Br J Pharmacol 2024; 181:1153-1164. [PMID: 37917871 PMCID: PMC10947960 DOI: 10.1111/bph.16278] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 11/04/2023] Open
Abstract
The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP-1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co-morbidities.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Andres Acosta
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
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10
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Pocai A. G protein-coupled receptors and obesity. Front Endocrinol (Lausanne) 2023; 14:1301017. [PMID: 38161982 PMCID: PMC10757641 DOI: 10.3389/fendo.2023.1301017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/29/2023] [Indexed: 01/03/2024] Open
Abstract
G protein-coupled receptors (GPCRs) have emerged as important drug targets for various chronic diseases, including obesity and diabetes. Obesity is a complex chronic disease that requires long term management predisposing to type 2 diabetes, heart disease, and some cancers. The therapeutic landscape for GPCR as targets of anti-obesity medications has undergone significant changes with the approval of semaglutide, the first peptide glucagon like peptide 1 receptor agonist (GLP-1RA) achieving double digit weight loss (≥10%) and cardiovascular benefits. The enhanced weight loss, with the expected beneficial effect on obesity-related complications and reduction of major adverse cardiovascular events (MACE), has propelled the commercial opportunity for the obesity market leading to new players entering the space. Significant progress has been made on approaches targeting GPCRs such as single peptides that simultaneously activate GIP and/or GCGR in addition to GLP1, oral tablet formulation of GLP-1, small molecules nonpeptidic oral GLP1R and fixed-dose combination as well as add-on therapy for patients already treated with a GLP-1 agonist.
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Affiliation(s)
- Alessandro Pocai
- Cardiovascular and Metabolic Disease, Johnson & Johnson Innovative Medicine Research & Development, Spring House, PA, United States
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11
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Lee J, Kim WK. Applications of Enteroendocrine Cells (EECs) Hormone: Applicability on Feed Intake and Nutrient Absorption in Chickens. Animals (Basel) 2023; 13:2975. [PMID: 37760373 PMCID: PMC10525316 DOI: 10.3390/ani13182975] [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: 08/14/2023] [Revised: 09/09/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
This review focuses on the role of hormones derived from enteroendocrine cells (EECs) on appetite and nutrient absorption in chickens. In response to nutrient intake, EECs release hormones that act on many organs and body systems, including the brain, gallbladder, and pancreas. Gut hormones released from EECs play a critical role in the regulation of feed intake and the absorption of nutrients such as glucose, protein, and fat following feed ingestion. We could hypothesize that EECs are essential for the regulation of appetite and nutrient absorption because the malfunction of EECs causes severe diarrhea and digestion problems. The importance of EEC hormones has been recognized, and many studies have been carried out to elucidate their mechanisms for many years in other species. However, there is a lack of research on the regulation of appetite and nutrient absorption by EEC hormones in chickens. This review suggests the potential significance of EEC hormones on growth and health in chickens under stress conditions induced by diseases and high temperature, etc., by providing in-depth knowledge of EEC hormones and mechanisms on how these hormones regulate appetite and nutrient absorption in other species.
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Affiliation(s)
| | - Woo Kyun Kim
- Department of Poultry Science, University of Georgia, Athens, GA 30602, USA;
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12
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Amatya R, Lee D, Min KA, Shin MC. Pharmaceutical Strategies to Improve Druggability of Potential Drug Candidates in Nonalcoholic Fatty Liver Disease Therapy. Pharmaceutics 2023; 15:1963. [PMID: 37514148 PMCID: PMC10386216 DOI: 10.3390/pharmaceutics15071963] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/10/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become globally prevalent and is the leading cause of chronic liver disease. Although NAFLD is reversible without medical intervention in the early stage, the condition could be sequentially worsened to nonalcoholic steatohepatitis (NASH) and, eventually, cirrhosis and hepatic cancer. The progression of NAFLD is related to various factors such as genetics, pre-disposed metabolic disorders, and immunologic factors. Thankfully, to date, there have been accumulating research efforts and, as a result, different classes of potent drug candidates have been discovered. In addition, there have also been various attempts to explore pharmaceutical strategies to improve the druggability of drug candidates. In this review, we provided a brief overview of the drug candidates that have undergone clinical trials. In the latter part, strategies for developing better drugs are discussed.
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Affiliation(s)
- Reeju Amatya
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Republic of Korea
| | - Donghee Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Republic of Korea
| | - Kyoung Ah Min
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae 50834, Republic of Korea
| | - Meong Cheol Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Republic of Korea
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13
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Novikoff A, Müller TD. The molecular pharmacology of glucagon agonists in diabetes and obesity. Peptides 2023; 165:171003. [PMID: 36997003 PMCID: PMC10265134 DOI: 10.1016/j.peptides.2023.171003] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 03/31/2023]
Abstract
Within recent decades glucagon receptor (GcgR) agonism has drawn attention as a therapeutic tool for the treatment of type 2 diabetes and obesity. In both mice and humans, glucagon administration enhances energy expenditure and suppresses food intake suggesting a promising metabolic utility. Therefore synthetic optimization of glucagon-based pharmacology to further resolve the physiological and cellular underpinnings mediating these effects has advanced. Chemical modifications to the glucagon sequence have allowed for greater peptide solubility, stability, circulating half-life, and understanding of the structure-function potential behind partial and "super"-agonists. The knowledge gained from such modifications has provided a basis for the development of long-acting glucagon analogues, chimeric unimolecular dual- and tri-agonists, and novel strategies for nuclear hormone targeting into glucagon receptor-expressing tissues. In this review, we summarize the developments leading toward the current advanced state of glucagon-based pharmacology, while highlighting the associated biological and therapeutic effects in the context of diabetes and obesity.
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Affiliation(s)
- Aaron Novikoff
- Institute of Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Timo D Müller
- Institute of Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
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Nogueiras R, Nauck MA, Tschöp MH. Gut hormone co-agonists for the treatment of obesity: from bench to bedside. Nat Metab 2023:10.1038/s42255-023-00812-z. [PMID: 37308724 DOI: 10.1038/s42255-023-00812-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 04/24/2023] [Indexed: 06/14/2023]
Abstract
The discovery and development of so-called gut hormone co-agonists as a new class of drugs for the treatment of diabetes and obesity is considered a transformative breakthrough in the field. Combining action profiles of multiple gastrointestinal hormones within a single molecule, these novel therapeutics achieve synergistic metabolic benefits. The first such compound, reported in 2009, was based on balanced co-agonism at glucagon and glucagon-like peptide-1 (GLP-1) receptors. Today, several classes of gut hormone co-agonists are in development and advancing through clinical trials, including dual GLP-1-glucose-dependent insulinotropic polypeptide (GIP) co-agonists (first described in 2013), and triple GIP-GLP-1-glucagon co-agonists (initially designed in 2015). The GLP-1-GIP co-agonist tirzepatide was approved in 2022 by the US Food and Drug Administration for the treatment of type 2 diabetes, providing superior HbA1c reductions compared to basal insulin or selective GLP-1 receptor agonists. Tirzepatide also achieved unprecedented weight loss of up to 22.5%-similar to results achieved with some types of bariatric surgery-in non-diabetic individuals with obesity. In this Perspective, we summarize the discovery, development, mechanisms of action and clinical efficacy of the different types of gut hormone co-agonists, and discuss potential challenges, limitations and future developments.
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Affiliation(s)
- Ruben Nogueiras
- CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- Galicia Agency of Innovation, Xunta de Galicia, Santiago de Compostela, Spain
| | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Medical Department I, St. Josef-Hospital, Katholisches Klinikum Bochum, Ruhr University of Bochum, Bochum, Germany
| | - Matthias H Tschöp
- Helmholtz Zentrum München, Neuherberg, Germany.
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, München, Germany.
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15
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Behary P, Alessimii H, Miras AD, Tharakan G, Alexiadou K, Aldhwayan MM, Purkayastha S, Moorthy K, Ahmed AR, Bloom SR, Tan TM. Tripeptide gut hormone infusion does not alter food preferences or sweet taste function in volunteers with obesity and prediabetes/diabetes but promotes restraint eating: A secondary analysis of a randomized single-blind placebo-controlled study. Diabetes Obes Metab 2023; 25:1731-1739. [PMID: 36811311 PMCID: PMC11497251 DOI: 10.1111/dom.15028] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/12/2023] [Accepted: 02/19/2023] [Indexed: 02/24/2023]
Abstract
AIMS To investigate whether the elevation in postprandial concentrations of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) accounts for the beneficial changes in food preferences, sweet taste function and eating behaviour after Roux-en-Y gastric bypass (RYGB). MATERIALS AND METHODS This was a secondary analysis of a randomized single-blind study in which we infused GLP-1, OXM, PYY (GOP) or 0.9% saline subcutaneously for 4 weeks in 24 subjects with obesity and prediabetes/diabetes, to replicate their peak postprandial concentrations, as measured at 1 month in a matched RYGB cohort (ClinicalTrials.gov NCT01945840). A 4-day food diary and validated eating behaviour questionnaires were completed. Sweet taste detection was measured using the method of constant stimuli. Correct sucrose identification (corrected hit rates) was recorded, and sweet taste detection thresholds (EC50s: half maximum effective concencration values) were derived from concentration curves. The intensity and consummatory reward value of sweet taste were assessed using the generalized Labelled Magnitude Scale. RESULTS Mean daily energy intake was reduced by 27% with GOP but no significant changes in food preferences were observed, whereas a reduction in fat and increase in protein intake were seen post-RYGB. There was no change in corrected hit rates or detection thresholds for sucrose detection following GOP infusion. Additionally, GOP did not alter the intensity or consummatory reward value of sweet taste. A significant reduction in restraint eating, comparable to the RYGB group was observed with GOP. CONCLUSION The elevation in plasma GOP concentrations after RYGB is unlikely to mediate changes in food preferences and sweet taste function after surgery but may promote restraint eating.
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Affiliation(s)
- Preeshila Behary
- Section of Endocrinology and Investigative Medicine, Imperial College LondonLondonUK
- Department of Endocrinology, Imperial College Healthcare NHS TrustLondonUK
| | - Haya Alessimii
- Clinical Nutrition Department, College of Applied Medical SciencesUmm Al Qura UniversityMeccaSaudi Arabia
| | - Alexander D. Miras
- Section of Endocrinology and Investigative Medicine, Imperial College LondonLondonUK
- Department of Endocrinology, Imperial College Healthcare NHS TrustLondonUK
- School of MedicineUlster UniversityLondonderryUK
| | - George Tharakan
- Section of Endocrinology and Investigative Medicine, Imperial College LondonLondonUK
- Department of Endocrinology, Imperial College Healthcare NHS TrustLondonUK
| | - Kleopatra Alexiadou
- Section of Endocrinology and Investigative Medicine, Imperial College LondonLondonUK
- Department of Endocrinology, Imperial College Healthcare NHS TrustLondonUK
| | - Madhawi M. Aldhwayan
- Community Health Sciences, College of Applied Medical SciencesKing Saud UniversityRiyadhSaudi Arabia
| | - Sanjay Purkayastha
- Department of Surgery and Cancer, Imperial College Healthcare National Health Service TrustLondonUK
| | - Krishna Moorthy
- Department of Surgery and Cancer, Imperial College Healthcare National Health Service TrustLondonUK
| | - Ahmed R. Ahmed
- Department of Surgery and Cancer, Imperial College Healthcare National Health Service TrustLondonUK
| | - Stephen R. Bloom
- Section of Endocrinology and Investigative Medicine, Imperial College LondonLondonUK
| | - Tricia M. Tan
- Section of Endocrinology and Investigative Medicine, Imperial College LondonLondonUK
- Department of Endocrinology, Imperial College Healthcare NHS TrustLondonUK
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Boix-Castejón M, Roche E, Olivares-Vicente M, Álvarez-Martínez FJ, Herranz-López M, Micol V. Plant compounds for obesity treatment through neuroendocrine regulation of hunger: A systematic review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 113:154735. [PMID: 36921427 DOI: 10.1016/j.phymed.2023.154735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 02/07/2023] [Accepted: 02/22/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Food intake behavior is influenced by both physiological and psychological complex processes, such as appetite, satiety, and hunger. The neuroendocrine regulation of food intake integrates short- and long-term acting signals that modulate the moment of intake and energy storage/expenditure, respectively. These signals are classified as orexigenic, those that activate anabolic pathways and the desire of eating, and anorexigenic, those that activate the catabolic pathways and a sensation of satiety. Appetite control by natural vegetal compounds is an intense area of research and new pharmacological interventions have been emerging based on an understanding of appetite regulation pathways. Several validated psychometric tools are used to assess the efficacy of these plant ingredients. However, these data are not conclusive if they are not complemented with physiological parameters, such as anthropometric evaluations (body weight and composition) and the analysis of hormones related to adipose tissue and appetite in blood. PURPOSE The purpose of this manuscript is the critical analysis of the plant compounds studied to date in the literature with potential for the neuroendocrine regulation of hunger in order to determine if the use of phytochemicals for the treatment of obesity constitutes an effective and/or promising therapeutic tool. METHODS Relevant information on neuroendocrine regulation of hunger and satiety for the treatment of obesity by plant compounds up to 2022 in English and/or Spanish were derived from online databases using the PubMed search engine and Google Scholar with relevant keywords and operators. RESULTS Accordingly, the comparison performed in this review between previous studies showed a high degree of experimental heterogeneity. Among the studies reviewed here, only a few of them establish comprehensively a potential correlation between the effect of the ingredient on hunger or satiety, body changes and a physiological response. CONCLUSIONS More systematic clinical studies are required in future research. The first approach should be to decode the pattern of circulating hormones regulating hunger, satiety, and appetite in overweight/obese subjects. Thereafter, studies should correlate brain connectivity at the level of the hypothalamus, gut and adipose tissue with the hormone patterns modulating appetite and satiety. Extracts whose mode of action have been well characterized and that are safe, can be used clinically to perform a moderate, but continuous, caloric restriction in overweight patients to lose weight excess into a controlled protocol.
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Affiliation(s)
- M Boix-Castejón
- Institute of Research, Development and Innovation in Health Biotechnology of Elche (IDiBE), Universitas Miguel Hernández (UMH), 03202, Elche, Spain
| | - E Roche
- Institute of Bioengineering, Applied Biology Department-Nutrition, University Miguel-Hernández, 03202, Elche, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010, Alicante, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - M Olivares-Vicente
- Institute of Research, Development and Innovation in Health Biotechnology of Elche (IDiBE), Universitas Miguel Hernández (UMH), 03202, Elche, Spain
| | - F J Álvarez-Martínez
- Institute of Research, Development and Innovation in Health Biotechnology of Elche (IDiBE), Universitas Miguel Hernández (UMH), 03202, Elche, Spain
| | - M Herranz-López
- Institute of Research, Development and Innovation in Health Biotechnology of Elche (IDiBE), Universitas Miguel Hernández (UMH), 03202, Elche, Spain.
| | - V Micol
- Institute of Research, Development and Innovation in Health Biotechnology of Elche (IDiBE), Universitas Miguel Hernández (UMH), 03202, Elche, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
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17
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Zhihong Y, Chen W, Qianqian Z, Lidan S, Qiang Z, Jing H, Wenxi W, Bhawal R. Emerging roles of oxyntomodulin-based glucagon-like peptide-1/glucagon co-agonist analogs in diabetes and obesity. Peptides 2023; 162:170955. [PMID: 36669563 DOI: 10.1016/j.peptides.2023.170955] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 01/13/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023]
Abstract
Oxyntomodulin (OXM) is an endogenous peptide hormone secreted from the intestines following nutrient ingestion that activates both glucagon-like peptide-1 (GLP-1) and glucagon receptors. OXM is known to exert various effects, including improvement in glucose tolerance, promotion of energy expenditure, acceleration of liver lipolysis, inhibition of food intake, delay of gastric emptying, neuroprotection, and pain relief. The antidiabetic and antiobesity properties have led to the development of biologically active and enzymatically stable OXM-based analogs with proposed therapeutic promise for metabolic diseases. Structural modification of OXM was ongoing to enhance its potency and prolong half-life, and several GLP-1/glucagon dual receptor agonist-based therapies are being explored in clinical trials for the treatment of type 2 diabetes mellitus and its complications. In the present article, we provide a brief overview of the physiology of OXM, focusing on its structural-activity relationship and ongoing clinical development.
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Affiliation(s)
- Yao Zhihong
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, China; College of Pharmacy, Zhejiang University of Technology, Hangzhou 310000, China
| | - Wang Chen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, China
| | - Zhu Qianqian
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, China
| | - Sun Lidan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, China.
| | - Zhou Qiang
- The First Hospital of Jiaxing & The Affiliated Hospital of Jiaxing University, Jiaxing 314001, China.
| | - Han Jing
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, China
| | - Wang Wenxi
- The First Hospital of Jiaxing & The Affiliated Hospital of Jiaxing University, Jiaxing 314001, China; College of Pharmacy, Zhejiang University of Technology, Hangzhou 310000, China
| | - Ruchika Bhawal
- Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA
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18
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de Laat MA, Fitzgerald DM. Equine metabolic syndrome: Role of the enteroinsular axis in the insulin response to oral carbohydrate. Vet J 2023; 294:105967. [PMID: 36858344 DOI: 10.1016/j.tvjl.2023.105967] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/17/2023] [Accepted: 02/26/2023] [Indexed: 03/02/2023]
Abstract
Equine insulin dysregulation (ID) comprises amplified insulin responses to oral carbohydrates or insulin resistance, or both, which leads to sustained or periodic hyperinsulinaemia. Hyperinsulinaemia is important in horses because of its clear association with laminitis risk, and the gravity of this common sequela justifies the need for a better understanding of insulin and glucose homoeostasis in this species. Post-prandial hyperinsulinaemia is the more commonly identified component of ID and is diagnosed using tests that include an assessment of the gastrointestinal tract (GIT). There are several factors present in the GIT that either directly, or indirectly, enhance insulin secretion from the endocrine pancreas, and these factors are collectively referred to as the enteroinsular axis (EIA). A role for key components of the EIA, such as the incretin peptides glucagon-like peptide-1 and 2, in the pathophysiology of ID has been investigated in horses. By comparison, the function (and even existence) of many EIA peptides of potential importance, such as glicentin and oxyntomodulin, remains unexplored. The incretins that have been examined all increase insulin responses to oral carbohydrate through one or more mechanisms. This review presents what is known about the EIA in horses, and discusses how it might contribute to ID, then compares this to current understanding derived from the extensive studies undertaken in other species. Future directions for research are discussed and knowledge gaps that should be prioritised are suggested.
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Affiliation(s)
- Melody A de Laat
- School of Biology and Environmental Science, Faculty of Science, Queensland University of Technology, Brisbane 4000, Australia.
| | - Danielle M Fitzgerald
- School of Biology and Environmental Science, Faculty of Science, Queensland University of Technology, Brisbane 4000, Australia
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19
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Zhang X, Cai Y, Yao Z, Chi H, Li Y, Shi J, Zhou Z, Sun L. Discovery of novel OXM-based glucagon-like peptide 1 (GLP-1)/glucagon receptor dual agonists. Peptides 2023; 161:170948. [PMID: 36646385 DOI: 10.1016/j.peptides.2023.170948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023]
Abstract
Novel glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have improved efficacy over GLP-1R mono-agonists in treating type 2 diabetes (T2DM) and obesity. Here, we describe the discovery of a novel oxyntomodulin (OXM) based GLP-1R/GCGR dual agonist with potent and balanced potency toward GLP-1R and GCGR. The lead peptide OXM-7 was obtained via stepwise rational design and long-acting modification. In ICR and db/db mice, OXM-7 exhibited prominent acute and long-acting hypoglycemic effects. In diet-induced obesity (DIO) mice, twice-daily administration of OXM-7 produced significant weight loss, normalized lipid metabolism, and improved glucose control. In DIO-nonalcoholic steatohepatitis (NASH) mice, OXM-7 treatment significantly reversed hepatic steatosis, and reduced serum and hepatic lipid levels. These preclinical data suggest the therapeutic potential of OXM-7 as a novel anti-diabetic, anti-steatotic and/or anti-obesity agent.
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Affiliation(s)
- Xiaolong Zhang
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Yuchen Cai
- School of Engineering, China Pharmaceutical University, Nanjing 210009, Jiangsu, PR China
| | - Zhihong Yao
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, PR China
| | - Heng Chi
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Yan Li
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Jingjing Shi
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Zhongbo Zhou
- School of Pharmacy, Youjiang Medical University for Nationalities, 98 Chengxiang Road, Baise 533000, Guangxi, PR China.
| | - Lidan Sun
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, PR China.
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Shehzad A, Rabail R, Munir S, Jan H, Fernández-Lázaro D, Aadil RM. Impact of Oats on Appetite Hormones and Body Weight Management: A Review. Curr Nutr Rep 2023; 12:66-82. [PMID: 36790719 PMCID: PMC9930024 DOI: 10.1007/s13668-023-00454-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2022] [Indexed: 02/16/2023]
Abstract
PURPOSE OF REVIEW This study aims to review the hunger hormones in obesity management and the impact of oats in regulating these hormones for hunger suppression and body weight management. In this review, the impact of various edible forms of oats like whole, naked, sprouted, or supplemented has been investigated for their appetite hormones regulation and weight management. RECENT FINDINGS The onset of obesity has been greatly associated with the appetite-regulating hormones that control, regulate, and suppress hunger, satiety, or energy expenditure. Many observational and clinical studies prove that oats have a positive effect on anthropometric measures like BMI, waist circumference, waist-to-hip ratio, lipid profile, total cholesterol, weight, appetite, and blood pressure. Many studies support the concept that oats are rich in protein, fiber, healthy fats, Fe, Zn, Mg, Mn, free phenolics, ß-glucan, ferulic acid, avenanthramides, and many more. Beta-glucan is the most important bioactive component that lowers cholesterol levels and supports the defense system of the body to prevent infections. Hence, several clinical studies supported oats utilization against obesity, appetite hormones, and energy regulation but still, some studies have shown no or little significance on appetite. Results of various studies revealed the therapeutic potentials of oats for body weight management, appetite control, strengthening the immune system, lowering serum cholesterol, and gut microbiota promotion by increased production of short-chain fatty acids.
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Affiliation(s)
- Amna Shehzad
- grid.413016.10000 0004 0607 1563National Institute of Food Science and Technology, University of Agriculture, Faisalabad, 38000 Pakistan
| | - Roshina Rabail
- grid.413016.10000 0004 0607 1563National Institute of Food Science and Technology, University of Agriculture, Faisalabad, 38000 Pakistan
| | - Seemal Munir
- grid.413016.10000 0004 0607 1563National Institute of Food Science and Technology, University of Agriculture, Faisalabad, 38000 Pakistan
| | - Hamza Jan
- grid.508534.fDepartment of Clinical Nutrition, Nur International University, Lahore, 54950 Pakistan
| | - Diego Fernández-Lázaro
- grid.5239.d0000 0001 2286 5329Departamento de Biología Celular, Genética, Histología y Farmacología, Facultad de Ciencias de la Salud, Campus de Soria, Universidad de Valladolid, Soria, 42004 Spain
- grid.5239.d0000 0001 2286 5329Grupo de Investigación Reconocido “Neurobiología”, Facultad de Medicina, Universidad de Valladolid, Valladolid, 47005 Spain
| | - Rana Muhammad Aadil
- grid.413016.10000 0004 0607 1563National Institute of Food Science and Technology, University of Agriculture, Faisalabad, 38000 Pakistan
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Inceu AI, Neag MA, Craciun AE, Buzoianu AD. Gut Molecules in Cardiometabolic Diseases: The Mechanisms behind the Story. Int J Mol Sci 2023; 24:3385. [PMID: 36834796 PMCID: PMC9965280 DOI: 10.3390/ijms24043385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023] Open
Abstract
Atherosclerotic cardiovascular disease is the most common cause of morbidity and mortality worldwide. Diabetes mellitus increases cardiovascular risk. Heart failure and atrial fibrillation are associated comorbidities that share the main cardiovascular risk factors. The use of incretin-based therapies promoted the idea that activation of alternative signaling pathways is effective in reducing the risk of atherosclerosis and heart failure. Gut-derived molecules, gut hormones, and gut microbiota metabolites showed both positive and detrimental effects in cardiometabolic disorders. Although inflammation plays a key role in cardiometabolic disorders, additional intracellular signaling pathways are involved and could explain the observed effects. Revealing the involved molecular mechanisms could provide novel therapeutic strategies and a better understanding of the relationship between the gut, metabolic syndrome, and cardiovascular diseases.
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Affiliation(s)
- Andreea-Ioana Inceu
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Maria-Adriana Neag
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Anca-Elena Craciun
- Department of Diabetes, and Nutrition Diseases, Iuliu Hatieganu University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania
| | - Anca-Dana Buzoianu
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
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22
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Corbin KD, Carnero EA, Allerton TD, Tillner J, Bock CP, Luyet PP, Göbel B, Hall KD, Parsons SA, Ravussin E, Smith SR. Glucagon-like peptide-1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: A randomized trial. Obesity (Silver Spring) 2023; 31:350-362. [PMID: 36695055 PMCID: PMC9881753 DOI: 10.1002/oby.23633] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/16/2022] [Accepted: 10/02/2022] [Indexed: 01/26/2023]
Abstract
OBJECTIVE This study tested the hypothesis that treatment with the glucagon-like peptide-1/glucagon receptor agonist SAR425899 would lead to a smaller decrease in sleeping metabolic rate (SMR; kilocalories/day) than expected from the loss of lean and fat mass (metabolic adaptation). METHODS This Phase 1b, double-blind, randomized, placebo-controlled study was conducted at two centers in inpatient metabolic wards. Thirty-five healthy males and females with overweight and obesity (age = 36.5 ± 7.1 years) were randomized to a calorie-reduced diet (-1000 kcal/d) and escalating doses (0.06-0.2 mg/d) of SAR425899 (n = 17) or placebo (n = 18) for 19 days. SMR was measured by whole-room calorimetry. RESULTS Both groups lost weight (-3.68 ± 1.37 kg placebo; -4.83 ± 1.44 kg SAR425899). Those treated with SAR425899 lost more weight, fat mass, and fat free mass (p < 0.05) owing to a greater achieved energy deficit than planned. The SAR425899 group had a smaller reduction in body composition-adjusted SMR (p = 0.002) as compared with placebo, but not 24-hour energy expenditure. Fat oxidation and ketogenesis increased in both groups, with significantly greater increases with SAR425899 (p < 0.05). CONCLUSIONS SAR425899 led to reduced selective metabolic adaptation and increased lipid oxidation, which are believed to be beneficial for weight loss and weight-loss maintenance.
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Affiliation(s)
- Karen D Corbin
- AdventHealth Translational Research Institute, Orlando, Florida, USA
| | - Elvis A Carnero
- AdventHealth Translational Research Institute, Orlando, Florida, USA
| | | | | | | | | | | | - Kevin D Hall
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | | | - Eric Ravussin
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Steven R Smith
- AdventHealth Translational Research Institute, Orlando, Florida, USA
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23
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Feris F, McRae A, Kellogg TA, McKenzie T, Ghanem O, Acosta A. Mucosal and hormonal adaptations after Roux-en-Y gastric bypass. Surg Obes Relat Dis 2023; 19:37-49. [PMID: 36243547 PMCID: PMC9797451 DOI: 10.1016/j.soard.2022.08.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 01/12/2023]
Abstract
The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.
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Affiliation(s)
- Fauzi Feris
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Alison McRae
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Todd A Kellogg
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Travis McKenzie
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Omar Ghanem
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Andres Acosta
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
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24
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Development of a selective, sensitive and robust oxyntomodulin dual monoclonal antibody immunoassay. Bioanalysis 2022; 14:1229-1239. [DOI: 10.4155/bio-2022-0084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background & Aim: Oxyntomodulin (Oxm) is a proglucagon-derived peptide agonist of both the GLP-1 and glucagon receptors and is a key regulator of gastric acid secretion and energy expenditure. Differential processing from proglucagon hinders assay immunoassay selectivity. Method & results: Antibody engineering was used to develop a sandwich immunoassay that selectively measures endogenous Oxm. The pre- and postprandial levels of Oxm from 19 healthy individuals over the course of 2 h were measured. Postprandial increases in Oxm occurred within minutes and levels significantly correlated with those obtained using previously published mass spectrometry assays. Conclusion: This sandwich immunoassay is appropriately sensitive and selective and is also amenable to high-throughput application for the reliable determination of endogenous levels of intact Oxm from human samples.
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25
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Martinou E, Stefanova I, Iosif E, Angelidi AM. Neurohormonal Changes in the Gut-Brain Axis and Underlying Neuroendocrine Mechanisms following Bariatric Surgery. Int J Mol Sci 2022; 23:3339. [PMID: 35328759 PMCID: PMC8954280 DOI: 10.3390/ijms23063339] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 02/05/2023] Open
Abstract
Obesity is a complex, multifactorial disease that is a major public health issue worldwide. Currently approved anti-obesity medications and lifestyle interventions lack the efficacy and durability needed to combat obesity, especially in individuals with more severe forms or coexisting metabolic disorders, such as poorly controlled type 2 diabetes. Bariatric surgery is considered an effective therapeutic modality with sustained weight loss and metabolic benefits. Numerous genetic and environmental factors have been associated with the pathogenesis of obesity, while cumulative evidence has highlighted the gut-brain axis as a complex bidirectional communication axis that plays a crucial role in energy homeostasis. This has led to increased research on the roles of neuroendocrine signaling pathways and various gastrointestinal peptides as key mediators of the beneficial effects following weight-loss surgery. The accumulate evidence suggests that the development of gut-peptide-based agents can mimic the effects of bariatric surgery and thus is a highly promising treatment strategy that could be explored in future research. This article aims to elucidate the potential underlying neuroendocrine mechanisms of the gut-brain axis and comprehensively review the observed changes of gut hormones associated with bariatric surgery. Moreover, the emerging role of post-bariatric gut microbiota modulation is briefly discussed.
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Affiliation(s)
- Eirini Martinou
- Department of Upper Gastrointestinal Surgery, Frimley Health NHS Foundation Trust, Camberley GU16 7UJ, UK;
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Irena Stefanova
- Department of General Surgery, Frimley Health NHS Foundation Trust, Camberley GU16 7UJ, UK;
| | - Evangelia Iosif
- Department of General Surgery, Royal Surrey County Hospital, Guildford GU2 7XX, UK;
| | - Angeliki M. Angelidi
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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26
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Bosch R, Petrone M, Arends R, Vicini P, Sijbrands EJG, Hoefman S, Snelder N. A novel integrated QSP model of in vivo human glucose regulation to support the development of a glucagon/GLP‐1 dual agonist. CPT Pharmacometrics Syst Pharmacol 2022; 11:302-317. [PMID: 34889083 PMCID: PMC8923724 DOI: 10.1002/psp4.12752] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 10/12/2021] [Accepted: 09/23/2021] [Indexed: 11/09/2022] Open
Affiliation(s)
| | - Marcella Petrone
- Clinical Pharmacology and Safety Sciences AstraZeneca Cambridge UK
| | | | - Paolo Vicini
- Clinical Pharmacology and Safety Sciences AstraZeneca Cambridge UK
| | - Eric J. G. Sijbrands
- Department of Internal Medicine Erasmus MC University Medical Center Rotterdam The Netherlands
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27
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Del Prato S, Gallwitz B, Holst JJ, Meier JJ. The incretin/glucagon system as a target for pharmacotherapy of obesity. Obes Rev 2022; 23:e13372. [PMID: 34713962 PMCID: PMC9286339 DOI: 10.1111/obr.13372] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/14/2022]
Abstract
Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single-targeting agents have limited efficacy. Proglucagon-derived peptides, glucagon, and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP-1/GIP and GLP-1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP-1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists.
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Affiliation(s)
- Stefano Del Prato
- Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Baptist Gallwitz
- Department of Internal Medicine IVEberhard Karls UniversityTübingenGermany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center MunichUniversity of TübingenTübingenGermany
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Juris J. Meier
- Division of Diabetology, Katholisches Klinikum Bochum, St. Josef HospitalRuhr UniversityBochumGermany
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28
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OUP accepted manuscript. Nutr Rev 2022; 80:1942-1957. [DOI: 10.1093/nutrit/nuac010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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29
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Conlon JM, O'Harte FPM, Flatt PR. Dual-agonist incretin peptides from fish with potential for obesity-related Type 2 diabetes therapy - A review. Peptides 2022; 147:170706. [PMID: 34861327 DOI: 10.1016/j.peptides.2021.170706] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 12/25/2022]
Abstract
The long-acting glucagon-like peptide-1 receptor (GLP1R) agonist, semaglutide and the unimolecular glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP1R dual-agonist, tirzepatide have been successfully introduced as therapeutic options for patients with Type-2 diabetes (T2DM) and obesity. Proglucagon-derived peptides from phylogenetically ancient fish act as naturally occurring dual agonists at the GLP1R and the glucagon receptor (GCGR) with lamprey GLP-1 and paddlefish glucagon being the most potent and effective in stimulating insulin release from BRIN-BD11 clonal β-cells. These peptides were also the most effective in lowering blood glucose and elevating plasma insulin concentrations when administered intraperitoneally to overnight-fasted mice together with a glucose load. Zebrafish GIP acts as a dual agonist at the GIPR and GLP1R receptors. Studies with the high fat-fed mouse, an animal model with obesity, impaired glucose-tolerance and insulin-resistance, have shown that twice-daily administration of the long-acting analogs [D-Ala2]palmitoyl-lamprey GLP-1 and [D-Ser2]palmitoyl-paddlefish glucagon over 21 days improves glucose tolerance and insulin sensitivity. This was associated with β-cell proliferation, protection of β-cells against apoptosis, decreased pancreatic glucagon content, improved lipid profile, reduced food intake and selective alteration in the expression of genes involved in β-cell stimulus-secretion coupling. In insulin-deficient GluCreERT2;ROSA26-eYFP transgenic mice, the peptides promoted an increase in β-cell mass with positive effects on transdifferentiation of glucagon-producing to insulin-producing cells. Naturally occurring fish dual agonist peptides, particularly lamprey GLP-1 and paddlefish glucagon, provide templates for development into therapeutic agents for obesity-related T2DM.
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Affiliation(s)
- J Michael Conlon
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
| | - Finbarr P M O'Harte
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK
| | - Peter R Flatt
- Diabetes Research Group, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK
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30
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Kimita W, Bharmal SH, Ko J, Cho J, Petrov MS. Relationship between Energy Balance and Circulating Levels of Hepcidin and Ferritin in the Fasted and Postprandial States. Nutrients 2021; 13:3557. [PMID: 34684558 PMCID: PMC8539037 DOI: 10.3390/nu13103557] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 02/07/2023] Open
Abstract
Markers of iron metabolism are altered in new-onset diabetes, but their relationship with metabolic signals involved in the maintenance of energy balance is poorly understood. The primary aim was to explore the associations between markers of iron metabolism (hepcidin and ferritin) and markers of energy balance (leptin, ghrelin, and the leptin/ghrelin ratio) in both the fasted and postprandial states. These associations were also studied in the sub-groups stratified by diabetes status. This was a cross-sectional study of individuals without disorders of iron metabolism who were investigated after an overnight fast and, in addition, some of these individuals underwent a mixed meal test to determine postprandial responses of metabolic signals. The associations between hepcidin, ferritin, and leptin, ghrelin, leptin/ghrelin ratio were studied using several multiple linear regression models. A total of 76 individuals in the fasted state and 34 individuals in the postprandial state were included. In the overall cohort, hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was -883.45 ± 400.94; p = 0.031) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was -148.26 ± 61.20; p = 0.018) in the fasted state. The same associations were not statistically significant in the postprandial state. In individuals with new-onset prediabetes or diabetes (but not in those with normoglycaemia or longstanding prediabetes or diabetes), hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was -806.09 ± 395.44; p = 0.050) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was -129.40 ± 59.14; p = 0.037). Leptin appears to be a mediator in the link between iron metabolism and new-onset diabetes mellitus. These findings add to the growing understanding of mechanisms underlying the derangements of glucose metabolism.
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Affiliation(s)
| | | | | | | | - Maxim S. Petrov
- School of Medicine, University of Auckland, Auckland 1023, New Zealand; (W.K.); (S.H.B.); (J.K.); (J.C.)
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31
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Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules 2021; 11:1426. [PMID: 34680059 PMCID: PMC8533625 DOI: 10.3390/biom11101426] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/16/2021] [Accepted: 09/22/2021] [Indexed: 12/13/2022] Open
Abstract
Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.
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Affiliation(s)
- Erind Gjermeni
- Department of Electrophysiology, Heart Center Leipzig at University of Leipzig, 04289 Leipzig, Germany;
- Department of Cardiology, Median Centre for Rehabilitation Schmannewitz, 04774 Dahlen, Germany;
| | - Anna S. Kirstein
- Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany; (A.S.K.); (F.K.); (A.G.)
| | - Florentien Kolbig
- Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany; (A.S.K.); (F.K.); (A.G.)
| | - Michael Kirchhof
- Department of Cardiology, Median Centre for Rehabilitation Schmannewitz, 04774 Dahlen, Germany;
| | - Linnaeus Bundalian
- Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany;
| | - Julius L. Katzmann
- Klinik und Poliklinik für Kardiologie, University Clinic Leipzig, 04103 Leipzig, Germany; (J.L.K.); (U.L.)
| | - Ulrich Laufs
- Klinik und Poliklinik für Kardiologie, University Clinic Leipzig, 04103 Leipzig, Germany; (J.L.K.); (U.L.)
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany;
| | - Antje Garten
- Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany; (A.S.K.); (F.K.); (A.G.)
| | - Diana Le Duc
- Institute of Human Genetics, University Medical Center Leipzig, 04103 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, 04103 Leipzig, Germany;
- Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany
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32
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Hope DCD, Vincent ML, Tan TMM. Striking the Balance: GLP-1/Glucagon Co-Agonism as a Treatment Strategy for Obesity. Front Endocrinol (Lausanne) 2021; 12:735019. [PMID: 34566894 PMCID: PMC8457634 DOI: 10.3389/fendo.2021.735019] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/18/2021] [Indexed: 12/24/2022] Open
Abstract
Obesity and Type 2 diabetes represent global health challenges, and there is an unmet need for long-lasting and effective pharmacotherapies. Although long-acting glucagon-like peptide-1 (GLP-1) analogues are now in routine use for diabetes and are now being utilised for obesity per se, the need for ever better treatments has driven the development of co-agonists, with the theoretical advantages of improved efficacy by targeting multiple pathways and reduced adverse effects. In this review, we highlight the past and present progress in our understanding and development of treatments based on GLP-1/glucagon co-agonism. We also reflect on the divergent effects of varying the GLP-1:glucagon activity and ratio in the context of pre-clinical and human clinical trial findings. In particular, the multiple metabolic actions of glucagon highlight the importance of understanding the contributions of individual hormone action to inform the safe, effective and tailored use of GLP-1/glucagon co-agonists to target weight loss and metabolic disease in the future.
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Affiliation(s)
| | | | - Tricia M. M. Tan
- Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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33
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Di Mauro A, Tuccinardi D, Watanabe M, Del Toro R, Monte L, Giorgino R, Rampa L, Rossini G, Kyanvash S, Soare A, Rosati M, Piccoli A, Napoli N, Fioriti E, Pozzilli P, Khazrai YM, Manfrini S. The Mediterranean diet increases glucagon-like peptide 1 and oxyntomodulin compared with a vegetarian diet in patients with type 2 diabetes: A randomized controlled cross-over trial. Diabetes Metab Res Rev 2021; 37:e3406. [PMID: 32926502 DOI: 10.1002/dmrr.3406] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/30/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022]
Abstract
AIM To compare a Mediterranean diet (MED) with a high-fibre vegetarian diet (HFV) in terms of hunger-satiety perception through post-prandial assessment of appetite-related hormones glucagon-like peptide 1 (GLP-1) and oxyntomodulin, as well as self-rated visual analogue scale (VAS) quantification, in overweight/obese subjects with type 2 diabetes (T2D). MATERIALS AND METHODS Twelve T2D subjects (Male to female ratio = 7:5), mean age 63 ± 8.5 years, were enrolled in a randomized, controlled, crossover study. Participants consumed an MED meal as well as an isocaloric meal rich in complex carbohydrate as well as an isocaloric MED meal in two different visits with a 1-week washout period between the two visits. Appetite ratings, glucose/insulin, and gastrointestinal hormone concentrations were measured at fasting and every 30' until 210' following meal consumption. RESULTS GLP-1 and oxyntomodulin levels were significantly higher following MED meal compared with HFV meals (210' area under the curve, p < 0.022 and p < 0.023, respectively). Both MED and HFV meal resulted in a biphasic pattern of GLP-1 and oxyntomodulin, although MED meal was related to a delayed, significantly higher second GLP-1 peak at 150' compared with that of HFV meal (p < 0.05). MED meal was related to lower glucose profile compared with HFV meal (p < 0.039), whereas we did not observe significant changes in terms of self-reported VAS scores and insulin trend. CONCLUSIONS In T2D overweight/obese subjects, an MED meal is more effective than a HFV meal in terms of post-prandial plasma glucose homoeostasis and GLP-1 and oxyntomodulin release. These changes were not confirmed by VAS appetite self-assessment over a 210' period.
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Affiliation(s)
- Antonio Di Mauro
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Dario Tuccinardi
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Mikiko Watanabe
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - Rossella Del Toro
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Lavinia Monte
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Riccardo Giorgino
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Lorenzo Rampa
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Giovanni Rossini
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Shadi Kyanvash
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Andreea Soare
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Milena Rosati
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Alessandra Piccoli
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Nicoli Napoli
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
- Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, Missouri, USA
| | - Elvira Fioriti
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Paolo Pozzilli
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
- Centre of Immunobiology, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Yeganeh M Khazrai
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Silvia Manfrini
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
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Nogueiras R. MECHANISMS IN ENDOCRINOLOGY: The gut-brain axis: regulating energy balance independent of food intake. Eur J Endocrinol 2021; 185:R75-R91. [PMID: 34260412 PMCID: PMC8345901 DOI: 10.1530/eje-21-0277] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022]
Abstract
Obesity is a global pandemic with a large health and economic burden worldwide. Bodyweight is regulated by the ability of the CNS, and especially the hypothalamus, to orchestrate the function of peripheral organs that play a key role in metabolism. Gut hormones play a fundamental role in the regulation of energy balance, as they modulate not only feeding behavior but also energy expenditure and nutrient partitioning. This review examines the recent discoveries about hormones produced in the stomach and gut, which have been reported to regulate food intake and energy expenditure in preclinical models. Some of these hormones act on the hypothalamus to modulate thermogenesis and adiposity in a food intake-independent fashion. Finally, the association of these gut hormones to eating, energy expenditure, and weight loss after bariatric surgery in humans is discussed.
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Affiliation(s)
- Ruben Nogueiras
- Department of Physiology, CIMUS, USC, CIBER Fisiopatología Obesidad y Nutrición (CiberOBN), Instituto Salud Carlos III, Galician Agency of Innovation, Xunta de Galicia, Santiago de Compostela, Spain
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35
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Hansen MS, Frost M. Alliances of the gut and bone axis. Semin Cell Dev Biol 2021; 123:74-81. [PMID: 34303607 DOI: 10.1016/j.semcdb.2021.06.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022]
Abstract
Gut hormones secreted from enteroendocrine cells following nutrient ingestion modulate metabolic processes including glucose homeostasis and food intake, and several of these gut hormones are involved in the regulation of the energy demanding process of bone remodelling. Here, we review the gut hormones considered or known to be involved in the gut-bone crosstalk and their role in orchestrating adaptions of bone formation and resorption as demonstrated in cellular and physiological experiments and clinical trials. Understanding the physiology and pathophysiology of the gut-bone axis may identify adverse effects of investigational drugs aimed to treat metabolic diseases such as type 2 diabetes and obesity and new therapeutic candidates for the treatment of bone diseases.
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Affiliation(s)
- Morten Steen Hansen
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark
| | - Morten Frost
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark.
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36
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Jepsen MM, Christensen MB. Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. Expert Opin Emerg Drugs 2021; 26:231-243. [PMID: 34176426 DOI: 10.1080/14728214.2021.1947240] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Introduction: Obesity is a growing threat to public health, increasing risks of numerous diseases and mortality, and impairing quality of life. If current trends continue, more than 1.1 billion individuals will have obesity in 2030, corresponding to almost 2.5 times the number of adults currently living with diabetes. There is a strong interest in developing obesity treatments based on glucagon-like peptide-1 (GLP-1) agonism, which have proved to limit morbidity and mortality in type 2 diabetes.Areas covered: This review provides an overview of current compounds containing GLP-1 receptor agonism in clinical development for obesity, with mono-activity at the GLP-1 receptor (PF-0688296, glutazumab, semaglutide) or engaging one or more other endogenous hormonal systems involved in energy balance and metabolism, including glucagon, oxyntomodulin, glucose-dependent inhibitory peptide and amylin (CT-868, CT-388, AMG 133, tirzepatide, NNC9204-1177, JNJ-54,728,518, SAR425899, pegapamodutide, MK8521, cotadutide, efinopegdutide, BI-456,906, cagrilintide + semaglutide 2,4 mg, HM15211, NNC9204-1706).Expert opinion: Many novel compounds employing GLP-1 receptor agonism are in clinical development. Semaglutide is farthest in clinical development and will presumably become a benchmark for this class of novel anti-obesity compounds.
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Affiliation(s)
- Mathies M Jepsen
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.,Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
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Camacho RC, You S, D'Aquino KE, Li W, Wang Y, Gunnet J, Littrell J, Qi JS, Kang L, Jian W, MacDonald M, Tat T, Steiner D, Zhang YM, Lanter J, Patch R, Zhang R, Li J, Edavettal S, Edwards W, Dinh T, Wang LY, Connor J, Hunter M, Chi E, Swanson RV, Leonard JN, Case MA. Conjugation of a peptide to an antibody engineered with free cysteines dramatically improves half-life and activity. MAbs 2021; 12:1794687. [PMID: 32744157 PMCID: PMC7531507 DOI: 10.1080/19420862.2020.1794687] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The long circulating half-life and inherently bivalent architecture of IgGs provide an ideal vehicle for presenting otherwise short-lived G-protein-coupled receptor agonists in a format that enables avidity-driven enhancement of potency. Here, we describe the site-specific conjugation of a dual agonist peptide (an oxyntomodulin variant engineered for potency and in vivo stability) to the complementarity-determining regions (CDRs) of an immunologically silent IgG4. A cysteine-containing heavy chain CDR3 variant was identified that provided clean conjugation to a bromoacetylated peptide without interference from any of the endogenous mAb cysteine residues. The resulting mAb-peptide homodimer has high potency at both target receptors (glucagon receptor, GCGR, and glucagon-like peptide 1 receptor, GLP-1R) driven by an increase in receptor avidity provided by the spatially defined presentation of the peptides. Interestingly, the avidity effects are different at the two target receptors. A single dose of the long-acting peptide conjugate robustly inhibited food intake and decreased body weight in insulin resistant diet-induced obese mice, in addition to ameliorating glucose intolerance. Inhibition of food intake and decrease in body weight was also seen in overweight cynomolgus monkeys. The weight loss resulting from dosing with the bivalently conjugated dual agonist was significantly greater than for the monomeric analog, clearly demonstrating translation of the measured in vitro avidity to in vivo pharmacology.
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Affiliation(s)
| | | | | | - Wenyu Li
- Janssen R&D , Spring House, PA, USA
| | | | | | | | | | - Lijuan Kang
- Pharmacokinetics, Dynamics, and Metabolism, Janssen R&D , Spring House, PA, USA
| | - Wenying Jian
- Pharmacokinetics, Dynamics, and Metabolism, Janssen R&D , Spring House, PA, USA
| | - Mary MacDonald
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | - Timothy Tat
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | - Derek Steiner
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | | | | | | | | | - Jiali Li
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | | | - Wilson Edwards
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | - Thai Dinh
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | - Li Ying Wang
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | - Judy Connor
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | - Michael Hunter
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | - Ellen Chi
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | - Ronald V Swanson
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
| | | | - Martin A Case
- Janssen Biotherapeutics, Janssen R&D , San Diego, La Jolla, CA, USA
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Satin LS, Soleimanpour SA, Walker EM. New Aspects of Diabetes Research and Therapeutic Development. Pharmacol Rev 2021; 73:1001-1015. [PMID: 34193595 PMCID: PMC8274312 DOI: 10.1124/pharmrev.120.000160] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose-lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans. SIGNIFICANCE STATEMENT: Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.
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Affiliation(s)
- Leslie S Satin
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.) ; ;
| | - Scott A Soleimanpour
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.)
| | - Emily M Walker
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.) ; ;
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Vega RB, Whytock KL, Gassenhuber J, Goebel B, Tillner J, Agueusop I, Truax AD, Yu G, Carnero E, Kapoor N, Gardell S, Sparks LM, Smith SR. A Metabolomic Signature of Glucagon Action in Healthy Individuals With Overweight/Obesity. J Endocr Soc 2021; 5:bvab118. [PMID: 34337278 PMCID: PMC8317630 DOI: 10.1210/jendso/bvab118] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Indexed: 11/19/2022] Open
Abstract
Context Glucagon is produced and released from the pancreatic alpha-cell to regulate glucose levels during periods of fasting. The main target for glucagon action is the liver, where it activates gluconeogenesis and glycogen breakdown; however, glucagon is postulated to have other roles within the body. Objective We sought to identify the circulating metabolites that would serve as markers of glucagon action in humans. Methods In this study (NCT03139305), we performed a continuous 72-hour glucagon infusion in healthy individuals with overweight/obesity. Participants were randomized to receive glucagon 12.5 ng/kg/min (GCG 12.5), glucagon 25 ng/kg/min (GCG 25), or a placebo control. A comprehensive metabolomics analysis was then performed from plasma isolated at several time points during the infusion to identify markers of glucagon activity. Results Glucagon (GCG 12.5 and GCG 25) resulted in significant changes in the plasma metabolome as soon as 4 hours following infusion. Pathways involved in amino acid metabolism were among the most affected. Rapid and sustained reduction of a broad panel of amino acids was observed. Additionally, time-dependent changes in free fatty acids and diacylglycerol and triglyceride species were observed. Conclusion These results define a distinct signature of glucagon action that is broader than the known changes in glucose levels. In particular, the robust changes in amino acid levels may prove useful to monitor changes induced by glucagon in the context of additional glucagon-like peptide-1 or gastric inhibitory polypeptide treatment, as these agents also elicit changes in glucose levels.
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Affiliation(s)
- Rick B Vega
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
| | - Katie L Whytock
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
| | | | | | | | | | | | - Gongxin Yu
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
| | - Elvis Carnero
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
| | - Nidhi Kapoor
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
| | - Stephen Gardell
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
| | - Lauren M Sparks
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
| | - Steven R Smith
- Translational Research Institute, AdventHealth, Orlando, FL 32804, USA
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Abstract
OBJECTIVE New-onset diabetes is an important sequela of acute pancreatitis, but there are no biomarkers to differentiate it from the much more common type 2 diabetes. The objective was to investigate whether postprandial circulating levels of gut hormones can serve this purpose. METHODS This was a case-control study nested into a prospective longitudinal cohort study that included 42 insulin-naive cases with new-onset prediabetes/diabetes after acute pancreatitis (NODAP) and prediabetes/diabetes followed by acute pancreatitis (T2D-AP), sex matched with 21 healthy controls. All individuals underwent a standardized mixed-meal test, and blood samples were assayed for gut hormones (glucose-dependent insulinotropic peptide, glucagon-like peptide-1, oxyntomodulin, and peptide YY). Analysis of variance and linear regression analysis were conducted in unadjusted and adjusted models (accounting for age, homeostatic model assessment of β-cell function, and magnetic resonance imaging-derived body fat composition). RESULTS Oxyntomodulin levels were significantly lower in NODAP compared with T2D-AP and healthy controls (P = 0.027 and P = 0.001, respectively, in the most adjusted model). Glucagon-like peptide-1 and peptide YY were significantly lower in NODAP compared with T2D-AP (P = 0.001 and P = 0.014, respectively, in the most adjusted model) but not compared with healthy controls (P = 1.000 and P = 0.265, respectively, in the most adjusted model). Glucose-dependent insulinotropic peptide levels were not significantly different between NODAP and T2D-AP. DISCUSSION Oxyntomodulin is a promising biomarker to guide the differential diagnosis of new-onset diabetes after acute pancreatitis. However, external validation studies are warranted before it can be recommended for routine use in clinical practice.
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Kinna S, Ouberaï MM, Sonzini S, Gomes Dos Santos AL, Welland ME. Thermo-Responsive self-assembly of a dual glucagon-like peptide and glucagon receptor agonist. Int J Pharm 2021; 604:120719. [PMID: 34015379 DOI: 10.1016/j.ijpharm.2021.120719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/13/2021] [Accepted: 05/13/2021] [Indexed: 01/02/2023]
Abstract
The human peptide hormone Oxyntomodulin (Oxm) is known to induce satiety, increase energy expenditure, and control blood glucose in humans, making it a promising candidate for treatment of obesity and/or type 2 diabetes mellitus. However, a pharmaceutical exploitation has thus far been impeded by fast in vivo clearance and the molecule's sensitivity to half-life extending structural modifications. We recently showed that Oxm self-assembles into amyloid-like nanofibrils that continuously release active, soluble Oxm in a peptide-deprived environment. S.c. injected Oxm nanofibrils extended plasma exposure from a few hours to five days in rodents, compared to s.c. applied soluble Oxm. Here we show that Oxm fibril elongation kinetics and thermodynamics display a uniquely low temperature optimum compared to previously reported amyloid-like peptide and protein assemblies. Elongation rate is optimal at room temperature, with association rates 2-3 times higher at 25 °C than at ≥37 °C or ≤20 °C. We deduce from a combination of Cryo electron microscopy and spectroscopic methods that Oxm fibrils have a double-layered, triangular cross-section composed of arch-shaped monomers. We suggest a thermodynamic model that links the necessary molecular rearrangements during fibrillation and peptide release to the unique temperature effects in Oxm self-assembly and disassembly.
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Affiliation(s)
- Sonja Kinna
- Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB30FF, UK
| | - Myriam M Ouberaï
- Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB30FF, UK.
| | - Silvia Sonzini
- Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca, Granta Park, Cambridge CB21 6GH, UK
| | - Ana L Gomes Dos Santos
- Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca, Granta Park, Cambridge CB21 6GH, UK.
| | - Mark E Welland
- Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca, Granta Park, Cambridge CB21 6GH, UK
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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.
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Affiliation(s)
| | | | | | - Victor A. Gault
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
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Schalla MA, Taché Y, Stengel A. Neuroendocrine Peptides of the Gut and Their Role in the Regulation of Food Intake. Compr Physiol 2021; 11:1679-1730. [PMID: 33792904 DOI: 10.1002/cphy.c200007] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The regulation of food intake encompasses complex interplays between the gut and the brain. Among them, the gastrointestinal tract releases different peptides that communicate the metabolic state to specific nuclei in the hindbrain and the hypothalamus. The present overview gives emphasis on seven peptides that are produced by and secreted from specialized enteroendocrine cells along the gastrointestinal tract in relation with the nutritional status. These established modulators of feeding are ghrelin and nesfatin-1 secreted from gastric X/A-like cells, cholecystokinin (CCK) secreted from duodenal I-cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY) secreted from intestinal L-cells and uroguanylin (UGN) released from enterochromaffin (EC) cells. © 2021 American Physiological Society. Compr Physiol 11:1679-1730, 2021.
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Affiliation(s)
- Martha A Schalla
- Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Yvette Taché
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.,VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Andreas Stengel
- Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.,Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany
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Abstract
Bariatric and metabolic surgery has evolved from simple experimental procedures for a chronic problem associated with significant morbidity into a sophisticated multidisciplinary treatment modality rooted in biology and physiology. Although the complete mechanistic narrative of bariatric surgery cannot yet be written, significant advance in knowledge has been made in the past 2 decades. This article provides a brief overview of the most studied hypotheses and their supporting evidence. Ongoing research, especially in frontier areas, such as the microbiome, will continue to refine, and perhaps even revise, current mechanistic understanding.
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45
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Ricardo-Silgado ML, McRae A, Acosta A. Role of Enteroendocrine Hormones in Appetite and Glycemia. ACTA ACUST UNITED AC 2021; 23. [PMID: 34179564 DOI: 10.1016/j.obmed.2021.100332] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Enteroendocrine cells (EECs) are specialized cells that are widely distributed throughout the gastrointestinal tract. EECs sense luminal content and release hormones, such as: ghrelin, cholecystokinin, glucagon like peptide 1, peptide YY, insulin like peptide 5, and oxyntomodulin. These hormones can enter the circulation to act on distant targets or act locally on neighboring cells and neuronal pathways to modulate food digestion, food intake, energy balance and body weight. Obesity, insulin resistance and diabetes are associated with alterations in the levels of enteroendocrine hormones. Evidence also suggests that modified regulation and release of gut hormones are the result of compensatory mechanisms in states of excess adipose tissue and hyperglycemia. This review collects the evidence available detailing pathophysiological alterations in enteroendocrine hormones and their association with appetite, obesity and glycemic control.
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Affiliation(s)
- Maria Laura Ricardo-Silgado
- Precision Medicine for Obesity Program, and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Alison McRae
- Precision Medicine for Obesity Program, and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Andres Acosta
- Precision Medicine for Obesity Program, and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
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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.
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Klockars A, Levine AS, Head MA, Perez-Leighton CE, Kotz CM, Olszewski PK. Impact of Gut and Metabolic Hormones on Feeding Reward. Compr Physiol 2021; 11:1425-1447. [PMID: 33577129 DOI: 10.1002/cphy.c190042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Ingestion of food activates a cascade of endocrine responses (thereby reflecting a contemporaneous feeding status) that include the release of hormones from the gastrointestinal (GI) tract, such as cholecystokinin (CCK), glucagonlike peptide YY (PYY), peptide PP, and oleoylethanolamide, as well as suppression of ghrelin secretion. The pancreas and adipose tissue, on the other hand, release hormones that serve as a measure of the current metabolic state or the long-term energy stores, that is, insulin, leptin, and adiponectin. It is well known and intuitively understandable that these hormones target either directly (by crossing the blood-brain barrier) or indirectly (e.g., via vagal input) the "homeostatic" brainstem-hypothalamic pathways involved in the regulation of appetite. The current article focuses on yet another target of the metabolic and GI hormones that is critical in inducing changes in food intake, namely, the reward system. We discuss the physiological basis of this functional interaction, its importance in the control of appetite, and the impact that disruption of this crosstalk has on energy intake in select physiological and pathophysiological states. We conclude that metabolic and GI hormones have a capacity to strengthen or weaken a response of the reward system to a given food, and thus, they are fundamental in ensuring that feeding reward is plastic and dependent on the energy status of the organism. © 2021 American Physiological Society. Compr Physiol 11:1425-1447, 2021.
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Affiliation(s)
- Anica Klockars
- Faculty of Science and Engineering, University of Waikato, Hamilton, New Zealand
| | - Allen S Levine
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota, USA
| | - Mitchell A Head
- Faculty of Science and Engineering, University of Waikato, Hamilton, New Zealand
| | | | - Catherine M Kotz
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota, USA.,Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Pawel K Olszewski
- Faculty of Science and Engineering, University of Waikato, Hamilton, New Zealand.,Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota, USA.,Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
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Alhabeeb H, AlFaiz A, Kutbi E, AlShahrani D, Alsuhail A, AlRajhi S, Alotaibi N, Alotaibi K, AlAmri S, Alghamdi S, AlJohani N. Gut Hormones in Health and Obesity: The Upcoming Role of Short Chain Fatty Acids. Nutrients 2021; 13:nu13020481. [PMID: 33572661 PMCID: PMC7911102 DOI: 10.3390/nu13020481] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 12/21/2020] [Accepted: 12/30/2020] [Indexed: 12/13/2022] Open
Abstract
We are currently facing an obesity pandemic, with worldwide obesity rates having tripled since 1975. Obesity is one of the main risk factors for the development of non-communicable diseases, which are now the leading cause of death worldwide. This calls for urgent action towards understanding the underlying mechanisms behind the development of obesity as well as developing more effective treatments and interventions. Appetite is carefully regulated in humans via the interaction between the central nervous system and peripheral hormones. This involves a delicate balance in external stimuli, circulating satiating and appetite stimulating hormones, and correct functioning of neuronal signals. Any changes in this equilibrium can lead to an imbalance in energy intake versus expenditure, which often leads to overeating, and potentially weight gain resulting in overweight or obesity. Several lines of research have shown imbalances in gut hormones are found in those who are overweight or obese, which may be contributing to their condition. Therefore, this review examines the evidence for targeting gut hormones in the treatment of obesity by discussing how their dysregulation influences food intake, the potential possibility of altering the circulating levels of these hormones for treating obesity, as well as the role of short chain fatty acids and protein as novel treatments.
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Affiliation(s)
- Habeeb Alhabeeb
- Research Center, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia; (A.A.); (E.K.); (D.A.); (A.A.); (S.A.); (S.A.)
- Correspondence:
| | - Ali AlFaiz
- Research Center, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia; (A.A.); (E.K.); (D.A.); (A.A.); (S.A.); (S.A.)
| | - Emad Kutbi
- Research Center, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia; (A.A.); (E.K.); (D.A.); (A.A.); (S.A.); (S.A.)
| | - Dayel AlShahrani
- Research Center, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia; (A.A.); (E.K.); (D.A.); (A.A.); (S.A.); (S.A.)
| | - Abdullah Alsuhail
- Research Center, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia; (A.A.); (E.K.); (D.A.); (A.A.); (S.A.); (S.A.)
| | - Saleh AlRajhi
- Family Medicine, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia;
| | - Nemer Alotaibi
- College of Medicine, Shaqra University, Shaqra 11961, Saudi Arabia; (N.A.); (K.A.)
| | - Khalid Alotaibi
- College of Medicine, Shaqra University, Shaqra 11961, Saudi Arabia; (N.A.); (K.A.)
| | - Saad AlAmri
- Research Center, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia; (A.A.); (E.K.); (D.A.); (A.A.); (S.A.); (S.A.)
| | - Saleh Alghamdi
- Research Center, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia; (A.A.); (E.K.); (D.A.); (A.A.); (S.A.); (S.A.)
| | - Naji AlJohani
- Obesity, Endocrine, and Metabolism Center, King Fahad Medical City—KFMC, Riyadh 11525, Saudi Arabia;
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Li W, Kirchner T, Ho G, Bonilla F, D'Aquino K, Littrell J, Zhang R, Jian W, Qiu X, Zheng S, Gao B, Wong P, Leonard JN, Camacho RC. Amino acids are sensitive glucagon receptor-specific biomarkers for glucagon-like peptide-1 receptor/glucagon receptor dual agonists. Diabetes Obes Metab 2020; 22:2437-2450. [PMID: 33463043 DOI: 10.1111/dom.14173] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 12/31/2022]
Abstract
AIM The aim of this study was to evaluate amino acids as glucagon receptor (GCGR)-specific biomarkers in rodents and cynomolgus monkeys in the presence of agonism of both glucagon-like peptide-1 receptor (GLP1R) and GCGR with a variety of dual agonist compounds. MATERIALS AND METHODS Primary hepatocytes, rodents (normal, diet-induced obese and GLP1R knockout) and cynomolgus monkeys were treated with insulin (hepatocytes only), glucagon (hepatocytes and cynomolgus monkeys), the GLP1R agonist, dulaglutide, or a variety of dual agonists with varying GCGR potencies. RESULTS A long-acting dual agonist, Compound 2, significantly decreased amino acids in both wild-type and GLP1R knockout mice in the absence of changes in food intake, body weight, glucose or insulin, and increased expression of hepatic amino acid transporters. Dulaglutide, or a variant of Compound 2 lacking GCGR agonism, had no effect on amino acids. A third variant with ~31-fold less GCGR potency than Compound 2 significantly decreased amino acids, albeit to a significantly lesser extent than Compound 2. Dulaglutide (with saline infusion) had no effect on amino acids, but an infusion of glucagon dose-dependently decreased amino acids on the background of GLP1R engagement (dulaglutide) in cynomolgus monkeys, as did Compound 2. CONCLUSIONS These results show that amino acids are sensitive and translatable GCGR-specific biomarkers.
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Affiliation(s)
- Wenyu Li
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
| | - Thomas Kirchner
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
| | - George Ho
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
| | - Fany Bonilla
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
| | - Katharine D'Aquino
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
| | - James Littrell
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
| | - Rui Zhang
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
| | - Wenying Jian
- Pharmacokinetics, Dynamics, and Metabolism, Janssen R&D, Spring House, Pennsylvania, USA
| | - Xi Qiu
- Pharmacokinetics, Dynamics, and Metabolism, Janssen R&D, Spring House, Pennsylvania, USA
| | - Songmao Zheng
- Janssen Biotherapeutics, Janssen R&D, Spring House, Pennsylvania, USA
| | - Bin Gao
- Translational Medicine and Early Development Statistics, Janssen R&D, Spring House, Pennsylvania, USA
| | - Peggy Wong
- Quantitative Sciences, Janssen R&D, Raritan, New Jersey, USA
| | - James N Leonard
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
| | - Raul C Camacho
- Cardiovascular Metabolism Discovery, Janssen R&D, Spring House, Pennsylvania, USA
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50
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Halter B, Chowdhury VS, Gilbert ER, Cline MA. Oxyntomodulin induces satiety and activates the arcuate nucleus of the hypothalamus in Japanese quail. Comp Biochem Physiol A Mol Integr Physiol 2020; 247:110721. [DOI: 10.1016/j.cbpa.2020.110721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/30/2020] [Accepted: 04/30/2020] [Indexed: 10/24/2022]
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