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Tarasiuk-Zawadzka A, Fichna J. Interaction between nutritional factors and the enteric nervous system in inflammatory bowel diseases. J Nutr Biochem 2025:109959. [PMID: 40354831 DOI: 10.1016/j.jnutbio.2025.109959] [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: 04/17/2024] [Revised: 01/30/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
The enteric nervous system (ENS) is a highly conserved, yet complicated network of neurons and glial cells located throughout the gut wall that controls digestive processes and gastrointestinal (GI) homeostasis. The intestinal epithelium, the immune system, and the gut microbiota are just a few examples of the cellular networks that the ENS interacts with on a variety of levels to maintain GI function. The presence or absence of nutrients in the intestinal lumen may cause short- and/or long-term changes in neurotransmitter expression, excitability, and neuronal survival, which ultimately affect gut motility, secretion, and permeability. Hence, the ENS should be identified as a key factor in initiating coordinated responses to nutrients. In this review we summarize current knowledge on nutrient-dependent ENS activity and how ENS secondary to nutrition may affect likelihood of developing inflammatory bowel disease. Our findings highlight that nutrients interact with enteroendocrine cells in the gut, triggering hormone secretion that plays a crucial role in signaling food-related information to the brain and regulating metabolic processes such as feeding behavior, insulin secretion, and energy balance; however, the complex interactions between nutrients, the ENS, and the immune system require further research to understand their contributions to GI disorders and potential therapeutic applications in treating obesity and metabolic diseases. Lay Summary: The enteric nervous system (ENS) controls digestion and interacts with nutrients in the gut to regulate processes like gut movement and hormone release, affecting metabolism and overall gut health. This review highlights the need for further research on how nutrient-ENS interactions contribute to conditions like inflammatory bowel disease, obesity, and metabolic disorders.
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Affiliation(s)
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland
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Müller TD, Adriaenssens A, Ahrén B, Blüher M, Birkenfeld AL, Campbell JE, Coghlan MP, D'Alessio D, Deacon CF, DelPrato S, Douros JD, Drucker DJ, Figueredo Burgos NS, Flatt PR, Finan B, Gimeno RE, Gribble FM, Hayes MR, Hölscher C, Holst JJ, Knerr PJ, Knop FK, Kusminski CM, Liskiewicz A, Mabilleau G, Mowery SA, Nauck MA, Novikoff A, Reimann F, Roberts AG, Rosenkilde MM, Samms RJ, Scherer PE, Seeley RJ, Sloop KW, Wolfrum C, Wootten D, DiMarchi RD, Tschöp MH. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab 2025; 95:102118. [PMID: 40024571 PMCID: PMC11931254 DOI: 10.1016/j.molmet.2025.102118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. MAJOR CONCLUSIONS Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.
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Affiliation(s)
- Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany.
| | - Alice Adriaenssens
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Bo Ahrén
- Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
| | - Matthias Blüher
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Matthew P Coghlan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - David D'Alessio
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Carolyn F Deacon
- School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano DelPrato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | | | - Daniel J Drucker
- The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Natalie S Figueredo Burgos
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Brian Finan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Fiona M Gribble
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christian Hölscher
- Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Patrick J Knerr
- Indianapolis Biosciences Research Institute, Indianapolis, IN, USA
| | - Filip K Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christine M Kusminski
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arkadiusz Liskiewicz
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France
| | | | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany
| | - Frank Reimann
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Anna G Roberts
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Ricardo J Samms
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Philip E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kyle W Sloop
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland
| | - Denise Wootten
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | | | - Matthias H Tschöp
- Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
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Abdul-Rahman T, Roy P, Ahmed FK, Mueller-Gomez JL, Sarkar S, Garg N, Femi-Lawal VO, Wireko AA, Thaalibi HI, Hashmi MU, Dzebu AS, Banimusa SB, Sood A. The power of three: Retatrutide's role in modern obesity and diabetes therapy. Eur J Pharmacol 2024; 985:177095. [PMID: 39515565 DOI: 10.1016/j.ejphar.2024.177095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 10/19/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
The increasing prevalence of obesity and type 2 diabetes mellitus has resulted in a significant challenge to public health throughout the globe. It required the development of novel therapeutic approaches. Retatrutide is a groundbreaking triple agonist that targets glucagon receptors, gastric inhibitory polypeptide, and glucagon-like peptide-1. Retatrutide's complex mechanism of action involves a synergistic interaction among these receptors, resulting in increased insulin secretion, improved glucose homeostasis, and refined appetite modulation. Clinical trials in phases 1 to 3 have demonstrated significant efficacy, highlighted by significant reductions in body weight and favorable glycemic control outcomes. Additionally, retatrutide shows promise in mitigating cardiovascular risk factors and addressing metabolic dysfunction-associated steatotic liver disease. However, careful attention is required to delineate its long-term safety profile, explore its potential in special populations, unravel its adjunctive therapeutic roles, and elucidate its mechanisms in pediatric cohorts. As a transformative therapeutic modality, retatrutide represents a beacon of hope, signifying transformative changes in the management landscape of obesity and type 2 diabetes mellitus (T2DM), and warranting continued exploration and refinement in clinical practice. This narrative review examines the therapeutic potential of retatrutide in the management of obesity and T2DM.
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Affiliation(s)
| | - Poulami Roy
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; Department of Medicine, North Bengal Medical College and Hospital, Siliguri, India
| | - Fatma Kamal Ahmed
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; University of Nairobi, Nairobi, Kenya
| | - Jann Ludwig Mueller-Gomez
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; Center for Research in Health Sciences (CICSA), Faculty of Medicine, Anahuac University North Campus, Huixquilucan, Mexico
| | - Sarmistha Sarkar
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; Department of Psychiatry, Community Clinical Research, Inc., Austin, TX, USA
| | - Neil Garg
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; Rowan-Virtua School of Osteopathic Medicine, One Medical Center Drive Stratford, New Jersey, USA
| | - Victor Oluwafemi Femi-Lawal
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; Department of Medicine and Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Hala Ibrahim Thaalibi
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; Beirut Arab University Faculty of Medicine, Beirut, Lebanon
| | - Muhammad Usman Hashmi
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; Department of Physiology, Rawalpindi Medical University, Rawalpindi, Pakistan
| | | | - Sewar Basheer Banimusa
- Department of Research, Toufik's World Medical Association, Sumy, Ukraine; Basic Medical Sciences, Yarmouk University, Irbid, Jordan
| | - Aayushi Sood
- Department of Medicine, The Wright Center for Graduate Medical Education, Scranton, PA, USA.
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Dimitri P, Roth CL. Treatment of Hypothalamic Obesity With GLP-1 Analogs. J Endocr Soc 2024; 9:bvae200. [PMID: 39703362 PMCID: PMC11655849 DOI: 10.1210/jendso/bvae200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Indexed: 12/21/2024] Open
Abstract
Introduction Congenital and acquired damage to hypothalamic nuclei or neuronal circuits controlling satiety and energy expenditure results in hypothalamic obesity (HO). To date, successful weight loss and satiety has only been achieved in a limited number of affected patients across multiple drug trials. Glucagon-like peptide-1 (GLP-1) acts via central pathways that are independent from the hypothalamus to induce satiety. GLP-1 receptor agonists (GLP-1RAs) may provide an alternative approach to treating HO. Methods We performed a comprehensive search in Medline, Google Scholar, and clinical trials registries (ClinicalTrials.gov; clinicaltrialsregister.eur). This nonsystematic literature review was conducted to identify scientific papers published from January 2005 to February 2024 using the Pubmed and Embase databases. Key words used were GLP-1, GLP-1RA, hypothalamic obesity, suprasellar tumor, and craniopharyngioma. Results Our search identified 7 case studies, 5 case series, and 2 published clinical trials relating to the use of GLP-1RAs in HO. All case studies demonstrated weight loss and improved metabolic function. In contrast, results from case series were variable, with some showing no weight loss and others demonstrating moderate to significant weight loss and improved metabolic parameters. In the ECHO clinical trial, nearly half the subjects randomized to weekly exenatide showed reduced body mass index (BMI). Paradoxically, BMI reduction was greater in patients with more extensive hypothalamic injuries. Conclusion GLP-1RAs potentially offer a new approach to treating HO. There is a need to stratify patients who are more likely to respond. Further randomized controlled trials are required to determine their efficacy either in isolation or combined with other therapies.
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Affiliation(s)
- Paul Dimitri
- The Department of Paediatric Endocrinology, Sheffield Children's NHS Foundation Trust, Sheffield, S10 2TH, UK
- University of Sheffield, Sheffield, S10 2TN, UK
| | - Christian L Roth
- Seattle Children's Research Institute, Seattle, WA 98101, USA
- Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA 98105, USA
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Cho H, Lim J. The emerging role of gut hormones. Mol Cells 2024; 47:100126. [PMID: 39426686 PMCID: PMC11577206 DOI: 10.1016/j.mocell.2024.100126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/13/2024] [Accepted: 10/13/2024] [Indexed: 10/21/2024] Open
Abstract
The gut is traditionally recognized as the central organ for the digestion and absorption of nutrients, however, it also functions as a significant endocrine organ, secreting a variety of hormones such as glucagon-like peptide 1, serotonin, somatostatin, and glucocorticoids. These gut hormones, produced by specialized intestinal epithelial cells, are crucial not only for digestive processes but also for the regulation of a wide range of physiological functions, including appetite, metabolism, and immune responses. While gut hormones can exert systemic effects, they also play a pivotal role in maintaining local homeostasis within the gut. This review discusses the role of the gut as an endocrine organ, emphasizing the stimuli, the newly discovered functions, and the clinical significance of gut-secreted hormones. Deciphering the emerging role of gut hormones will lead to a better understanding of gut homeostasis, innovative treatments for disorders in the gut, as well as systemic diseases.
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Affiliation(s)
- Hyeryeong Cho
- College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Jaechul Lim
- College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea.
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Baccari MC, Vannucchi MG, Idrizaj E. The Possible Involvement of Glucagon-like Peptide-2 in the Regulation of Food Intake through the Gut-Brain Axis. Nutrients 2024; 16:3069. [PMID: 39339669 PMCID: PMC11435434 DOI: 10.3390/nu16183069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/05/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Food intake regulation is a complex mechanism involving the interaction between central and peripheral structures. Among the latter, the gastrointestinal tract represents one of the main sources of both nervous and hormonal signals, which reach the central nervous system that integrates them and sends the resulting information downstream to effector organs involved in energy homeostasis. Gut hormones released by nutrient-sensing enteroendocrine cells can send signals to central structures involved in the regulation of food intake through more than one mechanism. One of these is through the modulation of gastric motor phenomena known to be a source of peripheral satiety signals. In the present review, our attention will be focused on the ability of the glucagon-like peptide 2 (GLP-2) hormone to modulate gastrointestinal motor activity and discuss how its effects could be related to peripheral satiety signals generated in the stomach and involved in the regulation of food intake through the gut-brain axis. A better understanding of the possible role of GLP-2 in regulating food intake through the gut-brain axis could represent a starting point for the development of new strategies to treat some pathological conditions, such as obesity.
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Affiliation(s)
- Maria Caterina Baccari
- Department of Experimental & Clinical Medicine, Section of Physiological Sciences, University of Florence, 50134 Florence, Italy;
| | - Maria Giuliana Vannucchi
- Department of Experimental & Clinical Medicine, Research Unit of Histology & Embryology, University of Florence, 50139 Florence, Italy;
| | - Eglantina Idrizaj
- Department of Experimental & Clinical Medicine, Section of Physiological Sciences, University of Florence, 50134 Florence, Italy;
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Hoffman S, Adeli K. Glucagon-like peptide (GLP)-1 regulation of lipid and lipoprotein metabolism. MEDICAL REVIEW (2021) 2024; 4:301-311. [PMID: 39135603 PMCID: PMC11317082 DOI: 10.1515/mr-2024-0011] [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: 01/31/2024] [Accepted: 03/13/2024] [Indexed: 08/15/2024]
Abstract
Metabolic health is highly dependent on intestinal and hepatic handling of dietary and endogenous lipids and lipoproteins. Disorders of lipid and lipoprotein metabolism are commonly observed in patients with insulin resistant states such as obesity, metabolic syndrome, and type 2 diabetes. Evidence from both animal models and human studies indicates that a major underlying factor in metabolic or diabetic dyslipidemia is the overproduction of hepatic and intestinal apolipoprotein (apo)B-containing lipoprotein particles. These particles are catabolized down into highly proatherogenic remnants, which can be taken up into the arterial intima and promote plaque development. Several gut-derived peptides have been identified as key regulators of energy metabolism; one such peptide is the incretin hormone glucagon-like peptide (GLP)-1. Our laboratory has previously demonstrated that GLP-1 can signal both centrally and peripherally to reduce postprandial and fasting lipoprotein secretion. Moreover, we have demonstrated that GLP-1 receptor (GLP-1R) agonists can ameliorate diet-induced dyslipidemia. Recently, we published evidence for a novel vagal neuroendocrine signalling pathway by which native GLP-1 may exert its anti-lipemic effects. Furthermore, we demonstrated a novel role for other gut-derived peptides in regulating intestinal lipoprotein production. Overall, ample evidence supports a key role for GLP-1R on the portal vein afferent neurons and nodose ganglion in modulating intestinal fat absorption and lipoprotein production and identifies other gut-derived peptides as novel regulators of postprandial lipemia. Insights from these data may support identification of potential drug targets and the development of new therapeutics targeting treatment of diabetic dyslipidemia.
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Affiliation(s)
- Simon Hoffman
- Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- Cardiovascular & Metabolic Disease, Merck Research Laboratories, South San Francisco, CA, USA
| | - Khosrow Adeli
- Molecular Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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Perez-Leighton C, Kerr B, Scherer PE, Baudrand R, Cortés V. The interplay between leptin, glucocorticoids, and GLP1 regulates food intake and feeding behaviour. Biol Rev Camb Philos Soc 2024; 99:653-674. [PMID: 38072002 DOI: 10.1111/brv.13039] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 11/21/2023] [Accepted: 12/01/2023] [Indexed: 05/09/2024]
Abstract
Nutritional, endocrine, and neurological signals converge in multiple brain centres to control feeding behaviour and food intake as part of the allostatic regulation of energy balance. Among the several neuroendocrine systems involved, the leptin, glucocorticoid, and glucagon-like peptide 1 (GLP1) systems have been extensively researched. Leptin is at the top hierarchical level since its complete absence is sufficient to trigger severe hyperphagia. Glucocorticoids are key regulators of the energy balance adaptation to stress and their sustained excess leads to excessive adiposity and metabolic perturbations. GLP1 participates in metabolic adaptation to food intake, regulating insulin secretion and satiety by parallel central and peripheral signalling systems. Herein, we review the brain and peripheral targets of these three hormone systems that integrate to regulate food intake, feeding behaviour, and metabolic homeostasis. We examine the functional relationships between leptin, glucocorticoids, and GLP1 at the central and peripheral levels, including the cross-regulation of their circulating levels and their cooperative or antagonistic actions at different brain centres. The pathophysiological roles of these neuroendocrine systems in dysregulated intake are explored in the two extremes of body adiposity - obesity and lipodystrophy - and eating behaviour disorders.
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Affiliation(s)
- Claudio Perez-Leighton
- Departmento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
| | - Bredford Kerr
- Centro de Biología Celular y Biomedicina-CEBICEM, Facultad de Medicina y Ciencia, Universidad San Sebastián, Carmen Sylva 2444, Providencia, Santiago, Chile
| | - Philipp E Scherer
- Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
| | - René Baudrand
- Departmento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
- Centro Translacional de Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
| | - Víctor Cortés
- Departmento de Nutrición, Diabetes y Metabolismo, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
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9
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Huber H, Schieren A, Holst JJ, Simon MC. Dietary impact on fasting and stimulated GLP-1 secretion in different metabolic conditions - a narrative review. Am J Clin Nutr 2024; 119:599-627. [PMID: 38218319 PMCID: PMC10972717 DOI: 10.1016/j.ajcnut.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 01/15/2024] Open
Abstract
Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide and central mediator of glucose metabolism, is secreted by L cells in the intestine in response to food intake. Postprandial secretion of GLP-1 is triggered by nutrient-sensing via transporters and G-protein-coupled receptors (GPCRs). GLP-1 secretion may be lower in adults with obesity/overweight (OW) or type 2 diabetes mellitus (T2DM) than in those with normal glucose tolerance (NGT), but these findings are inconsistent. Because of the actions of GLP-1 on stimulating insulin secretion and promoting weight loss, GLP-1 and its analogs are used in pharmacologic preparations for the treatment of T2DM. However, physiologically stimulated GLP-1 secretion through the diet might be a preventive or synergistic method for improving glucose metabolism in individuals who are OW, or have impaired glucose tolerance (IGT) or T2DM. This narrative review focuses on fasting and postprandial GLP-1 secretion in individuals with different metabolic conditions and degrees of glucose intolerance. Further, the influence of relevant diet-related factors (e.g., specific diets, meal composition, and size, phytochemical content, and gut microbiome) that could affect fasting and postprandial GLP-1 secretion are discussed. Some studies showed diminished glucose- or meal-stimulated GLP-1 response in participants with T2DM, IGT, or OW compared with those with NGT, whereas other studies have reported an elevated or unchanged GLP-1 response in T2DM or IGT. Meal composition, especially the relationship between macronutrients and interventions targeting the microbiome can impact postprandial GLP-1 secretion, although it is not clear which macronutrients are strong stimulants of GLP-1. Moreover, glucose tolerance, antidiabetic treatment, grade of overweight/obesity, and sex were important factors influencing GLP-1 secretion. The results presented in this review highlight the potential of nutritional and physiologic stimulation of GLP-1 secretion. Further research on fasting and postprandial GLP-1 concentrations and the resulting metabolic consequences under different metabolic conditions is needed.
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Affiliation(s)
- Hanna Huber
- Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology, Mölndal, Sweden; Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany
| | - Alina Schieren
- Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany
| | - Jens Juul Holst
- Department of Biomedical Sciences, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - Marie-Christine Simon
- Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany.
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Bullich-Vilarrubias C, Romaní-Pérez M, López-Almela I, Rubio T, García CJ, Tomás-Barberán FA, Sanz Y. Nav1.8-expressing neurons control daily oscillations of food intake, body weight and gut microbiota in mice. Commun Biol 2024; 7:219. [PMID: 38388698 PMCID: PMC10883928 DOI: 10.1038/s42003-024-05905-3] [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: 05/19/2023] [Accepted: 02/09/2024] [Indexed: 02/24/2024] Open
Abstract
Recent evidence suggests a role of sensory neurons expressing the sodium channel Nav1.8 on the energy homeostasis control. Using a murine diphtheria toxin ablation strategy and ad libitum and time-restricted feeding regimens of control or high-fat high-sugar diets, here we further explore the function of these neurons on food intake and on the regulation of gastrointestinal elements transmitting immune and nutrient sensing.The Nav1.8+ neuron ablation increases food intake in ad libitum and time-restricted feeding, and exacerbates daily body weight variations. Mice lacking Nav1.8+ neurons show impaired prandial regulation of gut hormone secretion and gut microbiota composition, and altered intestinal immunity.Our study demonstrates that Nav1.8+ neurons are required to control food intake and daily body weight changes, as well as to maintain physiological enteroendocrine and immune responses and the rhythmicity of the gut microbiota, which highlights the potential of Nav1.8+ neurons to restore energy balance in metabolic disorders.
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Affiliation(s)
- Clara Bullich-Vilarrubias
- Microbiome, Nutrition and Health Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Marina Romaní-Pérez
- Microbiome, Nutrition and Health Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain.
| | - Inmaculada López-Almela
- Microbiome, Nutrition and Health Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
- Research Group Intracellular Pathogens: Biology and Infection, Department of Animal Production and Health, Veterinary Public Health and Food Science and Technology, Faculty of Veterinary Medicine, Cardenal Herrera-CEU University, Valencia, Spain
| | - Teresa Rubio
- Microbiome, Nutrition and Health Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Carlos J García
- Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, Murcia, Spain
| | | | - Yolanda Sanz
- Microbiome, Nutrition and Health Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
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11
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Li S, Zhu H, Chen JDZ. Intestinal Electrical Stimulation Synchronized With Intestinal Slow Wave Ameliorates Glucagon-Induced Hyperglycemia in Rats. Neuromodulation 2024; 27:312-320. [PMID: 37897473 DOI: 10.1016/j.neurom.2023.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/26/2023] [Accepted: 10/03/2023] [Indexed: 10/30/2023]
Abstract
BACKGROUND Synchronized intestinal electrical stimulation (SIES), in which intestinal electrical stimulation (IES) is delivered in synchronization with the intrinsic slow wave of small intestine, was previously reported to be more potent in accelerating small intestine transit than IES delivered at fixed frequency and phase. We hypothesized that SIES is more potent in suppressing postprandial blood glucose by enhancing the release of glucagon-like peptide-1 (GLP-1) and insulin. MATERIALS AND METHODS Rats underwent long-term implant of two pairs of electrodes at the duodenum for IES and SIES, respectively. Acute hyperglycemia was induced with glucagon, and the oral glucose tolerance test was performed on separate days with IES, SIES, or sham (no stimulation). RESULTS 1. Glucagon reduced the percentage of normal slow wave in sham (70.9% ± 4.1%) from (84.9% ± 2.6%, p = 0.006) of control, which was ameliorated by SIES (82.5% ± 3.3%, p = 0.031). 2. IES and SIES reduced glucagon-induced increase of blood glucose (192 mg/dl) at 30 minutes by 17% and 20%, respectively. SIES showed a further inhibitory effect at 60 minutes (147 vs 171 mg/dl, p = 0.003, vs sham). 3. Compared with sham (139 pg/ml), GLP-1 at 30 minutes was increased in both IES (158 pg/ml) and SIES (169 pg/ml). GLP-1 level was still high at 60 minutes in rats with SIES. 4. At 30 minutes, the plasma insulin level was increased by 18.8 μIU/ml with SIES, which was significantly higher than that with sham (7.1 μIU/ml, p < 0.001) and IES (13.2 μIU/ml, p = 0.041). CONCLUSION SIES is more effective than IES in reducing glucagon-induced acute hyperglycemia by enhancing the release of GLP-1 and insulin.
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Affiliation(s)
- Shiying Li
- Division of Gastroenterology and Hepatology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Hongbing Zhu
- Transtimulation Research Inc, Oklahoma City, OK, USA
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
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Pal B, Chattopadhyay M. Recent clinical and pharmacological advancements of incretin-based therapy and the effects of incretin on physiology. JOURNAL OF DIABETOLOGY 2024; 15:24-37. [DOI: 10.4103/jod.jod_117_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/03/2024] [Indexed: 12/11/2024] Open
Abstract
Abstract
A novel therapeutic target for diabetes mellitus is incretin-based therapies, glucagon-like peptide-1, and glucose-dependent insulinotropic polypeptides are released from the gastrointestinal (GI) tract and act on beta cells of pancreatic islets by increasing the secretion of insulin. The management and prevention of diabetes require habitual and pharmacological therapies along with quality and healthy lifestyle. This includes maintaining the body weight, blood glucose level, cardiovascular risk, complexity, and co-morbidities. The utilization of glucagon-like peptide-1 (GLP-1) agonists is an object of research with favorable hemoglobin A1C levels and weight loss in type 1 diabetic patients. However, cost-effectiveness and tolerability, remain significant barriers for patients to using these medications. The risk of suicidal tendencies and thoughts of self-harm have been increased in patients receiving GLP-1 receptor agonists. Tirzepatide treatment showed a potent glucose-lowering effect and promoted weight loss with minimum GI adverse effects in animal studies as well as phase I and II human trials, in comparison with established GLP-1 receptor agonists. The glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide-antagonist effectively blocks the action of gastric-inhibitory-polypeptide (GIP) in vitro and ex vivo in human pancreas and in vivo in rodent models. However, incretin-based therapies have received enormous attention in the last few decades for the treatment of diabetes, obesity, and other repurposing including central nervous system disorders. Therefore, in this article, we demonstrate the overview, physiological, and pharmacological advances of incretin-based pharmacotherapies and their physiological roles. Furthermore, the recent updates of glucagon-like peptide-1 receptor agonist, Glucagon-like peptide-2 receptor agonist, GLP-1/GIP co-agonists, GIP/GLP-1/glucagon triple agonist and GIP-antagonist are also discussed.
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Affiliation(s)
- Bhaskar Pal
- Department of Pharmacology, Charaktala College of Pharmacy, Charaktala, Debipur, West Bengal, India
| | - Moitreyee Chattopadhyay
- Department of Pharmaceutical Technology, Maulana Abul Kalam Azad University of Technology, Nadia, West Bengal, India
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13
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Wang QY, Zhang W, Zhao Y, Chen HL, Liu Q, Wang ZH, Zeng LT, Li J, Chen SJ, Wei L, Iwakuma T, Cai JP. Colonic L-cell impairment in aged subjects with type 2 diabetes leads to diminished GLP-1 production. Diabetes Metab Syndr 2023; 17:102907. [PMID: 37980723 DOI: 10.1016/j.dsx.2023.102907] [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: 08/09/2023] [Revised: 10/27/2023] [Accepted: 11/08/2023] [Indexed: 11/21/2023]
Abstract
AIMS Glucagon-like peptide 1 (GLP-1) is produced by the L subtype of enteroendocrine cells (EECs). Patients with type 2 diabetes (T2D) exhibit reduced incretin effect, but the pathophysiology and functional change of the L-cells remain unclear. Deciphering the mechanisms of the biological changes in L-cells under T2D conditions may assist in the research of gut-based strategies for T2D therapy. METHODS We investigated the fasting serum GLP-1 levels and the distribution of colonic L-cells in young and aged participants with and without T2D. Additionally, we established an aged male T2D Wistar rat model subjected to a long-term high-fat and high-fructose (HFHF) diet. Histological investigations and single-cell RNA sequencing (scRNA-seq) analyses were performed to explore the mechanisms underlying functional changes in the colonic EECs. RESULTS We observed a decline in circulating GLP-1 levels and a reduced number of colonic L-cells in elderly patients with T2D. The mechanisms underlying impaired L-cell formation and disturbed GLP-1 production were revealed using aged T2D rats induced by a long-term HFHF diet. The scRNA-seq results showed that the transcription factors that regulate L-cell commitment, such as Foxa1, were downregulated, and the expression of genes that participate in encoding GLP-1, GLP-1 posttranslational processing, hormone secretion, and nutrient sensing was disturbed. CONCLUSIONS Taken together, the reduced L-cell lineage commitment and disturbed L-cell functions might be the major cause of the reduced GLP-1 production in aged populations with T2D. Our study provides new insights for identifying novel targets in colonic L-cells for improving endogenous GLP-1 production.
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Affiliation(s)
- Qing-Yu Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Wei Zhang
- Department of Pathology, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yue Zhao
- Clinical Laboratory, The Second Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Hui-Lian Chen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Qian Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zi-Hui Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Lv-Tao Zeng
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jin Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Si-Jie Chen
- MOE Key Lab of Bioinformatics, Bioinformatics Division of BNRIST and Department of Automation, Tsinghua University, Beijing, 100084, China
| | - Lei Wei
- MOE Key Lab of Bioinformatics, Bioinformatics Division of BNRIST and Department of Automation, Tsinghua University, Beijing, 100084, China
| | - Tomoo Iwakuma
- Children's Mercy Research Institute, Kansas City, MO, 64108, USA
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
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Minis E, Stanford FC, Mahalingaiah S. Glucagon-like peptide-1 receptor agonists and safety in the preconception period. Curr Opin Endocrinol Diabetes Obes 2023; 30:273-279. [PMID: 37678163 PMCID: PMC10615799 DOI: 10.1097/med.0000000000000835] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
PURPOSE OF REVIEW Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are becoming increasingly popular for the treatment of type II diabetes and obesity. Body mass index (BMI) thresholds at in vitro fertilization (IVF) clinics may further drive the use of these medications before infertility treatment. However, most clinical guidance regarding optimal time to discontinue these medications prior to conception is based on animal data. The purpose of this review was to evaluate the literature for evidence-based guidance regarding the preconception use of GLP-1 RA. RECENT FINDINGS 16 articles were found in our PubMed search, 10 were excluded as they were reviews or reported on animal data. Included were 3 case reports detailing pregnancy outcomes in individual patients that conceived while on a GLP-1 RA and 2 randomized controlled trials (RCTs) and a follow-up study to one of the RCTs that reported on patients randomized to GLP-1 RA or metformin prior to conception. No adverse pregnancy or neonatal outcomes were reported. SUMMARY There are limited data from human studies to guide decision-making regarding timing of discontinuation of GLP-1 RA before conception. Studies focused on pregnancy and neonatal outcomes would provide additional information regarding a safe washout period. Based on the available literature a 4-week washout period prior to attempting conception may be considered for the agents reviewed in this publication.
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Affiliation(s)
- Evelyn Minis
- Massachusetts General Hospital, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility
| | - Fatima Cody Stanford
- Massachusetts General Hospital, MGH Weight Center, Department of Medicine-Division of Endocrinology-Neuroendocrine, Department of Pediatrics-Division of Endocrinology, Nutrition Obesity Research Center at Harvard (NORCH), Boston, MA
| | - Shruthi Mahalingaiah
- Massachusetts General Hospital, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility
- Harvard T.H. Chan School of Public Health, USA
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15
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Prahm AP, Hvistendahl MK, Brandt CF, Blanche P, Hartmann B, Holst JJ, Jeppesen PB. Post-prandial secretion of glucagon-like peptide-2 (GLP-2) after carbohydrate-, fat- or protein enriched meals in healthy subjects. Peptides 2023; 169:171091. [PMID: 37640265 DOI: 10.1016/j.peptides.2023.171091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/15/2023] [Accepted: 08/25/2023] [Indexed: 08/31/2023]
Abstract
Glucagon-like peptide 2 (GLP-2) is an important regulator of intestinal growth and function. In adherable mixed meals the macronutrient composition with the best potential for stimulating GLP-2 secretion is not known. We compared the effect of 3 iso-energetic meals, where approximately 60 % of the energy ratio was provided as either carbohydrate, fat, or protein, respectively, on the post-prandial endogenous GLP-2 secretion. The responses were compared to secretion profiles of peptide YY (PYY), and glucose-dependent insulinotropic peptide (GIP). Ten healthy subjects were admitted on three occasions, at least a week apart, after a night of fasting. In an open-label, crossover design, they were randomized to receive a high carbohydrate (HC), high fat (HF) or high protein (HP) meal. The meals were approximately ∼3.9 MJ. Venous blood was collected for 240 min, and plasma concentrations of GLP-2, GIP and PYY were measured with specific radioimmunoassays. Mean GLP-2 levels peaked already at 30 min for the HC meal, however the HP meal induced the highest mean GLP-2 peaking levels, resulting in significantly higher mean GLP-2 area under the curve (AUC) from baseline of 7279 pmol*min/L, 95 %-CI [6081;8477] compared to the HC meal: 4764 pmol*min/L, 95 %-CI [3498;6029], p = 0.020 and the HF meal: 4796 pmol*min/L, [3385;6207], p = 0.011. Findings were similar for the PYY. The HC meal provided a greater AUC for GIP compared to the HP- and HF meals. The HP meal was most effective with respect to stimulation of the postprandial GLP-2 and PYY secretion, whereas the HC meal was more effective for GIP.
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Affiliation(s)
- August Pilegaard Prahm
- Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
| | - Mark Krogh Hvistendahl
- Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Christopher Filtenborg Brandt
- Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Paul Blanche
- Section of Biostatistics, University of Copenhagen, Øster Farimagsgade 5, 1353 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences and the NovoNordisk Foundation, Center for Basic Metabolic Research, Faculty of Health Science, Panum Institute 12.2, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences and the NovoNordisk Foundation, Center for Basic Metabolic Research, Faculty of Health Science, Panum Institute 12.2, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Palle Bekker Jeppesen
- Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark
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16
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Jalleh RJ, Trahair LG, Wu T, Standfield S, Feinle‐Bisset C, Rayner CK, Horowitz M, Jones KL. Effect of gastric distension with concurrent small intestinal saline or glucose infusion on incretin hormone secretion in healthy individuals: A randomized, controlled, crossover study. Diabetes Obes Metab 2023; 25:1849-1854. [PMID: 36864654 PMCID: PMC10947269 DOI: 10.1111/dom.15042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/16/2023] [Accepted: 02/27/2023] [Indexed: 03/04/2023]
Abstract
AIM To evaluate the effect of gastric distension, induced using a gastric 'barostat', on the secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the presence and absence of small intestinal nutrients in healthy individuals. MATERIALS AND METHODS Eight healthy participants (two females, six males, mean age 69.3 ± 1.2 years, body mass index 23.5 ± 0.8 kg/m2 ) were each studied on four occasions when they received an intraduodenal infusion of either (i) 0.9% saline or (ii) glucose delivered at a rate of 3 kcal/min both with, and without, an intragastric balloon with the pressure set to 8 mmHg above the intragastric minimum distending pressure. RESULTS Following intraduodenal saline or glucose infusion, there was no difference in plasma GLP-1 with or without gastric distension (P = 1.00 for both saline and glucose infusions). There was also no difference in plasma GIP with or without gastric distension (P = 1.00 for saline infusion and P = .99 for glucose infusion). CONCLUSIONS Gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans.
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Affiliation(s)
- Ryan J. Jalleh
- Adelaide Medical SchoolThe University of AdelaideAdelaideAustralia
- Centre of Research Excellence in Translating Nutritional Science to Good HealthAdelaideAustralia
- Endocrine and Metabolic UnitRoyal Adelaide HospitalAdelaideAustralia
- Diabetes and Endocrine ServicesNorthern Adelaide Local Health NetworkAdelaideAustralia
| | - Laurence G. Trahair
- Adelaide Medical SchoolThe University of AdelaideAdelaideAustralia
- Centre of Research Excellence in Translating Nutritional Science to Good HealthAdelaideAustralia
| | - Tongzhi Wu
- Adelaide Medical SchoolThe University of AdelaideAdelaideAustralia
- Centre of Research Excellence in Translating Nutritional Science to Good HealthAdelaideAustralia
| | - Scott Standfield
- Adelaide Medical SchoolThe University of AdelaideAdelaideAustralia
| | - Christine Feinle‐Bisset
- Adelaide Medical SchoolThe University of AdelaideAdelaideAustralia
- Centre of Research Excellence in Translating Nutritional Science to Good HealthAdelaideAustralia
| | - Christopher K. Rayner
- Adelaide Medical SchoolThe University of AdelaideAdelaideAustralia
- Centre of Research Excellence in Translating Nutritional Science to Good HealthAdelaideAustralia
- Department of Gastroenterology and HepatologyRoyal Adelaide HospitalAdelaideAustralia
| | - Michael Horowitz
- Adelaide Medical SchoolThe University of AdelaideAdelaideAustralia
- Centre of Research Excellence in Translating Nutritional Science to Good HealthAdelaideAustralia
- Endocrine and Metabolic UnitRoyal Adelaide HospitalAdelaideAustralia
| | - Karen L. Jones
- Adelaide Medical SchoolThe University of AdelaideAdelaideAustralia
- Centre of Research Excellence in Translating Nutritional Science to Good HealthAdelaideAustralia
- Endocrine and Metabolic UnitRoyal Adelaide HospitalAdelaideAustralia
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17
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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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18
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Alsalim W, Lindgren O, Ahrén B. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secretion in humans: Characteristics and regulation. J Diabetes Investig 2022; 14:354-361. [PMID: 36539382 PMCID: PMC9951578 DOI: 10.1111/jdi.13962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
AIMS/INTRODUCTION Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important incretin hormones. They are released from the gut after meal ingestion and potentiate glucose-stimulated insulin secretion. Their release after meal ingestion and oral glucose are well established and have been characterized previously. During recent years, knowledge of other regulatory aspects that potentially may affect GIP and GLP-1 secretion after meal ingestion have also begun to emerge. Here, the results of human studies on these novel aspects of meal- and nutrient-stimulated incretin hormone secretion are reviewed. MATERIALS AND METHODS The human literature was revisited by identifying articles in PubMed using key words GIP, GLP-1, secretion, meal, and nutrients. RESULTS The results show that all macronutrients individually stimulate GIP and GLP-1 secretion. However, there was no synergistic action when given in combination. A pre-load 30 min before a meal augments the GIP and GLP-1 response. GIP and GLP-1 secretion have a diurnal variation with a higher response to an identical meal in the morning than in the afternoon. There is no difference in GIP and GLP-1 secretion whether a meal is ingested slowly or rapidly. GIP and GLP-1 secretion after dinner are the same whether or not breakfast and lunch have been ingested. The temperature of the food may be of importance for the incretin hormone response. CONCLUSIONS These novel findings have increased our knowledge on the regulation of the complexity of the incretin system and are also important knowledge when designing future studies.
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Affiliation(s)
- Wathik Alsalim
- Department of Clinical Sciences LundLund UniversityLundSweden,Department of EndocrinologySkåne University HospitalLundSweden
| | - Ola Lindgren
- Department of Clinical Sciences LundLund UniversityLundSweden,Department of EndocrinologySkåne University HospitalLundSweden
| | - Bo Ahrén
- Department of Clinical Sciences LundLund UniversityLundSweden,Department of EndocrinologySkåne University HospitalLundSweden
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19
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Sharma RK, Azmi A, Kaka N, Sethi Y, Chopra H, Emran TB. Role of gut hormones in diabetes mellitus: An update. Int J Surg 2022; 108:106985. [PMID: 36356828 DOI: 10.1016/j.ijsu.2022.106985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022]
Affiliation(s)
- Rahul Kumar Sharma
- Department of Pharmacology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India GMERS Medical College Himmatnagar, Himmatnagar, Gujarat, India Government Doon Medical College, Dehradun, Uttarakhand, India Chitkara College of Pharmacy, Chitkara University, Punjab, India Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
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Biancolin AD, Srikrishnaraj A, Jeong H, Martchenko A, Brubaker PL. The Cytoskeletal Transport Protein, Secretagogin, Is Essential for Diurnal Glucagon-like Peptide-1 Secretion in Mice. Endocrinology 2022; 163:6678475. [PMID: 36036556 DOI: 10.1210/endocr/bqac142] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Indexed: 11/19/2022]
Abstract
The intestinal L-cell incretin, glucagon-like peptide-1 (GLP-1), exhibits a circadian pattern of secretion, thereby entraining diurnal insulin release. Secretagogin (Scgn), an actin-binding regulatory protein, is essential for the temporal peak of GLP-1 secretion in vitro. To interrogate the role of Scgn in diurnal GLP-1 secretion in vivo, peak and trough GLP-1 release were evaluated in knockout mice (Scgn-/-, Gcg-CreERT2/+; Scgnfl/fl and Vil-CreERT2/+; Scgnfl/fl), and RNA sequencing (RNA-Seq) was conducted in Scgn knockdown L-cells. All 3 knockout models demonstrated loss of the diurnal rhythm of GLP-1 secretion in response to oral glucose. Gcg-CreERT2/+; Scgnfl/fl mice also lost the normal pattern in glucagon secretion, while Scgn-/- and Vil-CreERT2/+; Scgnfl/fl animals demonstrated impaired diurnal secretion of the related incretin, glucose-dependent insulinotrophic polypeptide. RNA-Seq of mGLUTag L-cells showed decreased pathways regulating vesicle transport, transport and binding, and protein-protein interaction at synapse, as well as pathways related to proteasome-mediated degradation including chaperone-mediated protein complex assembly following Scgn knockdown. Scgn is therefore essential for diurnal L-cell GLP-1 secretion in vivo, likely mediated through effects on secretory granule dynamics.
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Affiliation(s)
| | - Arjuna Srikrishnaraj
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Hyerin Jeong
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Alexandre Martchenko
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Patricia Lee Brubaker
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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21
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Brubaker PL. The Molecular Determinants of Glucagon-like Peptide Secretion by the Intestinal L cell. Endocrinology 2022; 163:6717959. [PMID: 36156130 DOI: 10.1210/endocr/bqac159] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Indexed: 11/19/2022]
Abstract
The intestinal L cell secretes a diversity of biologically active hormones, most notably the glucagon-like peptides, GLP-1 and GLP-2. The highly successful introduction of GLP-1-based drugs into the clinic for the treatment of patients with type 2 diabetes and obesity, and of a GLP-2 analog for patients with short bowel syndrome, has led to the suggestion that stimulation of the endogenous secretion of these peptides may serve as a novel therapeutic approach in these conditions. Situated in the intestinal epithelium, the L cell demonstrates complex relationships with not only circulating, paracrine, and neural regulators, but also ingested nutrients and other factors in the lumen, most notably the microbiota. The integrated input from these numerous secretagogues results in a variety of temporal patterns in L cell secretion, ranging from minutes to 24 hours. This review combines the findings of traditional, physiological studies with those using newer molecular approaches to describe what is known and what remains to be elucidated after 5 decades of research on the intestinal L cell and its secreted peptides, GLP-1 and GLP-2.
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Affiliation(s)
- Patricia L Brubaker
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
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22
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Lee CJ, Clark JM, Egan JM, Carlson OD, Schweitzer M, Langan S, Brown T. Comparison of Hormonal Response to a Mixed-Meal Challenge in Hypoglycemia After Sleeve Gastrectomy vs Gastric Bypass. J Clin Endocrinol Metab 2022; 107:e4159-e4166. [PMID: 35914520 PMCID: PMC9516126 DOI: 10.1210/clinem/dgac455] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). OBJECTIVE We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB. METHODS We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups. RESULTS Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB. CONCLUSION Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.
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Affiliation(s)
- Clare J Lee
- Correspondence: Clare J. Lee, MD, MHS, Division of Endocrinology and Metabolism, The Johns Hopkins University, 1830 E Monument St, Ste 333, Baltimore, MD 21287, USA.
| | - Jeanne M Clark
- Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21287, USA
- Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21287, USA
| | - Josephine M Egan
- National Institute On Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
| | - Olga D Carlson
- National Institute On Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
| | - Michael Schweitzer
- Department of Surgery, The Johns Hopkins University, Baltimore, Maryland 21287, USA
| | - Susan Langan
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21287, USA
| | - Todd Brown
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21287, USA
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Wachsmuth HR, Weninger SN, Duca FA. Role of the gut-brain axis in energy and glucose metabolism. Exp Mol Med 2022; 54:377-392. [PMID: 35474341 PMCID: PMC9076644 DOI: 10.1038/s12276-021-00677-w] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/01/2021] [Accepted: 07/08/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract plays a role in the development and treatment of metabolic diseases. During a meal, the gut provides crucial information to the brain regarding incoming nutrients to allow proper maintenance of energy and glucose homeostasis. This gut-brain communication is regulated by various peptides or hormones that are secreted from the gut in response to nutrients; these signaling molecules can enter the circulation and act directly on the brain, or they can act indirectly via paracrine action on local vagal and spinal afferent neurons that innervate the gut. In addition, the enteric nervous system can act as a relay from the gut to the brain. The current review will outline the different gut-brain signaling mechanisms that contribute to metabolic homeostasis, highlighting the recent advances in understanding these complex hormonal and neural pathways. Furthermore, the impact of the gut microbiota on various components of the gut-brain axis that regulates energy and glucose homeostasis will be discussed. A better understanding of the gut-brain axis and its complex relationship with the gut microbiome is crucial for the development of successful pharmacological therapies to combat obesity and diabetes.
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Affiliation(s)
| | | | - Frank A Duca
- School of Animal and Comparative Biomedical Sciences, College of Agricultural and Life Sciences, University of Arizona, Tucson, AZ, USA. .,BIO5, University of Arizona, Tucson, AZ, USA.
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Watts AG, Kanoski SE, Sanchez-Watts G, Langhans W. The physiological control of eating: signals, neurons, and networks. Physiol Rev 2022; 102:689-813. [PMID: 34486393 PMCID: PMC8759974 DOI: 10.1152/physrev.00028.2020] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 08/30/2021] [Indexed: 02/07/2023] Open
Abstract
During the past 30 yr, investigating the physiology of eating behaviors has generated a truly vast literature. This is fueled in part by a dramatic increase in obesity and its comorbidities that has coincided with an ever increasing sophistication of genetically based manipulations. These techniques have produced results with a remarkable degree of cell specificity, particularly at the cell signaling level, and have played a lead role in advancing the field. However, putting these findings into a brain-wide context that connects physiological signals and neurons to behavior and somatic physiology requires a thorough consideration of neuronal connections: a field that has also seen an extraordinary technological revolution. Our goal is to present a comprehensive and balanced assessment of how physiological signals associated with energy homeostasis interact at many brain levels to control eating behaviors. A major theme is that these signals engage sets of interacting neural networks throughout the brain that are defined by specific neural connections. We begin by discussing some fundamental concepts, including ones that still engender vigorous debate, that provide the necessary frameworks for understanding how the brain controls meal initiation and termination. These include key word definitions, ATP availability as the pivotal regulated variable in energy homeostasis, neuropeptide signaling, homeostatic and hedonic eating, and meal structure. Within this context, we discuss network models of how key regions in the endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, and spinal cord work together with the gastrointestinal tract to enable the complex motor events that permit animals to eat in diverse situations.
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Affiliation(s)
- Alan G Watts
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Scott E Kanoski
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Graciela Sanchez-Watts
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Eidgenössische Technische Hochschule-Zürich, Schwerzenbach, Switzerland
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25
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Keller BN, Hajnal A, Browning KN, Arnold AC, Silberman Y. Involvement of the Dorsal Vagal Complex in Alcohol-Related Behaviors. Front Behav Neurosci 2022; 16:801825. [PMID: 35330845 PMCID: PMC8940294 DOI: 10.3389/fnbeh.2022.801825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/19/2022] [Indexed: 12/20/2022] Open
Abstract
The neurobiological mechanisms that regulate the development and maintenance of alcohol use disorder (AUD) are complex and involve a wide variety of within and between systems neuroadaptations. While classic reward, preoccupation, and withdrawal neurocircuits have been heavily studied in terms of AUD, viable treatment targets from this established literature have not proven clinically effective as of yet. Therefore, examination of additional neurocircuitries not classically studied in the context of AUD may provide novel therapeutic targets. Recent studies demonstrate that various neuropeptides systems are important modulators of alcohol reward, seeking, and intake behaviors. This includes neurocircuitry within the dorsal vagal complex (DVC), which is involved in the control of the autonomic nervous system, control of intake of natural rewards like food, and acts as a relay of interoceptive sensory information via interactions of numerous gut-brain peptides and neurotransmitter systems with DVC projections to central and peripheral targets. DVC neuron subtypes produce a variety of neuropeptides and transmitters and project to target brain regions critical for reward such as the mesolimbic dopamine system as well as other limbic areas important for the negative reinforcing and aversive properties of alcohol withdrawal such as the extended amygdala. This suggests the DVC may play a role in the modulation of various aspects of AUD. This review summarizes the current literature on neurotransmitters and neuropeptides systems in the DVC (e.g., norepinephrine, glucagon-like peptide 1, neurotensin, cholecystokinin, thyrotropin-releasing hormone), and their potential relevance to alcohol-related behaviors in humans and rodent models for AUD research. A better understanding of the role of the DVC in modulating alcohol related behaviors may lead to the elucidation of novel therapeutic targets for drug development in AUD.
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Morrow NM, Hanson AA, Mulvihill EE. Distinct Identity of GLP-1R, GLP-2R, and GIPR Expressing Cells and Signaling Circuits Within the Gastrointestinal Tract. Front Cell Dev Biol 2021; 9:703966. [PMID: 34660576 PMCID: PMC8511495 DOI: 10.3389/fcell.2021.703966] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 08/16/2021] [Indexed: 12/17/2022] Open
Abstract
Enteroendocrine cells directly integrate signals of nutrient content within the gut lumen with distant hormonal responses and nutrient disposal via the production and secretion of peptides, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). Given their direct and indirect control of post-prandial nutrient uptake and demonstrated translational relevance for the treatment of type 2 diabetes, malabsorption and cardiometabolic disease, there is significant interest in the locally engaged circuits mediating these metabolic effects. Although several specific populations of cells in the intestine have been identified to express endocrine receptors, including intraepithelial lymphocytes (IELs) and αβ and γδ T-cells (Glp1r+) and smooth muscle cells (Glp2r+), the definitive cellular localization and co-expression, particularly in regards to the Gipr remain elusive. Here we review the current state of the literature and evaluate the identity of Glp1r, Glp2r, and Gipr expressing cells within preclinical and clinical models. Further elaboration of our understanding of the initiating G-protein coupled receptor (GPCR) circuits engaged locally within the intestine and how they become altered with high-fat diet feeding can offer insight into the dysregulation observed in obesity and diabetes.
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Affiliation(s)
- Nadya M Morrow
- Energy Substrate Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Antonio A Hanson
- Energy Substrate Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Erin E Mulvihill
- Energy Substrate Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Montreal Diabetes Research Center CRCHUM-Pavillion R, Montreal, QC, Canada.,Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
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27
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Murata Y, Harada N, Kishino S, Iwasaki K, Ikeguchi-Ogura E, Yamane S, Kato T, Kanemaru Y, Sankoda A, Hatoko T, Kiyobayashi S, Ogawa J, Hirasawa A, Inagaki N. Medium-chain triglycerides inhibit long-chain triglyceride-induced GIP secretion through GPR120-dependent inhibition of CCK. iScience 2021; 24:102963. [PMID: 34466786 PMCID: PMC8382997 DOI: 10.1016/j.isci.2021.102963] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 01/14/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Long-chain triglycerides (LCTs) intake strongly stimulates GIP secretion from enteroendocrine K cells and induces obesity and insulin resistance partly due to GIP hypersecretion. In this study, we found that medium-chain triglycerides (MCTs) inhibit GIP secretion after single LCT ingestion and clarified the mechanism underlying MCT-induced inhibition of GIP secretion. MCTs reduced the CCK effect after single LCT ingestion in wild-type (WT) mice, and a CCK agonist completely reversed MCT-induced inhibition of GIP secretion. In vitro studies showed that medium-chain fatty acids (MCFAs) inhibit long-chain fatty acid (LCFA)-stimulated CCK secretion and increase in intracellular Ca2+ concentrations through inhibition of GPR120 signaling. Long-term administration of MCTs reduced obesity and insulin resistance in high-LCT diet-fed WT mice, but not in high-LCT diet-fed GIP-knockout mice. Thus, MCT-induced inhibition of GIP hypersecretion reduces obesity and insulin resistance under high-LCT diet feeding condition.
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Affiliation(s)
- Yuki Murata
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shigenobu Kishino
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Kanako Iwasaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Eri Ikeguchi-Ogura
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomoko Kato
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yoshinori Kanemaru
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akiko Sankoda
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomonobu Hatoko
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Sakura Kiyobayashi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Jun Ogawa
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Akira Hirasawa
- Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
- Corresponding author
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Dolo PR, Yao L, Shao Y, Widjaja J, Li C, Zhu X. The effect of sleeve ablation of gastric mucosa on body weight and glucose homeostasis in Sprague-Dawley rat model. Surg Obes Relat Dis 2021; 17:1984-1994. [PMID: 34479813 DOI: 10.1016/j.soard.2021.07.025] [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: 02/05/2021] [Revised: 07/25/2021] [Accepted: 07/31/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND The gastric mucosa is an important endocrine organ, most of which is resected in sleeve gastrectomy (SG). The effect of removing most of the gastric mucosa has not been studied. OBJECTIVE To assess the effect of ablating the gastric mucosa (an area proportional to that in SG), on obesity and diabetes in a rat model. SETTING The Affiliated Hospital of Xuzhou Medical University in Xuzhou Jiangsu, P. R. China. METHODS Among 34 fatty Sprague-Dawley rats, 26 randomly received low-dose streptozotocin (STZ) to induce diabetes and then were randomly assigned to gastric mucosa ablation (GMA, n = 10), sleeve gastrectomy (SG, n = 8), and sham (n = 8) groups. The remaining normal fatty rats were assigned to the non-diabetic gastric mucosa ablation (nGMA, n = 8) group. In the GMA groups, the gastric mucosa was thermally ablated using electrocautery. Rats were followed for 8 weeks postoperatively. Preoperative oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and mixed meal tolerance test (MMTT) were repeated at designated time points postoperatively. Changes in body weight, food intake, and fasting blood glucose were also recorded. RESULTS Fasting ghrelin concentration and area under curve (AUC) decreased significantly (P < .05) in the GMA groups and the SG group after surgery. Gastrin concentration remained unchanged in SG but decreased significantly in the GMA groups after surgery. Significantly increased GLP-1 AUC was found in the GMA groups and the SG group postoperatively. The decrease in fasting blood glucose did not differ significantly between the diabetic GMA and SG groups after surgery. Glucose AUC during OGTT in both SG and diabetic GMA groups was decreased significantly from the preoperative level, but the decreased glucose AUC in the SG group was significantly greater (P < .05). The decrease in body weight and food intake in the SG group was significantly greater than in the GMA groups. CONCLUSION Ablation of most of the gastric mucosa along the greater curvature is effective in weight loss and glycemic control in a rodent model.
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Affiliation(s)
- Ponnie Robertlee Dolo
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Jiangsu, P. R. China; Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou Jiangsu, P. R. China
| | - Libin Yao
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Jiangsu, P. R. China; Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou Jiangsu, P. R. China
| | - Yong Shao
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Jiangsu, P. R. China; Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou Jiangsu, P. R. China
| | - Jason Widjaja
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Jiangsu, P. R. China; Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou Jiangsu, P. R. China
| | - Chao Li
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Jiangsu, P. R. China; Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou Jiangsu, P. R. China
| | - Xiaocheng Zhu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Jiangsu, P. R. China; Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou Jiangsu, P. R. China.
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Lahiry S, Chatterjee M, Chatterjee S. Impact of oral anticholinergic on insulin response to oral glucose load in patients with impaired glucose tolerance. Indian J Pharmacol 2021; 53:294-297. [PMID: 34414907 PMCID: PMC8411968 DOI: 10.4103/ijp.ijp_792_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Preliminary data indicates there is a cholinergic basis to insulin secretion. Aims & Objective To investigate the impact of oral anticholinergics on insulin secretion in subjects with impaired glucose tolerance (IGT), in comparison with volunteers having normal glucose tolerance (NGT). Material & Methods: This prospective observational study recruited 10 IGT and 10 NGT subjects. An oral glucose tolerance test (OGTT) was conducted twice in the absence and presence of hyoscine butyl-bromide (HBB). The plasma glucose (PG) and insulin levels were serially estimated at 30-min increments for 2 h after the OGTT. Early (ΔI30/ΔPG30) & late (insulin/PGAUC 60-120) phase insulin activity were assessed subsequently. Results The study constituted of 10 IGT (4M/6F, BMI: 28.80 ± 2.30) and 10 NGT (5M/5F, BMI: 23.00 ± 0.80) subjects. In the NGT group, the pre-HBB mean glucose levels (0-120 min) were comparable with those recorded after HBB intake. However, after HBBB, the mean insulin levels decreased significantly at t = 90 and 120min, confirmed by attenuated late phase insulin activity in IGT (P = 0.023) & NGT (P = 0.006) group. On the other hand, in the IGT group, however, HBB did not impact on the mean PG and insulin levels (0-120 min). Conclusions Our study findings indicate that insulin secretion is influenced by cholinergic system and that oral anticholinergics may attenuate the late phase insulin activity in varying degrees of glycemic status.
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30
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Qin W, Ying W, Hamaker B, Zhang G. Slow digestion-oriented dietary strategy to sustain the secretion of GLP-1 for improved glucose homeostasis. Compr Rev Food Sci Food Saf 2021; 20:5173-5196. [PMID: 34350681 DOI: 10.1111/1541-4337.12808] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/08/2021] [Accepted: 06/24/2021] [Indexed: 12/18/2022]
Abstract
Dysregulated glucose metabolism is associated with many chronic diseases such as obesity and type 2 diabetes mellitus (T2DM), and strategies to restore and maintain glucose homeostasis are essential to health. The incretin hormone of glucagon-like peptide-1 (GLP-1) is known to play a critical role in regulating glucose homeostasis and dietary nutrients are the primary stimuli to the release of intestinal GLP-1. However, the GLP-1 producing enteroendocrine L-cells are mainly distributed in the distal region of the gastrointestinal tract where there are almost no nutrients to stimulate the secretion of GLP-1 under normal situations. Thus, a dietary strategy to sustain the release of GLP-1 was proposed, and the slow digestion property and dipeptidyl peptidase IV (DPP-IV) inhibitory activity of food components, approaches to reduce the rate of food digestion, and mechanisms to sustain the release of GLP-1 were reviewed. A slow digestion-oriented dietary approach through encapsulation of nutrients, incorporation of viscous dietary fibers, and enzyme inhibitors of phytochemicals in a designed whole food matrix will be implemented to efficiently reduce the digestion rate of food nutrients, potentiate their distal deposition and a sustained secretion of GLP-1, which will be beneficial to improved glucose homeostasis and health.
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Affiliation(s)
- Wangyan Qin
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Wang Ying
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Bruce Hamaker
- Whistler Center for Carbohydrate Research, Purdue University, West Lafayette, Indiana, USA
| | - Genyi Zhang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
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Andreasen CR, Andersen A, Knop FK, Vilsbøll T. How glucagon-like peptide 1 receptor agonists work. Endocr Connect 2021; 10:R200-R212. [PMID: 34137731 PMCID: PMC8346189 DOI: 10.1530/ec-21-0130] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022]
Abstract
In recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of action, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.
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Affiliation(s)
- Christine Rode Andreasen
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Andreas Andersen
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Filip Krag Knop
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Watkins JD, Koumanov F, Gonzalez JT. Protein- and Calcium-Mediated GLP-1 Secretion: A Narrative Review. Adv Nutr 2021; 12:2540-2552. [PMID: 34192748 PMCID: PMC8634310 DOI: 10.1093/advances/nmab078] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/31/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Glucagon-like peptide 1 (GLP-1) is an incretin hormone produced in the intestine that is secreted in response to nutrient exposure. GLP-1 potentiates glucose-dependent insulin secretion from the pancreatic β cells and promotes satiety. These important actions on glucose metabolism and appetite have led to widespread interest in GLP-1 receptor agonism. Typically, this involves pharmacological GLP-1 mimetics or targeted inhibition of dipeptidyl peptidase-IV, the enzyme responsible for GLP-1 degradation. However, nutritional strategies provide a widely available, cost-effective alternative to pharmacological strategies for enhancing hormone release. Recent advances in nutritional research have implicated the combined ingestion of protein and calcium with enhanced endogenous GLP-1 release, which is likely due to activation of receptors with high affinity and/or sensitivity for amino acids and calcium. Specifically targeting these receptors could enhance gut hormone secretion, thus providing a new therapeutic option. This narrative review provides an overview of the latest research on protein- and calcium-mediated GLP-1 release with an emphasis on human data, and a perspective on potential mechanisms that link potent GLP-1 release to the co-ingestion of protein and calcium. In light of these recent findings, potential future research directions are also presented.
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Affiliation(s)
- Jonathan D Watkins
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, United Kingdom
| | - Françoise Koumanov
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, United Kingdom
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Brierley DI, de Lartigue G. Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating. Br J Pharmacol 2021; 179:584-599. [PMID: 34185884 PMCID: PMC8714868 DOI: 10.1111/bph.15603] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/03/2021] [Accepted: 06/16/2021] [Indexed: 12/19/2022] Open
Abstract
Here, we provide a focused review of the evidence for the roles of the vagus nerve in mediating the regulatory effects of peripherally and centrally produced GLP-1 on eating behaviour and energy balance. We particularly focus on recent studies which have used selective genetic, viral, and transcriptomic approaches to provide important insights into the anatomical and functional organisation of GLP-1-mediated gut-brain signalling pathways. A number of these studies have challenged canonical ideas of how GLP-1 acts in the periphery and the brain to regulate eating behaviour, with important implications for the development of pharmacological treatments for obesity.
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Affiliation(s)
- Daniel I Brierley
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Guillaume de Lartigue
- Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, Florida, USA
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Acute Low-Intensity Treadmill Running Upregulates the Expression of Intestinal Glucose Transporters via GLP-2 in Mice. Nutrients 2021; 13:nu13051735. [PMID: 34065342 PMCID: PMC8160680 DOI: 10.3390/nu13051735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/11/2021] [Accepted: 05/18/2021] [Indexed: 01/08/2023] Open
Abstract
The effects of exercise on nutrient digestion and absorption in the intestinal tract are not well understood. A few studies have reported that exercise training increases the expression of molecules involved in carbohydrate digestion and absorption. Exercise was also shown to increase the blood concentration of glucagon-like peptide-2 (GLP-2), which regulates carbohydrate digestion and absorption in the small intestine. Therefore, we investigated the effects of exercise on the expression of molecules involved in intestinal digestion and absorption, including GLP-2. Six-week-old male mice were divided into a sedentary (SED) and low-intensity exercise (LEx) group. LEx mice were required to run on a treadmill (12.5 m/min, 1 h), whereas SED mice rested. All mice were euthanized 1 h after exercise or rest, and plasma, jejunum, ileum, and colon samples were collected, followed by analysis via IHC, EIA, and immunoblotting. The levels of plasma GLP-2 and the jejunum expression of the GLP-2 receptor, sucrase-isomaltase (SI), and glucose transporter 2 (GLUT2) were higher in LEx mice. Thus, we showed that acute low-intensity exercise affects the expression of molecules involved in intestinal carbohydrate digestion and absorption via GLP-2. Our results suggest that exercise might be beneficial for small intestine function in individuals with intestinal frailty.
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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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Tanday N, Flatt PR, Irwin N. Metabolic responses and benefits of glucagon-like peptide-1 (GLP-1) receptor ligands. Br J Pharmacol 2021; 179:526-541. [PMID: 33822370 PMCID: PMC8820187 DOI: 10.1111/bph.15485] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/19/2021] [Accepted: 03/30/2021] [Indexed: 12/19/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has undergone a revolutionary turnaround from discovery to clinically approved therapeutic. Rapid progress in drug design and formulation has led from initial development of short- and long-acting drugs suitable for daily or weekly parenteral administration, respectively, through to the most recent approval of an orally active GLP-1 agent. The current review outlines the biological action profile of GLP-1 including the various beneficial metabolic responses in pancreatic and extra-pancreatic tissues, including the gastrointestinal tract, liver, bone and kidney as well as the reproductive cardiovascular and CNS. We then briefly consider clinically approved GLP-1 receptor ligands and recent advances in this field. Given the sustained evolution in the area of GLP-1 drug development and excellent safety profile, as well as the plethora of metabolic benefits, clinical approval for use in diseases beyond diabetes and obesity is very much conceivable.
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Affiliation(s)
- Neil Tanday
- Diabetes Research Group, Ulster University, Coleraine, UK
| | - Peter R Flatt
- Diabetes Research Group, Ulster University, Coleraine, UK
| | - Nigel Irwin
- Diabetes Research Group, Ulster University, Coleraine, UK
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Abstract
PURPOSE OF REVIEW In this review, we present recent insights into the role of the gut microbiota on gastrointestinal (GI) peptide secretion and signalling, with a focus on the orexigenic hormone, ghrelin. RECENT FINDINGS Evidence is accumulating suggesting that secretion of GI peptides is modulated by commensal bacteria present in our GI tract. Recent data shows that the gut microbiome impacts on ghrelinergic signalling through its metabolites, at the level of the ghrelin receptor (growth hormone secretagogue receptor) and highlights concomitant changes in circulating ghrelin levels with specific gut microbiota changes. However, the mechanisms by which the gut microbiota interacts with gut peptide secretion and signalling, including ghrelin, are still largely unknown. SUMMARY The gut microbiota may directly or indirectly influence secretion of the orexigenic hormone, ghrelin, similar to the modulation of satiety inducing GI hormones. Although data demonstrating a role of the microbiota on ghrelinergic signalling is starting to emerge, future mechanistic studies are needed to understand the full impact of the microbiota-ghrelin axis on metabolism and central-regulated homeostatic and non-homeostatic controls of food intake.
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Affiliation(s)
- Natasha K. Leeuwendaal
- Department of Anatomy and Neuroscience
- APC Microbiome, Ireland University College Cork, Cork, Ireland
| | | | - Harriët Schellekens
- Department of Anatomy and Neuroscience
- APC Microbiome, Ireland University College Cork, Cork, Ireland
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Espinoza L, Fedorchak S, Boychuk CR. Interplay Between Systemic Metabolic Cues and Autonomic Output: Connecting Cardiometabolic Function and Parasympathetic Circuits. Front Physiol 2021; 12:624595. [PMID: 33776789 PMCID: PMC7991741 DOI: 10.3389/fphys.2021.624595] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 02/12/2021] [Indexed: 12/21/2022] Open
Abstract
There is consensus that the heart is innervated by both the parasympathetic and sympathetic nervous system. However, the role of the parasympathetic nervous system in controlling cardiac function has received significantly less attention than the sympathetic nervous system. New neuromodulatory strategies have renewed interest in the potential of parasympathetic (or vagal) motor output to treat cardiovascular disease and poor cardiac function. This renewed interest emphasizes a critical need to better understand how vagal motor output is generated and regulated. With clear clinical links between cardiovascular and metabolic diseases, addressing this gap in knowledge is undeniably critical to our understanding of the interaction between metabolic cues and vagal motor output, notwithstanding the classical role of the parasympathetic nervous system in regulating gastrointestinal function and energy homeostasis. For this reason, this review focuses on the central, vagal circuits involved in sensing metabolic state(s) and enacting vagal motor output to influence cardiac function. It will review our current understanding of brainstem vagal circuits and their unique position to integrate metabolic signaling into cardiac activity. This will include an overview of not only how metabolic cues alter vagal brainstem circuits, but also how vagal motor output might influence overall systemic concentrations of metabolic cues known to act on the cardiac tissue. Overall, this review proposes that the vagal brainstem circuits provide an integrative network capable of regulating and responding to metabolic cues to control cardiac function.
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Affiliation(s)
- Liliana Espinoza
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Stephanie Fedorchak
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Carie R Boychuk
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
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Duca FA, Waise TMZ, Peppler WT, Lam TKT. The metabolic impact of small intestinal nutrient sensing. Nat Commun 2021; 12:903. [PMID: 33568676 PMCID: PMC7876101 DOI: 10.1038/s41467-021-21235-y] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract maintains energy and glucose homeostasis, in part through nutrient-sensing and subsequent signaling to the brain and other tissues. In this review, we highlight the role of small intestinal nutrient-sensing in metabolic homeostasis, and link high-fat feeding, obesity, and diabetes with perturbations in these gut-brain signaling pathways. We identify how lipids, carbohydrates, and proteins, initiate gut peptide release from the enteroendocrine cells through small intestinal sensing pathways, and how these peptides regulate food intake, glucose tolerance, and hepatic glucose production. Lastly, we highlight how the gut microbiota impact small intestinal nutrient-sensing in normal physiology, and in disease, pharmacological and surgical settings. Emerging evidence indicates that the molecular mechanisms of small intestinal nutrient sensing in metabolic homeostasis have physiological and pathological impact as well as therapeutic potential in obesity and diabetes. The gastrointestinal tract participates in maintaining metabolic homeostasis in part through nutrient-sensing and subsequent gut-brain signalling. Here the authors review the role of small intestinal nutrient-sensing in regulation of energy intake and systemic glucose metabolism, and link high-fat diet, obesity and diabetes with perturbations in these pathways.
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Affiliation(s)
- Frank A Duca
- BIO5 Institute, University of Arizona, Tucson, AZ, USA. .,School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA.
| | - T M Zaved Waise
- Toronto General Hospital Research Institute, UHN, Toronto, Canada
| | - Willem T Peppler
- Toronto General Hospital Research Institute, UHN, Toronto, Canada
| | - Tony K T Lam
- Toronto General Hospital Research Institute, UHN, Toronto, Canada. .,Department of Physiology, University of Toronto, Toronto, Canada. .,Department of Medicine, University of Toronto, Toronto, Canada. .,Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada.
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Wang Y, Alkhalidy H, Liu D. The Emerging Role of Polyphenols in the Management of Type 2 Diabetes. Molecules 2021; 26:molecules26030703. [PMID: 33572808 PMCID: PMC7866283 DOI: 10.3390/molecules26030703] [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: 11/13/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic β-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.
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Affiliation(s)
- Yao Wang
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA;
| | - Hana Alkhalidy
- Department of Nutrition and Food Technology, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Dongmin Liu
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA;
- Correspondence: ; Tel.: +1-540-231-3402; Fax: +1-540-231-3916
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Intestinal Electrical Stimulation Enhances Release of Postprandial Incretin Hormones Via Cholinergic Mechanisms. Obes Surg 2021; 31:1957-1966. [PMID: 33469859 DOI: 10.1007/s11695-021-05228-w] [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: 10/15/2020] [Revised: 01/05/2021] [Accepted: 01/08/2021] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Intestinal electrical stimulation (IES) has been reported to reduce body weight and improve glucose tolerance in obese and diabetic rats. Our study aimed to investigate possible IES mechanisms involving incretin hormones using intraduodenal glucose infusion in rats. We hypothesized that the enhanced release of postprandial glucagon-like peptide-1 (GLP-1) at early phase by IES was mediated through neuro/paracrine mechanisms involving the vagal nerve and glucose-dependent insulinotropic peptide (GIP). METHODS Fifteen normal male Sprague-Dawley rats chronically implanted with duodenal electrodes for IES, and an intra-duodenum catheter for the infusion of glucose were studied in a series of sessions with IES of different parameters with and without atropine and M3 receptor antagonist. Blood samples were collected via the tail vein for the measurement of blood glucose, and plasma GLP-1, and GIP. RESULTS (1) Compared to sham-IES, IES of 0.3 ms reduced blood glucose by 16.5-28.4% between 30 and 120 min (all time points p < 0.05), and IES of 3-ms reduced blood glucose at 60 (12.6%) and 90 min (11.8%). IES of 0.3 ms showed a greater hypoglycemic effect than 3 ms (p = 0.024) at 30 min. (2) IES elevated plasma GLP-1 with 0.3 ms (p = 0.001) and with 3 ms p = 0.03). (3) IES substantially elevated plasma GIP with 0.3 ms (p = 0.002) and with 3 ms (p < 0.001). (4) Pretreatment of atropine and the M3 receptor antagonist 4-DAMP blocked the effects of IES on GLP-1, GIP, and blood glucose. CONCLUSIONS IES reduces postprandial blood glucose by enhancing the release of GLP-1 and GIP mediated via the cholinergic mechanism.
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Abstract
Glucagon-like peptide-1 (GLP-1) is an enterohormone with a key role in several processes controlling body homeostasis, including glucose homeostasis and food intake regulation. It is secreted by the intestinal cells in response to nutrients, such as glucose, fat and amino acids. In the present review, we analyse the effect of protein on GLP-1 secretion and clearance. We review the literature on the GLP-1 secretory effects of protein and protein hydrolysates, and the mechanisms through which they exert these effects. We also review the studies on protein from different sources that has inhibitory effects on dipeptidyl peptidase-4 (DPP4), the enzyme responsible for GLP-1 inactivation, with particular emphasis on specific sources and treatments, and the gaps there still are in knowledge. There is evidence that the protein source and the hydrolytic processing applied to them can influence the effects on GLP-1 signalling. The gastrointestinal digestion of proteins, for example, significantly changes their effectiveness at modulating this enterohormone secretion in both in vivo and in vitro studies. Nevertheless, little information is available regarding human studies and more research is required to understand their potential as regulators of glucose homeostasis.
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Ribeiro-Parenti L, Jarry AC, Cavin JB, Willemetz A, Le Beyec J, Sannier A, Benadda S, Pelletier AL, Hourseau M, Léger T, Morlet B, Couvelard A, Anini Y, Msika S, Marmuse JP, Ledoux S, Le Gall M, Bado A. Bariatric surgery induces a new gastric mucosa phenotype with increased functional glucagon-like peptide-1 expressing cells. Nat Commun 2021; 12:110. [PMID: 33397977 PMCID: PMC7782689 DOI: 10.1038/s41467-020-20301-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/19/2020] [Indexed: 12/19/2022] Open
Abstract
Glucagon-Like Peptide-1 (GLP-1) undergoes rapid inactivation by dipeptidyl peptidase-4 (DPP4) suggesting that target receptors may be activated by locally produced GLP-1. Here we describe GLP-1 positive cells in the rat and human stomach and found these cells co-expressing ghrelin or somatostatin and able to secrete active GLP-1 in the rats. In lean rats, a gastric load of glucose induces a rapid and parallel rise in GLP-1 levels in both the gastric and the portal veins. This rise in portal GLP-1 levels was abrogated in HFD obese rats but restored after vertical sleeve gastrectomy (VSG) surgery. Finally, obese rats and individuals operated on Roux-en-Y gastric bypass and SG display a new gastric mucosa phenotype with hyperplasia of the mucus neck cells concomitant with increased density of GLP-1 positive cells. This report brings to light the contribution of gastric GLP-1 expressing cells that undergo plasticity changes after bariatric surgeries, to circulating GLP-1 levels.
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Affiliation(s)
- Lara Ribeiro-Parenti
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
- Service de Chirurgie Générale Œsogastrique et Bariatrique, Hôpital Bichat - Claude-Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Anne-Charlotte Jarry
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
| | - Jean-Baptiste Cavin
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
| | - Alexandra Willemetz
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
| | - Johanne Le Beyec
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
- Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière-Charles Foix, Biochimie Endocrinienne et Oncologique, Paris, France
| | - Aurélie Sannier
- Department of Pathology Bichat Hospital, AP-HP, 75018, Paris, France
| | - Samira Benadda
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
- Cell and Tissue Imaging Platform, Inserm, U1149, CNRS, ERL8252, 75018, Paris, France
| | - Anne-Laure Pelletier
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
| | - Muriel Hourseau
- Department of Pathology Bichat Hospital, AP-HP, 75018, Paris, France
| | - Thibaut Léger
- Université de Paris, Mass Spectrometry Laboratory, Institut Jacques Monod, UMR 7592, CNRS, 75205, Paris, France
- Université Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, 35000, Rennes, France
| | - Bastien Morlet
- Université de Paris, Mass Spectrometry Laboratory, Institut Jacques Monod, UMR 7592, CNRS, 75205, Paris, France
| | - Anne Couvelard
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
- Department of Pathology Bichat Hospital, AP-HP, 75018, Paris, France
| | - Younes Anini
- Department of Obstetrics and Gynecology, Dalhousie University, IWK Health Centre, Halifax, New Brunswick, Canada
| | - Simon Msika
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
- Service de Chirurgie Générale Œsogastrique et Bariatrique, Hôpital Bichat - Claude-Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Jean-Pierre Marmuse
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
- Service de Chirurgie Générale Œsogastrique et Bariatrique, Hôpital Bichat - Claude-Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Sévérine Ledoux
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France
- Service des Explorations Fonctionnelles Hôpital Louis Mourier, AP-HP, Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), 92701, Colombes, France
| | - Maude Le Gall
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France.
| | - André Bado
- Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France.
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Han JC, Weiss R. Obesity, Metabolic Syndrome and Disorders of Energy Balance. SPERLING PEDIATRIC ENDOCRINOLOGY 2021:939-1003. [DOI: 10.1016/b978-0-323-62520-3.00024-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Tassinari D, Giovanelli A, Asteria C. Obesity: Medical and Surgical Treatment. THYROID, OBESITY AND METABOLISM 2021:131-175. [DOI: 10.1007/978-3-030-80267-7_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hira T, Sekishita M, Hara H. Blood Sampling From Rat Ileal Mesenteric Vein Revealed a Major Role of Dietary Protein in Meal-Induced GLP-1 Response. Front Endocrinol (Lausanne) 2021; 12:689685. [PMID: 34149624 PMCID: PMC8206781 DOI: 10.3389/fendo.2021.689685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [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: 05/17/2021] [Indexed: 11/29/2022] Open
Abstract
The present study was conducted to examine region-dependent glucagon-like peptide-1 (GLP-1) responses to "meal ingestion" under physiological (conscious and unrestrained) conditions using rats with a catheter inserted into either the portal vein (PV) or the ileal mesenteric vein (ILMV). After recovery from the cannulation surgery, blood samples were collected from either PV or ILMV catheter before and after the voluntary ingestion of test diets. After an AIN-93G standard diet ingestion, GLP-1 concentration was higher in ILMV than in PV, and postprandial responses of peptide-YY (PYY) had similar trend, while that of glucose dependent-insulinotropic polypeptide showed an opposite trend to GLP-1/PYY responses. In a separated experiment, a protein-enriched diet containing casein at 25% wt/wt transiently increased GLP-1 concentration only in ILMV; however, a protein-free diet did not increase GLP-1 concentrations in PV or ILMV. These results indicate that postprandial GLP-1 is immediately released from the distal intestine under physiological conditions, and that dietary protein has a critical role in the enhancement of postprandial GLP-1 response.
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Affiliation(s)
- Tohru Hira
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
- Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
- *Correspondence: Tohru Hira,
| | - Madoka Sekishita
- Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
| | - Hiroshi Hara
- Faculty of Human Life Science, Fuji Women’s University, Ishikari, Japan
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Xie H, Yepuri N, Meng Q, Dhawan R, Leech CA, Chepurny OG, Holz GG, Cooney RN. Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation. Rev Endocr Metab Disord 2020; 21:431-447. [PMID: 32851581 PMCID: PMC7572644 DOI: 10.1007/s11154-020-09584-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2020] [Indexed: 12/12/2022]
Abstract
The cholinergic anti-inflammatory reflex (CAIR) represents an important homeostatic regulatory mechanism for sensing and controlling the body's response to inflammatory stimuli. Vagovagal reflexes are an integral component of CAIR whose anti-inflammatory effects are mediated by acetylcholine (ACh) acting at α7 nicotinic acetylcholine receptors (α7nAChR) located on cells of the immune system. Recently, it is appreciated that CAIR and α7nAChR also participate in the control of metabolic homeostasis. This has led to the understanding that defective vagovagal reflex circuitry underlying CAIR might explain the coexistence of obesity, diabetes, and inflammation in the metabolic syndrome. Thus, there is renewed interest in the α7nAChR that mediates CAIR, particularly from the standpoint of therapeutics. Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Furthermore, α7nAChR agonist PNU 282987 exerts trophic factor-like actions to support pancreatic β-cell survival under conditions of stress resembling diabetes. This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.
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Affiliation(s)
- Han Xie
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Natesh Yepuri
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Qinghe Meng
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Ravi Dhawan
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Colin A Leech
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Oleg G Chepurny
- Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
| | - George G Holz
- Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
| | - Robert N Cooney
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA.
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Tocchetti GN, Domínguez CJ, Zecchinati F, Arana MR, Rigalli JP, Ruiz ML, Villanueva SSM, Mottino AD. Intraluminal nutrients acutely strengthen rat intestinal MRP2 barrier function by a glucagon-like peptide-2-mediated mechanism. Acta Physiol (Oxf) 2020; 230:e13514. [PMID: 32476256 DOI: 10.1111/apha.13514] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/22/2020] [Accepted: 05/24/2020] [Indexed: 01/02/2023]
Abstract
AIM MRP2 is an intestinal ABC transporter that prevents the absorption of dietary xenobiotics. The aims of this work were: (1) to evaluate whether a short-term regulation of intestinal MRP2 barrier function takes place in vivo after luminal incorporation of nutrients and (2) to explore the underlying mechanism. METHODS MRP2 activity and localization were assessed in an in vivo rat model with preserved irrigation and innervation. Nutrients were administered into distal jejunum. After 30-minutes treatments, MRP2 activity was assessed in proximal jejunum by quantifying the transport of the model substrate 2,4-dinitrophenyl-S-glutathione. MRP2 localization was determined by quantitative confocal microscopy. Participation of extracellular mediators was evaluated using selective inhibitors and by immunoneutralization. Intracellular pathways were explored in differentiated Caco-2 cells. RESULTS Oleic acid, administered intraluminally at dietary levels, acutely stimulated MRP2 insertion into brush border membrane. This was associated with increased efflux activity and, consequently, enhanced barrier function. Immunoneutralization of the gut hormone glucagon-like peptide-2 (GLP-2) prevented oleic acid effect on MRP2, demonstrating the participation of this trophic factor as a main mediator. Further experiments using selective inhibitors demonstrated that extracellular adenosine synthesis and its subsequent binding to enterocytic A2B adenosine receptor (A2BAR) take place downstream GLP-2. Finally, studies in intestinal Caco-2 cells revealed the participation of A2BAR/cAMP/PKA intracellular pathway, ultimately leading to increased MRP2 localization in apical domains. CONCLUSION These findings reveal an on-demand, acute regulation of MRP2-associated barrier function, constituting a novel physiological mechanism of protection against the absorption of dietary xenobiotics in response to food intake.
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Affiliation(s)
- Guillermo N. Tocchetti
- Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET)National University of Rosario (UNR) Rosario Argentina
- Department of Clinical Pharmacology and Pharmacoepidemiology University of Heidelberg Heidelberg Germany
| | - Camila J. Domínguez
- Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET)National University of Rosario (UNR) Rosario Argentina
| | - Felipe Zecchinati
- Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET)National University of Rosario (UNR) Rosario Argentina
| | - Maite R. Arana
- Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET)National University of Rosario (UNR) Rosario Argentina
| | - Juan P. Rigalli
- Department of Clinical Pharmacology and Pharmacoepidemiology University of Heidelberg Heidelberg Germany
| | - María L. Ruiz
- Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET)National University of Rosario (UNR) Rosario Argentina
| | - Silvina S. M. Villanueva
- Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET)National University of Rosario (UNR) Rosario Argentina
| | - Aldo D. Mottino
- Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET)National University of Rosario (UNR) Rosario Argentina
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El K, Capozzi ME, Campbell JE. Repositioning the Alpha Cell in Postprandial Metabolism. Endocrinology 2020; 161:5910252. [PMID: 32964214 PMCID: PMC7899437 DOI: 10.1210/endocr/bqaa169] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 09/17/2020] [Indexed: 12/24/2022]
Abstract
Glucose homeostasis is maintained in large part due to the actions of the pancreatic islet hormones insulin and glucagon, secreted from β- and α-cells, respectively. The historical narrative positions these hormones in opposition, with insulin primarily responsible for glucose-lowering and glucagon-driving elevations in glucose. Recent progress in this area has revealed a more complex relationship between insulin and glucagon, highlighted by data demonstrating that α-cell input is essential for β-cell function and glucose homeostasis. Moreover, the common perception that glucagon levels decrease following a nutrient challenge is largely shaped by the inhibitory effects of glucose administration alone on the α-cell. Largely overlooked is that a mixed nutrient challenge, which is more representative of typical human feeding, actually stimulates glucagon secretion. Thus, postprandial metabolism is associated with elevations, not decreases, in α-cell activity. This review discusses the recent advances in our understanding of how α-cells regulate metabolism, with a particular focus on the postprandial state. We highlight α- to β-cell communication, a term that describes how α-cell input into β-cells is a critical axis that regulates insulin secretion and glucose homeostasis. Finally, we discuss the open questions that have the potential to advance this field and continue to evolve our understanding of the role that α-cells play in postprandial metabolism.
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Affiliation(s)
- Kimberley El
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Megan E Capozzi
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
- Department of Medicine, Division of Endocrinology, Duke University, Durham, North Carolina
- Correspondence: Jonathan E. Campbell, 300 N Duke Street, Durham, North Carolina 27701. E-mail:
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Cena H, Chiovato L, Nappi RE. Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists. J Clin Endocrinol Metab 2020; 105:5842158. [PMID: 32442310 PMCID: PMC7457958 DOI: 10.1210/clinem/dgaa285] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023]
Abstract
CONTEXT Obesity is responsible for an increased risk of sub-fecundity and infertility. Obese women show poorer reproductive outcomes regardless of the mode of conception, and higher body mass index (BMI) is associated with poorer fertility prognosis. Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility, and many women with PCOS are also overweight or obese. EVIDENCE ACQUISITION The aim of the present narrative review is to describe the mechanisms responsible for the development of infertility and PCOS in women with obesity/overweight, with a focus on the emerging role of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) as a therapeutic option for obese women with PCOS. EVIDENCE SYNTHESIS Weight reduction represents the most significant factor affecting fertility and pregnancy outcomes. Current experimental and clinical evidence suggests the presence of an underlying pathophysiological link between obesity, GLP-1 kinetic alterations, and PCOS pathogenesis. Based on the positive results in patients affected by obesity, with or without diabetes, the administration of GLP-1 RA (mainly liraglutide) alone or in combination with metformin has been investigated in women with obesity and PCOS. Several studies demonstrated significant weight loss and testosterone reduction, with mixed results relative to improvements in insulin resistance parameters and menstrual patterns. CONCLUSIONS The weight loss effects of GLP-1 RA offer a unique opportunity to expand the treatment options available to PCOS patients.
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Affiliation(s)
- Hellas Cena
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
- Clinical Nutrition and Dietetics Service, Unit of Internal Medicine and Endocrinology, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
- Correspondence and Reprint Requests: Hellas Cena, Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Via Forlanini 2, 27100, Pavia, Italy. E-mail:
| | - Luca Chiovato
- Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Rossella E Nappi
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
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