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Moszak M, Marcickiewicz J, Pelczyńska M, Bogdański P. The Interplay Between Psychological and Neurobiological Predictors of Weight Regain: A Narrative Review. Nutrients 2025; 17:1662. [PMID: 40431402 PMCID: PMC12114007 DOI: 10.3390/nu17101662] [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] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 05/07/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction: Obesity is a global health problem requiring effective interventions to achieve weight loss and maintain it in the long term. A major challenge for clinicians is weight regain (WR), defined as progressive weight gain following successful weight loss. WR is affected by multiple factors, including psychological traits linked to specific brain alterations. Understanding these mechanisms is crucial in developing strategies to prevent WR and to ensure effective weight control. Objectives: This narrative review aims to gather current findings on the psychological and neurobiological determinants of WR and to discuss the interplay between these factors. Methods: A literature search was conducted on PubMed, Medline, and Web of Science for English-language studies published between December 1990 and November 2024. Results: WR is driven by interconnected psychological and neurobiological factors that influence eating behavior and the regulation of body weight. Certain personality traits and emotional patterns are associated with specific changes in brain activity, which together affect vulnerability to WR. Although distinct mechanisms can be identified, the complexity of homeostatic and nonhomeostatic appetite control suggests that no single factor predominates. Conclusions: This review highlights the dynamic interplay between psychological and neurobiological predictors of WR. However, due to the narrative nature of this review, the focus on selected determinants, and the limited quality and size of the available studies, further research is needed to comprehensively understand causality and to improve relapse prevention strategies.
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Affiliation(s)
- Małgorzata Moszak
- Department of Obesity and Metabolic Disorder Treatment and Clinical Dietetics, Poznań University of Medical Sciences, 49 Przybyszewskiego Street, 60-355 Poznan, Poland; (M.P.); (P.B.)
| | - Justyna Marcickiewicz
- Faculty of Medicine, Poznań University of Medical Sciences, 70 Bukowska Street, 60-812 Poznan, Poland;
| | - Marta Pelczyńska
- Department of Obesity and Metabolic Disorder Treatment and Clinical Dietetics, Poznań University of Medical Sciences, 49 Przybyszewskiego Street, 60-355 Poznan, Poland; (M.P.); (P.B.)
| | - Paweł Bogdański
- Department of Obesity and Metabolic Disorder Treatment and Clinical Dietetics, Poznań University of Medical Sciences, 49 Przybyszewskiego Street, 60-355 Poznan, Poland; (M.P.); (P.B.)
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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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Dagbasi A, Fuller A, Hanyaloglu AC, Carroll B, McLaughlin J, Frost G, Holliday A. The role of nutrient sensing dysregulation in anorexia of ageing: The little we know and the much we don't. Appetite 2024; 203:107718. [PMID: 39423861 DOI: 10.1016/j.appet.2024.107718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/01/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
The age-related decline in appetite and food intake - termed "anorexia of ageing" - is implicated in undernutrition in later life and hence provides a public health challenge for our ageing population. Eating behaviour is controlled, in part, by homeostatic mechanisms which sense nutrient status and provide feedback to appetite control regions of the brain. Such feedback signals, propagated by episodic gut hormones, are dysregulated in some older adults. The secretory responses of appetite-related gut hormones to feeding are amplified, inducing a more anorexigenic signal which is associated with reduced appetite and food intake. Such an augmented response would indicate an increase in gut sensitivity to nutrients. Consequently, this review explores the role of gastrointestinal tract nutrient sensing in age-related appetite dysregulation. We review and synthesise evidence for age-related alterations in nutrient sensing which may explain the observed hormonal dysregulation. Drawing on what is known regarding elements of nutrient sensing pathways in animal models, in other tissues of the body, and in certain models of disease, we identify potential causal mechanisms including alterations in enteroendocrine cell number and distribution, dysregulation of cell signalling pathways, and changes in the gut milieu. From identified gaps in evidence, we highlight interesting and important avenues for future research.
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Affiliation(s)
- Aygul Dagbasi
- Section of Nutrition, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, London, W12 0NN, UK
| | - Amy Fuller
- Research Centre for Health and Life Sciences, Institute of Health and Wellbeing, Faculty of Health and Life Science, Coventry University, Coventry, CV1 5FB, UK
| | - Aylin C Hanyaloglu
- Institute of Reproductive and Developmental Biology (IRDB), Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK
| | - Bernadette Carroll
- School of Biochemistry, University of Bristol, University Walk, Bristol, BS1 8TD, UK
| | - John McLaughlin
- Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester and Manchester Academic Health Sciences Centre, Manchester, M13 9PT, UK
| | - Gary Frost
- Section of Nutrition, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, London, W12 0NN, UK
| | - Adrian Holliday
- School of Biomedical, Nutritional, and Sport Science, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK; Human Nutrition and Exercise Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
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Aydin Ö, Meijnikman AS, de Jonge PA, van Stralen K, Börger H, Okur K, Iqbal Z, Warmbrunn MV, Acherman YIZ, Bruin S, Winkelmeijer M, Schimmel AWM, Holst JJ, Poulsen SS, Bäckhed F, Nieuwdorp M, Groen AK, Gerdes VEA. Post-Bariatric Hypoglycemia: an Impaired Metabolic Response to a Meal. Obes Surg 2024; 34:3796-3806. [PMID: 39153140 PMCID: PMC11481667 DOI: 10.1007/s11695-024-07309-y] [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: 02/12/2024] [Revised: 05/09/2024] [Accepted: 05/23/2024] [Indexed: 08/19/2024]
Abstract
AIMS/HYPOTHESIS Post-bariatric hypoglycemia (PBH) is caused by postprandial hyperinsulinemia, due to anatomical alterations and changes in post-prandial metabolism after bariatric surgery. The mechanisms underlying the failing regulatory and compensatory systems are unclear. In this study, we investigated the differences in post-prandial hormones and metabolic profiles between patients with and without PBH. METHODS We performed a mixed meal test (MMT) in 63 subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery. Blood was withdrawn at 0, 10, 20, 30, 60, and 120 min after ingestion of a standardized meal. Glucose, insulin, GLP-1, FGF-19, and FGF-21 were measured and untargeted metabolomics analysis was performed on blood plasma to analyze which hormonal and metabolic systems were altered between patients with and without PBH. RESULTS Out of 63, a total of 21 subjects (33%) subjects developed PBH (glucose < 3.1 mmol/L) after surgery. Decreased glucose and increased insulin excursions during MMT were seen in PBH (p < 0.05). GLP-1, FGF-19, and FGF-21 were elevated after surgery (p < 0.001), but did not differ between PBH and non-PBH groups. We identified 20 metabolites possibly involved in carbohydrate metabolism which differed between the two groups, including increased carnitine and acylcholines in PBH. CONCLUSION Overall, 33% of the subjects developed PBH 1 year after RYGB surgery. While GLP-1, FGF-19, and FGF-21 were similar in PBH and non-PBH patients, metabolomics analysis revealed changes in carnitine and acyclcholines that are possibly involved in energy metabolism, which may play a role in the occurrence of PBH.
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Affiliation(s)
- Ömrüm Aydin
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Abraham S Meijnikman
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Patrick A de Jonge
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Karlijn van Stralen
- Department of Scientific Research, Spaarne Gasthuis, Hoofddorp, the Netherlands
| | - Hanneke Börger
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Kadriye Okur
- Department of Bariatric Surgery, Spaarne Gasthuis, Hoofddorp, the Netherlands
| | - Zainab Iqbal
- Cardiometabolic Research, Vrije Universiteit, Amsterdam, the Netherlands
| | - Moritz V Warmbrunn
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Yair I Z Acherman
- Department of Bariatric Surgery, Spaarne Gasthuis, Hoofddorp, the Netherlands
| | - Sjoerd Bruin
- Department of Bariatric Surgery, Spaarne Gasthuis, Hoofddorp, the Netherlands
| | - Maaike Winkelmeijer
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Alinda W M Schimmel
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | - Steen S Poulsen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Fredrik Bäckhed
- Department of Cardiovascular and Metabolic Research, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Max Nieuwdorp
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Albert K Groen
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands
| | - Victor E A Gerdes
- Department of Vascular Medicine, Amsterdam UMC - AMC, Amsterdam, the Netherlands.
- Department of Bariatric Surgery, Spaarne Gasthuis, Hoofddorp, the Netherlands.
- Department of Internal Medicine, Spaarne Gasthuis, Hoofddorp, the Netherlands.
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Li RJ, Yang T, Zeng YH, Natsuyama Y, Ren K, Li J, Nagakawa Y, Yi SQ. Impacts of different pancreatic resection ranges on endocrine function in Suncus murinus. World J Gastrointest Surg 2024; 16:2308-2318. [PMID: 39087135 PMCID: PMC11287669 DOI: 10.4240/wjgs.v16.i7.2308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/23/2024] [Accepted: 06/12/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND Surgical intervention involving the pancreas can lead to impaired glucose tolerance and other types of endocrine dysfunction. The scope of pancreatectomy and whether it includes the ventral pancreas are the key factors in the development of postoperative diabetes. The ventral and dorsal pancreases are almost separated in Suncus murinus (S. murinus). AIM To investigate the effects of different extents of pancreatic resection on endocrine function in S. murinus. METHODS Eight-week-old male S. murinus shrews were randomly divided into three experimental groups according to different pancreatic resection ranges as follows: ventral pancreatectomy (VPx) group; partial pancreatectomy (PPx) group; subtotal pancreatectomy (SPx) group; and a sham-operated group. Postprandial serum insulin, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and somatostatin (SST) levels, as well as food intake, weight, blood glucose, and glucose tolerance were regularly measured for each animal. RESULTS S. murinus treated with PPx and SPx suffered from varying degrees of impaired glucose tolerance, but only a small proportion of the SPx group developed diabetes. Only S. murinus in the SPx group showed a significant decrease in food intake accompanied by severe weight loss, as well as a significant increase in postprandial serum GLP-1 levels. Postprandial serum PP levels decreased in both the VPx and PPx groups, but not in the SPx group. Postprandial serum SST levels decreased in both VPx and PPx groups, but the decrease was marginal. CONCLUSION Severe weight loss after pancreatectomy may be related to loss of appetite caused by compensatory elevation of GLP-1. PP and GLP-1 may play a role in resisting blood glucose imbalance.
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Affiliation(s)
- Ru-Jia Li
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Ting Yang
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Yu-Hao Zeng
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Yutaro Natsuyama
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Ke Ren
- Faculty of Physical Education, Qujing Normal University, Qujing 655000, Yunnan Province, China
| | - Jun Li
- School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo 160-0023, Japan
| | - Shuang-Qin Yi
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
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Holst JJ, Madsbad S, Bojsen-Møller KN, Dirksen C, Svane M. New Lessons from the gut: Studies of the role of gut peptides in weight loss and diabetes resolution after gastric bypass and sleeve gastrectomy. Peptides 2024; 176:171199. [PMID: 38552903 DOI: 10.1016/j.peptides.2024.171199] [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: 01/29/2024] [Revised: 03/18/2024] [Accepted: 03/22/2024] [Indexed: 04/05/2024]
Abstract
It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.
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Affiliation(s)
- Jens Juul Holst
- The NovoNordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Denmark.
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
| | | | - Carsten Dirksen
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Maria Svane
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
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Bailey CJ, Flatt PR. Duodenal enteroendocrine cells and GIP as treatment targets for obesity and type 2 diabetes. Peptides 2024; 174:171168. [PMID: 38320643 DOI: 10.1016/j.peptides.2024.171168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 02/02/2024] [Accepted: 02/02/2024] [Indexed: 02/08/2024]
Abstract
The duodenum is an important source of endocrine and paracrine signals controlling digestion and nutrient disposition, notably including the main incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Bariatric procedures that prevent nutrients from contact with the duodenal mucosa are particularly effective interventions to reduce body weight and improve glycaemic control in obesity and type 2 diabetes. These procedures take advantage of increased nutrient delivery to more distal regions of the intestine which enhances secretion of the other incretin hormone glucagon-like peptide-1 (GLP-1). Preclinical experiments have shown that either an increase or a decrease in the secretion or action of GIP can decrease body weight and blood glucose in obesity and non-insulin dependent hyperglycaemia, but clinical studies involving administration of GIP have been inconclusive. However, a synthetic dual agonist peptide (tirzepatide) that exerts agonism at receptors for GIP and GLP-1 has produced marked weight-lowering and glucose-lowering effects in people with obesity and type 2 diabetes. This appears to result from chronic biased agonism in which the novel conformation of the peptide triggers enhanced signalling by the GLP-1 receptor through reduced internalisation while reducing signalling by the GIP receptor directly or via functional antagonism through increased internalisation and degradation.
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Affiliation(s)
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA Northern Ireland, UK
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Wei J, Ou Y, Chen J, Yu Z, Wang Z, Wang K, Yang D, Gao Y, Liu Y, Liu J, Zheng X. Mapping global new-onset, worsening, and resolution of diabetes following partial pancreatectomy: a systematic review and meta-analysis. Int J Surg 2024; 110:1770-1780. [PMID: 38126341 PMCID: PMC10942179 DOI: 10.1097/js9.0000000000000998] [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: 10/17/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND AND AIMS Partial pancreatectomy, commonly used for chronic pancreatitis, or pancreatic lesions, has diverse impacts on endocrine and metabolism system. The study aims to determine the global prevalence of new-onset, worsening, and resolution of diabetes following partial pancreatectomy. METHODS The authors searched PubMed, Embase, Web of Science, and Cochrane Library from inception to October, 2023. DerSimonian-Laird random-effects model with Logit transformation was used. Sensitivity analysis, meta-regression, and subgroup analysis were employed to investigate determinants of the prevalence of new-onset diabetes. RESULTS A total of 82 studies involving 13 257 patients were included. The overall prevalence of new-onset diabetes after partial pancreatectomy was 17.1%. Univariate meta-regression indicated that study size was the cause of heterogeneity. Multivariable analysis suggested that income of country or area had the highest predictor importance (49.7%). For subgroup analysis, the prevalence of new-onset diabetes varied from 7.6% (France, 95% CI: 4.3-13.0) to 38.0% (UK, 95% CI: 28.2-48.8, P <0.01) across different countries. Patients with surgical indications for chronic pancreatitis exhibited a higher prevalence (30.7%, 95% CI: 21.8-41.3) than those with pancreatic lesions (16.4%, 95% CI: 14.3-18.7, P <0.01). The type of surgical procedure also influenced the prevalence, with distal pancreatectomy having the highest prevalence (23.7%, 95% CI: 22.2-25.3, P <0.01). Moreover, the prevalence of worsening and resolution of preoperative diabetes was 41.1 and 25.8%, respectively. CONCLUSIONS Postoperative diabetes has a relatively high prevalence in patients undergoing partial pancreatectomy, which calls for attention and dedicated action from primary care physicians, specialists, and health policy makers alike.
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Affiliation(s)
- Junlun Wei
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research
| | - Yiran Ou
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research
| | - Jiaoting Chen
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research
| | - Zhicheng Yu
- Department of Economics, Keio University, Minato city, Tokyo, Japan
| | - Zhenghao Wang
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research
| | - Ke Wang
- Department of Vascular Surgery, University Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Dujiang Yang
- Department of General Surgery, Division of Pancreatic Surgery, West China Hospital, Sichuan University
| | - Yun Gao
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research
| | - Yong Liu
- Department of General Surgery, Division of Pancreatic Surgery, West China Hospital, Sichuan University
| | - Jiaye Liu
- Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease-Related Molecular Network, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province
- Laboratory of Thyroid and Parathyroid diseases, Frontiers Science Center for Disease-Related Molecular Network
- Department of General Surgery, Division of Thyroid Surgery, West China Hospital, Sichuan University
| | - Xiaofeng Zheng
- Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research
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9
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Tsilingiris D, Kokkinos A. Advances in obesity pharmacotherapy; learning from metabolic surgery and beyond. Metabolism 2024; 151:155741. [PMID: 37995806 DOI: 10.1016/j.metabol.2023.155741] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 11/05/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023]
Abstract
Currently, metabolic surgery (MS) constitutes the most effective means for durable weight loss of clinically meaningful magnitude, type 2 diabetes remission and resolution of non-alcoholic steatohepatitis, as well as other obesity-related comorbidities. Accumulating evidence on the mechanisms through which MS exerts its actions has highlighted the altered secretion of hormonally active peptides of intestinal origin with biological actions crucial to energy metabolism as key drivers of MS clinical effects. The initial success of glucagon-like peptide-1 (GLP-1) receptor agonists regarding weight loss and metabolic amelioration have been followed by the development of unimolecular dual and triple polyagonists, additionally exploiting the effects of glucagon and/or glucose-dependent insulinotropic polypeptide (GIP) which achieves a magnitude of weight loss approximating that of common MS operations. Through the implementation of such therapies, the feasibility of a "medical bypass", namely the replication of the clinical effects of MS through non-surgical interventions may be foreseeable in the near future. Apart from weight loss, this approach ought to be put to the test also regarding other clinical outcomes, such as liver steatosis and steatohepatitis, cardiovascular disease, and overall prognosis, on which MS has a robustly demonstrated impact. Besides, a medical bypass as an alternative, salvage, or combination strategy to MS may promote precision medicine in obesity therapeutics.
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Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Alexander Kokkinos
- 1st Department of Propaedeutic Internal Medicine, Athens University Medical School, Laiko Hospital, Athens, Greece.
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10
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Lim WH, Lin SY, Ng CH, Tan DJH, Xiao J, Yong JN, Tay PWL, Syn N, Chin YH, Chan KE, Khoo CM, Chew N, Foo RSY, Shabbir A, Tan EX, Huang DQ, Noureddin M, Sanyal AJ, Siddiqui MS, Muthiah MD. Foregut bypass vs. restrictive bariatric procedures for nonalcoholic fatty liver disease: a meta-analysis of 3,355 individuals. Hepatobiliary Surg Nutr 2023; 12:658-670. [PMID: 37886204 PMCID: PMC10598314 DOI: 10.21037/hbsn-21-520] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/12/2022] [Indexed: 10/28/2023]
Abstract
Background Bariatric surgery represents an important treatment option for severely obese patients with nonalcoholic fatty liver disease (NAFLD). However, there remains inadequate data regarding the effects of different bariatric procedures on various NAFLD parameters, especially for histological outcomes. Thus, this meta-analysis aimed to compare the effects of restrictive bariatric procedures and foregut bypass on the metabolic, biochemical, and histological parameters for patients with NAFLD. Methods Medline and Embase were searched for articles relating to bariatric procedures and NAFLD. Pairwise meta-analysis was conducted to compare efficacy of bariatric procedures pre- vs. post-procedure with subgroup analysis to further compare restrictive against foregut bypass procedures. Results Thirty-one articles involving 3,355 patients who underwent restrictive bariatric procedures (n=1,460) and foregut bypass (n=1,895) were included. Both foregut bypass (P<0.01) and restrictive procedures (P=0.03) significantly increased odds of fibrosis resolution. Compared to restrictive procedures, foregut bypass resulted in a borderline non-significant decrease in fibrosis score (P=0.06) and significantly lower steatosis score (P<0.001). For metabolic parameters, foregut bypass significantly lowered body mass index (P=0.003) and low-density lipoprotein (P=0.008) compared to restrictive procedures. No significant differences were observed between both procedures for aspartate aminotransferase (P=0.17) and alkaline phosphatase (P=0.61). However, foregut bypass resulted in significantly lower gamma-glutamyl transferase than restrictive procedures (P=0.01) while restrictive procedures resulted in significantly lower alanine transaminase than foregut bypass (P=0.02). Conclusions The significant histological and metabolic advantages and comparable improvements in biochemical outcomes support the choice of foregut bypass over restrictive bariatric procedures in NAFLD management.
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Affiliation(s)
- Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Snow Yunni Lin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jieling Xiao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jie Ning Yong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Phoebe Wen Lin Tay
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yip Han Chin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kai En Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chin Meng Khoo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Endocrinology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Nicholas Chew
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Hospital, Singapore, Singapore
| | - Roger S. Y. Foo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Hospital, Singapore, Singapore
| | - Asim Shabbir
- Division of General Surgery (Upper Gastrointestinal Surgery), Department of Surgery, National University Hospital, Singapore, Singapore
| | - Eunice X. Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Daniel Q. Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mazen Noureddin
- Cedars-Sinai Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Centre, Los Angeles, CA, USA
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Mark D. Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
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11
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Rai C, Priyadarshini P. Whey protein hydrolysates improve high-fat-diet-induced obesity by modulating the brain-peripheral axis of GLP-1 through inhibition of DPP-4 function in mice. Eur J Nutr 2023; 62:2489-2507. [PMID: 37154934 DOI: 10.1007/s00394-023-03162-4] [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: 01/12/2023] [Accepted: 04/18/2023] [Indexed: 05/10/2023]
Abstract
PURPOSE Obesity is a growing global health concern. Recent literature indicates a prominent role of glucagon-like peptide-1 (GLP-1) in glucose metabolism and food intake. The synergistic action of GLP-1 in the gut and brain is responsible for its satiety-inducing effect, suggesting that upregulation of active GLP-1 levels could be an alternative strategy to combat obesity. Dipeptidyl peptidase-4 (DPP-4) is an exopeptidase known to inactivate GLP-1, suggesting that its inhibition could be a crucial strategy for effectively extending the half-life of endogenous GLP-1. Peptides derived from partial hydrolysis of dietary proteins are gaining traction due to their inhibitory activity on DPP-4. METHODS Whey protein hydrolysate from bovine milk (bmWPH) was produced using simulated in situ digestion, purified using RP-HPLC, and characterized for DPP-4 inhibition. The antiadipogenic and antiobesity activity of bmWPH was then studied in 3T3-L1 preadipocytes and high-fat diet-induced obesity (HFD) mice model, respectively. RESULTS The dose-dependent inhibitory effect of bmWPH on the catalytic activity of DPP-4 was observed. Additionally, bmWPH suppressed adipogenic transcription factors and DPP-4 protein levels, leading to a negative effect on preadipocyte differentiation. In an HFD mice model, co-administration of WPH for 20 weeks downregulated adipogenic transcription factors, resulting in a concomitant reduction in whole body weight and adipose tissues. Mice fed with bmWPH also showed a marked reduction in DPP-4 levels in WAT, liver, and serum. Furthermore, HFD mice fed with bmWPH exhibited increased serum and brain GLP levels, which led to a significant decrease in food intake. CONCLUSION In conclusion, bmWPH reduces body weight in HFD mice by suppressing appetite through GLP-1, a satiety-inducing hormone, in both the brain and peripheral circulation. This effect is achieved through modulation of both the catalytic and non-catalytic activity of DPP-4.
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Affiliation(s)
- Chaitra Rai
- Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysuru, 570020, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Poornima Priyadarshini
- Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysuru, 570020, Karnataka, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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12
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Al-Sabah S, Jamal MH, Al-Khaledi G, Dsouza C, AlOtaibi F, Al-Ali W, Cherian P, Al-Khairi I, Ali H, Abu-Farha M, Abubaker J, Al-Mulla F. Increased Glucagon Immunoreactivity in a Rat Model of Diet-induced Obesity following Sleeve Gastrectomy. Med Princ Pract 2023; 32:000533746. [PMID: 37634505 PMCID: PMC10659591 DOI: 10.1159/000533746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 08/22/2023] [Indexed: 08/29/2023] Open
Abstract
OBJECTIVE Bariatric surgery is currently the most effective treatment for obesity, and procedures such as Roux-en Y gastric bypass and sleeve gastrectomy (SG) also result in rapid improvements in insulin sensitivity and glucose tolerance. In addition, these procedures cause changes in the secretion of various gut-derived hormones. The role these hormones play in the mechanism of the beneficial effects of bariatric surgery is still debated, but nonetheless, their importance provides inspiration for novel obesity-targeted pharmacotherapies. METHODS Male Sprague Dawley rats were fed either regular chow or a cafeteria diet to induce obesity. A sub-group of the obese animals then underwent either sham surgery or SG. RESULTS Following a 4-week recovery period, SG rats weighed significantly less than obese or sham-operated rats. Improvements in glucose tolerance and insulin sensitivity also occurred in the SG group, but these were not always statistically significant. We measured the intracellular lipid content of liver samples and found that obese rats showed signs of non-alcoholic fatty liver disease, which were significantly ameliorated by SG. There were significantly higher glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to a standard mixed meal in the SG group, as well as paradoxically higher glucagon secretion. CONCLUSION These data highlight the need for more specific anti-glucagon antibodies to characterize the changes in proglucagon-derived peptide concentrations that occur following SG. Further studies are required to determine whether these peptides contribute to the therapeutic effects of SG.
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Affiliation(s)
- Suleiman Al-Sabah
- Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Mohammad H. Jamal
- Department of Surgery, College of Medicine, Kuwait University, Kuwait City, Kuwait
- Department of Organ Transplant, College of Medicine, Kuwait City, Kuwait
| | - Ghanim Al-Khaledi
- Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Carol Dsouza
- Department of Surgery, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Fatemah AlOtaibi
- Department of Surgery, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Waleed Al-Ali
- Department of Pathology, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Preethi Cherian
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Irina Al-Khairi
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Hamad Ali
- Department of Medical Laboratory Sciences, College of Allied Health Sciences, Kuwait University, Kuwait City, Kuwait
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
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13
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Burlina S, Dalfrà MG, Lapolla A. Pregnancy after Bariatric Surgery: Nutrition Recommendations and Glucose Homeostasis: A Point of View on Unresolved Questions. Nutrients 2023; 15:nu15051244. [PMID: 36904243 PMCID: PMC10005384 DOI: 10.3390/nu15051244] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Obesity is increasing in all age groups and, consequently, its incidence has also risen in women of childbearing age. In Europe, the prevalence of maternal obesity varies from 7 to 25%. Maternal obesity is associated with short- and long-term adverse outcomes for both mother and child, and it is necessary to reduce weight before gestation to improve maternal and fetal outcomes. Bariatric surgery is an important treatment option for people with severe obesity. The number of surgeries performed is increasing worldwide, even in women of reproductive age, because improving fertility is a motivating factor. Nutritional intake after bariatric surgery is dependent on type of surgery, presence of symptoms, such as pain and nausea, and complications. There is also a risk of malnutrition after bariatric surgery. In particular, during pregnancy following bariatric surgery, there is a risk of protein and calorie malnutrition and micronutrient deficiencies due to increased maternal and fetal demand and possibly due to reduction of food intake (nausea, vomiting). As such, it is necessary to monitor and manage nutrition in pregnancy following bariatric surgery with a multidisciplinary team to avoid any deficiencies in each trimester and to ensure the well-being of the mother and fetus.
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14
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Albaugh VL, He Y, Münzberg H, Morrison CD, Yu S, Berthoud HR. Regulation of body weight: Lessons learned from bariatric surgery. Mol Metab 2023; 68:101517. [PMID: 35644477 PMCID: PMC9938317 DOI: 10.1016/j.molmet.2022.101517] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/04/2022] [Accepted: 05/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bariatric or weight loss surgery is currently the most effective treatment for obesity and metabolic disease. Unlike dieting and pharmacology, its beneficial effects are sustained over decades in most patients, and mortality is among the lowest for major surgery. Because there are not nearly enough surgeons to implement bariatric surgery on a global scale, intensive research efforts have begun to identify its mechanisms of action on a molecular level in order to replace surgery with targeted behavioral or pharmacological treatments. To date, however, there is no consensus as to the critical mechanisms involved. SCOPE OF REVIEW The purpose of this non-systematic review is to evaluate the existing evidence for specific molecular and inter-organ signaling pathways that play major roles in bariatric surgery-induced weight loss and metabolic benefits, with a focus on Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), in both humans and rodents. MAJOR CONCLUSIONS Gut-brain communication and its brain targets of food intake control and energy balance regulation are complex and redundant. Although the relatively young science of bariatric surgery has generated a number of hypotheses, no clear and unique mechanism has yet emerged. It seems increasingly likely that the broad physiological and behavioral effects produced by bariatric surgery do not involve a single mechanism, but rather multiple signaling pathways. Besides a need to improve and better validate surgeries in animals, advanced techniques, including inducible, tissue-specific knockout models, and the use of humanized physiological traits will be necessary. State-of-the-art genetically-guided neural identification techniques should be used to more selectively manipulate function-specific pathways.
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Affiliation(s)
- Vance L Albaugh
- Translational and Integrative Gastrointestinal and Endocrine Research Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Yanlin He
- Brain Glycemic and Metabolism Control Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Heike Münzberg
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Christopher D Morrison
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Sangho Yu
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Hans-Rudolf Berthoud
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
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15
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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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16
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Timmermans M, Topal B, Sanches EE, DE Jongh FW, Cagiltay E, Celik A, Ribeiro R, Parmar C, Ugale S, Proczko M, Stepaniak PS, Buise MP, Severin R, Pouwels S. The effects of glucagon like peptide-1 (GLP-1) on cardiac remodeling: exploring the role of medication and physiological modulation after metabolic surgery. Minerva Endocrinol (Torino) 2022; 47:449-459. [PMID: 33759444 DOI: 10.23736/s2724-6507.21.03296-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Obesity and associated comorbidities reach epidemic proportions nowadays. Several treatment strategies exist, but bariatric surgery has the only longstanding effects. Since a few years, there is increasing interest in the effects of gastro-intestinal hormones, in particular Glucagon-Like Peptide-1 (GLP-1) on the remission of Type 2 Diabetes (T2DM) and its effects on cardiac cardiovascular morbidity, cardiac remodeling, and mortality. In the past years several high quality multicenter randomized controlled trials were developed to assess the effects of GLP-1 receptor agonist therapy on cardiovascular morbidity and mortality. Most of the trials were designed and powered as non-inferiority trials to demonstrate cardiovascular safety. Most of these trials show a reduction in cardiovascular morbidity in patients with T2DM. Some follow-up studies indicate potential beneficial effects of GLP-1 receptor agonists on cardiovascular function in patients with heart failure, however the results are contradictory, and we need long-term studies to make firm conclusions about the pleiotropic properties of incretin-based therapies. However, it seems that GLP-1 receptor agonists have different effects than the increased GLP-1 production after bariatric surgery on cardiovascular remodeling. One of the hypotheses is that the blood concentrations of GLP-1 receptor agonists are three times higher compared to GLP-1 increase after bariatric and metabolic surgery. The purpose of this narrative review is to summarize the effects of GLP-1 on cardiovascular morbidity, mortality and remodeling due to medication but also due to bariatric and metabolic surgery. The second objective is to explain the possible differences in effects of GLP-1 agonists and bariatric and metabolic surgery.
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Affiliation(s)
- Marieke Timmermans
- Department of Surgery, Haaglanden Medical Center, The Hague, the Netherlands
| | - Besir Topal
- Department of Cardiothoracic Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands
| | - Elijah E Sanches
- Department of Surgery, Haaglanden Medical Center, The Hague, the Netherlands
| | - Frank W DE Jongh
- Department of Plastic Surgery, Haaglanden Medical Center, The Hague, the Netherlands
| | - Eylem Cagiltay
- School of Medicine, Department of Physiology, Istanbul Bilim University, Istanbul, Turkey
| | | | - Rui Ribeiro
- Multidisciplinary Center for Metabolic Disease, Santo António Clinic, Amadora, Portugal
| | - Chetan Parmar
- Department of Surgery, Whittington Hospital, London, UK
| | - Surendra Ugale
- Bariatric and Metabolic Surgery Clinic, Virinchi Hospitals, Hyderabad, India
| | - Monika Proczko
- Department of General, Endocrine and Transplant Surgery, University Medical Center, Gdansk University, Gdansk, Poland
| | - Pieter S Stepaniak
- Department of Health Operations Management, Noordwest Hospital Group, Alkmaar, the Netherlands
| | - Marc P Buise
- Department of Anesthesiology, Intensive Care and Pain Medicine, Catharina Hospital, Eindhoven, the Netherlands
| | - Rich Severin
- Department of Physical Therapy, College of Applied Health Sciences, University of Illinois, Chicago, IL, USA.,Doctor of Physical Therapy Program, Robbins College of Health and Human Sciences, Baylor University, Waco, TX, USA
| | - Sjaak Pouwels
- Department of Intensive Care Medicine, Elisabeth-Tweesteden Hospital, Tilburg, the Netherlands -
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17
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Elias K, Webb DL, Diaz Tartera HO, Hellström PM, Sundbom M. Impact of biliopancreatic diversion with duodenal switch on glucose homeostasis and gut hormones and their correlations with appetite. Surg Obes Relat Dis 2022; 18:1392-1398. [PMID: 36151028 DOI: 10.1016/j.soard.2022.08.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 08/07/2022] [Accepted: 08/21/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Biliopancreatic diversion with duodenal switch (BPD/DS) results in lifelong changes in gastrointestinal physiology with unclear associations with appetite perception. OBJECTIVE To explore mixed meal-induced changes in glucose homeostasis and gut hormones and their correlations with appetite perception. SETTING University hospital. METHODS Of 28 patients studied preoperatively (age: 38.4 ± 11.3 years; body mass index [BMI]: 56.5 ± 5.1 kg/m2; 14 women), 19 (68%) returned for postoperative follow-up. Plasma was sampled for 180 minutes during a 260-kcal standardized mixed meal. Concentrations of leptin, glucose, insulin, triglycerides, active acyl-ghrelin, motilin, total glucose-dependent insulinotropic polypeptide (GIP), active glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) were measured. Subjective appetite sensations were scored. RESULTS BPD/DS resulted in 66.1% ± 23.3% excess BMI loss. Leptin was halved. Glucose and insulin levels were reduced, blunting a preoperative peak at 30 minutes, giving a lower homeostasis model assessment for insulin resistance (HOMA-IR; 13.9 versus 4.8). In contrast, reduced ghrelin and motilin concentrations were accompanied by pronounced peaks 20-30 minutes prior to meal responses. GIP was reduced, whereas GLP-1 and PYY responses were markedly increased, with an early postprandial peak (P < .05, for all). HOMA-IR correlated with insulin (r = .72) and GIP (r = .57). Postoperatively, satiety correlated with GLP-1 (r = .56), whereas the gastric motility index correlated with the desire to eat (r = .60), percentage excess BMI loss (r = -.55), and percentage total weight loss (r = -.49). Delta insulin, GLP-1, and leptin correlated positively with percentage total weight loss (r = .51, r = .48, and r = .58, respectively). CONCLUSIONS BPD/DS reduces leptin, HOMA-IR, and GIP while markedly increasing GLP-1 and PYY. This study marks the magnitude change in GLP-1 with additional effects of PYY as important factors for weight loss.
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Affiliation(s)
- Khalid Elias
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
| | - Dominic-Luc Webb
- Department of Medical Sciences, Gastroenterology and Hepatology, Uppsala University, Uppsala, Sweden
| | - Hetzel O Diaz Tartera
- Department of Medical Sciences, Gastroenterology and Hepatology, Uppsala University, Uppsala, Sweden
| | - Per M Hellström
- Department of Medical Sciences, Gastroenterology and Hepatology, Uppsala University, Uppsala, Sweden
| | - Magnus Sundbom
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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18
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 190] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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Lin C, Yeong TJJM, Lim WH, Ng CH, Yau CE, Chin YH, Muthiah MD, Loh PH, Foo RSY, Mok SF, Shabbir A, Dimitriadis GK, Khoo CM, Chew NWS. Comparison of mechanistic pathways of bariatric surgery in patients with diabetes mellitus: A Bayesian network meta-analysis. Obesity (Silver Spring) 2022; 30:1380-1390. [PMID: 35715979 DOI: 10.1002/oby.23453] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/09/2022] [Accepted: 03/25/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Metabolic bariatric procedures are potentially efficacious treatment options in patients with type 2 diabetes mellitus (T2DM). Previous meta-analyses focused on individual operative approaches rather than the mechanistic pathways behind different bariatric procedures. This updated network meta-analysis aimed to synthesize new evidence and comparatively evaluate the efficacy of metabolic surgery against restrictive procedures and standard first-line treatment for patients with T2DM. METHODS Embase, MEDLINE, and trial registries were searched for randomized controlled trials on bariatric surgeries in patients with T2DM on September 3, 2021. A Bayesian network meta-analysis was conducted. The primary outcome was T2DM remission. Secondary outcomes included changes in BMI, lipoprotein levels, and blood pressure. RESULTS Thirty-two articles were included. Metabolic surgery was statistically superior to restrictive procedures (risk ratio [RR]: 2.57, 95% credibility intervals [CrI]: 1.36-5.43), medical therapy (RR: 35.29, 95% Crl: 10.56-183.23), and lifestyle intervention (RR: 40.51, 95% Crl: 5.32-402.59) in T2DM remission. Metabolic surgery significantly lowered BMI and blood pressure compared with other interventions. Restrictive procedures significantly increased high-density lipoprotein compared with metabolic surgery. Lifestyle intervention and metabolic surgery were statistically superior to restrictive procedures in reducing low-density lipoprotein. CONCLUSIONS The superiority in diabetes remission and favorable metabolic profile support the choice of metabolic surgery over restrictive bariatric procedures.
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Affiliation(s)
- Chaoxing Lin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Chun En Yau
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yip Han Chin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Mark D Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Poay Huan Loh
- Department of Cardiology, National University Heart Centre, National University Hospital, Singapore
| | - Roger S Y Foo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Hospital, Singapore
| | - Shao Feng Mok
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Endocrinology, Department of Medicine, National University Hospital, Singapore
| | - Asim Shabbir
- Division of General Surgery (Upper Gastrointestinal Surgery), Department of Surgery, National University Hospital, Singapore
| | - Georgios K Dimitriadis
- Department of Endocrinology, King's College Hospital NHS Foundation Trust, London, UK
- Obesity, Type 2 Diabetes and Immunometabolism Research Group, Department of Diabetes, Faculty of Cardiovascular Medicine & Sciences, School of Life Course Sciences, King's College London, London, UK
| | - Chin Meng Khoo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Endocrinology, Department of Medicine, National University Hospital, Singapore
| | - Nicholas W S Chew
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Cardiology, National University Heart Centre, National University Hospital, Singapore
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20
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The Sensory Mechanisms of Nutrient-Induced GLP-1 Secretion. Metabolites 2022; 12:metabo12050420. [PMID: 35629924 PMCID: PMC9147592 DOI: 10.3390/metabo12050420] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/03/2022] [Accepted: 05/05/2022] [Indexed: 02/05/2023] Open
Abstract
The enteroendocrine system of the gut regulates energy homeostasis through the release of hormones. Of the gut-derived hormones, GLP-1 is particularly interesting, as analogs of the hormone have proven to be highly effective for the treatment of type 2 diabetes mellitus and obesity. Observations on increased levels of GLP-1 following gastric bypass surgery have enhanced the interest in endogenous hormone secretion and highlighted the potential of endogenous secretion in therapy. The macronutrients and their digestive products stimulate the secretion of GLP-1 through various mechanisms that we have only begun to understand. From findings obtained from different experimental models, we now have strong indications for a role for both Sodium-Glucose Transporter 1 (SGLT1) and the K+ATP channel in carbohydrate-induced GLP-1 secretion. For fat, the free fatty acid receptor FFA1 and the G-protein-coupled receptor GPR119 have been linked to GLP-1 secretion. For proteins, Peptide Transporter 1 (Pept1) and the Calcium-Sensing Receptor (CaSR) are thought to mediate the secretion. However, attempts at clinical application of these mechanisms have been unsuccessful, and more work is needed before we fully understand the mechanisms of nutrient-induced GLP-1 secretion.
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Wierdak M, Korbut E, Hubalewska-Mazgaj M, Surmiak M, Magierowska K, Wójcik-Grzybek D, Pędziwiatr M, Brzozowski T, Magierowski M. Impact of Vagotomy on Postoperative Weight Loss, Alimentary Intake, and Enterohormone Secretion After Bariatric Surgery in Experimental Translational Models. Obes Surg 2022; 32:1586-1600. [PMID: 35277793 DOI: 10.1007/s11695-022-05987-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 02/18/2022] [Accepted: 02/23/2022] [Indexed: 10/18/2022]
Abstract
Obesity may be treated by bariatric procedures and is related to enterohormone release modulation. Nevertheless, a majority of commonly used surgical procedures have a significant impact on vagus nerve function by breaking the connections with its gastric branches. In the case of an intragastric balloon (BAL), this interaction is unclear. However, BAL-induced weight reduction is not long-lasting. Interestingly, this method has not been used in combination with vagotomy (VAG). Thus, we evaluated, for the first time, the short- and long-term effects of combined BAL and VAG using the animal-based translational model and compared these effects with sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). Wistar rats were fed a high-calorie diet for 8 weeks to induce obesity before SG, RYGB, BAL + / - VAG. Animals' weight and eating behaviors were monitored weekly. After 90 days, serum samples were collected to evaluate postprandial and fasting GLP-1, GIP, PYY, ghrelin, glucagon, insulin, leptin, and pancreatic polypeptide concentrations by fluorescent assay. VAG, SG, RYGB, and BAL + VAG significantly reduced body weight 30 and 90 days after surgery. BAL alone induced temporal weight reduction observed after 30 days, reversed after 90 days. Calories intake was reduced at the first half of the observation period in all groups. Fluid intake was reduced in all groups except SG and BAL. Enterohormone profile for BAL + VAG was comparable to SG and RYGB but not BAL. VAG and BAL + VAG but not BAL alone maintain weight reduction, alimentary intake changes, and enterohormone release after long-term observation. VAG may improve the effectiveness of bariatric procedures for obesity treatment in clinical practice.
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Affiliation(s)
- Mateusz Wierdak
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland
- 2Nd Department of Surgery, Jagiellonian University Medical College, 2 Jakubowskiego Street, 30-688, Kraków, Poland
| | - Edyta Korbut
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland
| | - Magdalena Hubalewska-Mazgaj
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland
| | - Marcin Surmiak
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland
- Department of Internal Medicine, Jagiellonian University Medical College, 8 Skawinska Street, 31-066, Kraków, Poland
| | - Katarzyna Magierowska
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland
| | - Dagmara Wójcik-Grzybek
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland
| | - Michał Pędziwiatr
- 2Nd Department of Surgery, Jagiellonian University Medical College, 2 Jakubowskiego Street, 30-688, Kraków, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland
| | - Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland.
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22
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Blonde GD, Mathes CM, Inui T, Hamel EA, Price RK, Livingstone MBE, Le Roux CW, Spector AC. Oromotor and somatic taste reactivity during sucrose meals reveals internal state and stimulus palatability after gastric bypass in rats. Am J Physiol Regul Integr Comp Physiol 2022; 322:R204-R218. [PMID: 35043683 PMCID: PMC8858674 DOI: 10.1152/ajpregu.00285.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 11/22/2022]
Abstract
After Roux-en-Y gastric bypass (RYGB), rats consume less high-energy foods and fluids, though whether this reflects a concomitant change in palatability remains unclear. By measuring behavior during intraorally delivered liquid meals across days (1 water, 8 sucrose sessions), we showed that RYGB rats (RYGB, n = 8/sex) consumed less 1.0 M sucrose than their sham surgery counterparts (SHAM, n = 8 males, n = 11 females) but displayed similarly high levels of ingestive taste reactivity responses at the start of infusions. Relative to water, both groups increased intake of sucrose, and ingestive responses were dominated by tongue protrusions rather than mouth movements. Thus, RYGB animals still found sucrose palatable despite consuming less than the SHAM group. As the intraoral infusion progressed but before meal termination, aversive behavior remained low and both RYGB and SHAM animals showed fewer ingestive responses, predominantly mouth movements as opposed to tongue protrusions. This shift in responsiveness unrelated to surgical manipulation suggests negative alliesthesia, or a decreased palatability, as rats approach satiation. Notably, only in RYGB rats, across sessions, there was a striking emergence of aversive behavior immediately after the sucrose meal. Thus, although lower intake in RYGB rats seems independent of the hedonic taste properties of sucrose, taste reactivity behavior in these animals immediately after termination of a liquid meal appears to be influenced by postoral events and reflects a state of nimiety or excessive consumption. Measurement of taste reactivity behaviors during an intraorally delivered meal represents a promising way to make inferences about internal state in nonverbal preclinical models.
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Affiliation(s)
- Ginger D Blonde
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida
| | - Clare M Mathes
- Department of Neuroscience, Baldwin Wallace University, Berea, Ohio
| | - Tadashi Inui
- Department of Oral Physiology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Elizabeth A Hamel
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida
| | - Ruth K Price
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - M Barbara E Livingstone
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Carel W Le Roux
- Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland
| | - Alan C Spector
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida
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23
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Meng Q, Culnan DM, Ahmed T, Sun M, Cooney RN. Roux-en-Y gastric bypass alters intestinal glucose transport in the obese Zucker rat. Front Endocrinol (Lausanne) 2022; 13:901984. [PMID: 36034439 PMCID: PMC9405183 DOI: 10.3389/fendo.2022.901984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/18/2022] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION The gastrointestinal tract plays a major role in regulating glucose homeostasis and gut endocrine function. The current study examines the effects of Roux-en-Y gastric bypass (RYGB) on intestinal GLP-1, glucose transporter expression and function in the obese Zucker rat (ZR). METHODS Two groups of ZRs were studied: RYGB and sham surgery pair-fed (PF) fed rats. Body weight and food intake were measured daily. On post-operative day (POD) 21, an oral glucose test (OGT) was performed, basal and 30-minute plasma, portal venous glucose and glucagon-like peptide-1 (GLP-1) levels were measured. In separate ZRs, the biliopancreatic, Roux limb (Roux) and common channel (CC) intestinal segments were harvested on POD 21. RESULTS Body weight was decreased in the RYGB group. Basal and 30-minute OGT plasma and portal glucose levels were decreased after RYGB. Basal plasma GLP-1 levels were similar, while a 4.5-fold increase in GLP-1 level was observed in 30-minute after RYGB (vs. PF). The increase in basal and 30-minute portal venous GLP-1 levels after RYGB were accompanied by increased mRNA expressions of proglucagon and PC 1/3, GPR119 protein in the Roux and CC segments. mRNA and protein levels of FFAR2/3 were increased in Roux segment. RYGB decreased brush border glucose transport, transporter proteins (SGLT1 and GLUT2) and mRNA levels of Tas1R1/Tas1R3 and α-gustducin in the Roux and CC segments. CONCLUSIONS Reductions in intestinal glucose transport and enhanced post-prandial GLP-1 release were associated with increases in GRP119 and FFAR2/3 after RYGB in the ZR model. Post-RYGB reductions in the regulation of intestinal glucose transport and L cell receptors regulating GLP-1 secretion represent potential mechanisms for improved glycemic control.
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Affiliation(s)
- Qinghe Meng
- Department of Surgery, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, United States
| | - Derek M. Culnan
- Burn and Reconstructive Centers of America, Jackson, MS, United States
| | - Tamer Ahmed
- Department of Surgery, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, United States
| | - Mingjie Sun
- Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Robert N. Cooney
- Department of Surgery, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, United States
- *Correspondence: Robert N. Cooney,
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Khalid SI, Thomson KB, Becerra AZ, Omotosho P, Spagnoli A, Torquati A. Rates, Risks, and Time to Fracture in Patients Undergoing Laparoscopic Vertical Sleeve Gastrectomy versus Roux-en-Y Gastric Bypass. ANNALS OF SURGERY OPEN 2021; 2:e099. [PMID: 37637884 PMCID: PMC10455321 DOI: 10.1097/as9.0000000000000099] [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: 04/07/2021] [Accepted: 08/27/2021] [Indexed: 11/25/2022] Open
Abstract
Objective To assess the rates, risks, and time to fracture in patients undergoing laparoscopic vertical sleeve gastrectomy (VSG) versus those undergoing Roux-en-Y gastric bypass (RYGB). Summary Background Data Metabolic and bariatric surgery has been implicated in significant bone loss and may increase fracture risk. Preoperative patient characteristics that might impact fracture risk and the time to fractures have not been established. Furthermore, the patient characteristics that might impact fracture risk and the time to fractures by surgical approach are unknown. Methods This population-based retrospective cohort analysis used Humana claims data from January 1, 2007 to March 31, 2017, and included 4073 patients undergoing laparoscopic RYGB and VSG as a first surgical intervention for weight loss. The primary outcomes were the incidence of fractures (Humeral, Radial or Ulnar, Pelvic, Hip, and Vertebral) within 48 months after laparoscopic VSG versus RYGB and days to these fractures. Results An analysis of total fractures (odds ratio [OR] 0.53; 95% confidence interval [CI], 0.38-0.73), vertebral fractures (OR 0.61; 95% CI, 0.38-0.99), hip fractures (OR 0.36; 95% CI, 0.15-0.84), and humeral fractures (OR 0.44; 95% CI, 0.22-0.90) demonstrated a reduction in fracture risk in patients undergoing VSG versus RYGB. Furthermore, postmenopausal status was independently associated with increased odds of total fractures and hip fractures (OR 2.18; 95% CI, 1.06-4.50; OR 5.83; 95% CI, 1.16-29.27; respectively). Likewise, osteoporosis at the time of surgery was associated with increased odds of total fractures (OR 1.61; 95% CI, 1.09-2.37), vertebral fractures (OR 2.01; 95% CI, 1.19-3.39), and hip fractures (OR 2.38; 95% CI, 1.19-4.77). Except for a significantly decreased odds of vertebral fractures in osteoporotic patients undergoing VSG versus RYGB (OR 0.41; 95% CI, 0.18-0.95), osteoporotic or postmenopausal status at the time of surgery was not found to increase odds of fracture depending on surgical intervention. However, time to fracture (total) and for all site-specific fractures, except for pelvic fractures, was significantly reduced in postmenopausal women undergoing RYGB versus VSG. Time to fracture (total) and for all site-specific fractures except pelvic and radial or ulnar fractures was significantly reduced in osteoporotic patients undergoing RYGB versus VSG. Conclusions and Relevance Though bariatric surgery is associated with several health-related benefits, increased fracture risk is an important factor to discuss with patients undergoing bariatric surgery. Bariatric surgery strategy, RYGB versus VSG, carries a differential risk of fracture, with RYGB carrying a higher risk of fracture and decreased time to fracture. Furthermore, patients who are postmenopausal or osteoporotic at the time of surgery carry an increased risk of total fractures, independent of bariatric surgery strategy. Being mindful of patient-specific fracture risk after bariatric surgery may help anticipate, identify, and prevent fractures.
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Affiliation(s)
- Syed I. Khalid
- From the Department of Surgery, Rush University Medical Center, Chicago, IL
- Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL
| | | | - Adan Z. Becerra
- From the Department of Surgery, Rush University Medical Center, Chicago, IL
| | - Philip Omotosho
- From the Department of Surgery, Rush University Medical Center, Chicago, IL
| | - Anna Spagnoli
- From the Department of Surgery, Rush University Medical Center, Chicago, IL
| | - Alfonso Torquati
- From the Department of Surgery, Rush University Medical Center, Chicago, IL
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GLP-1: 10-year follow-up after Roux-en-Y gastric bypass. Langenbecks Arch Surg 2021; 407:559-568. [PMID: 34651238 DOI: 10.1007/s00423-021-02341-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 09/23/2021] [Indexed: 12/30/2022]
Abstract
PURPOSE Glucagon-like peptide-1 (GLP-1) is a hormone widely studied in the short-term postoperative follow-up of Roux-en-Y gastric bypass due to its elevation and association with improvement of the glucose metabolism, but there are few studies in 10 years after RYGB follow-up with the same patient. METHODS Twenty morbidity obesity patients were submitted to RYGB; these patients were divided into two groups: normal glucose-tolerant morbidly obese patients (NGT) 11 patients and abnormal glucose metabolism morbidly obese patients (AGM) 9 patients. Oral glucose tolerance test (OGTT) was done during four different periods: T1 (first evaluation), T2 (pre-surgery), T3 (9 months after surgery) and T4 (10 years after surgery). RESULTS Groups were matched for age and gender, and as NGT and AGM had BMI of 46.31 ± 5.03 kg/m2 and 50.87 ± 10.31 kg/m2. After 10 years of RYGB, they were obesity grade I with BMI for NGT 32.45 ± 4.99 kg/m2 and AGM 34.85 ± 4.46 kg/m2. Plasma glucose levels decreased NGT group at T4 period had a significant reduction at 120 min after OGTT for NGT 55.49 ± 17.15 mg/dL (p˂0.001). Insulin levels changed from T1 to T4 for the NGT group. GLP-1 curves were statistically different between the NGT and AGM groups. The AGM group had a higher mean for GLP-1 secretion at T4 period and at 30 min of OGTT 63.85 ± 37.98 pmol/L when compared to NGT 50.73 ± 24.82 pmol/L with AGM > NGT with p˂0.001. CONCLUSION Evaluation of the same patient during 4 different periods shows that, even with weight regain, after 10-years of RYGB high levels of GLP-1 remained which can be associated with metabolic improvement especially at the NGT group.
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Smith KR, Moran TH. Gastrointestinal peptides in eating-related disorders. Physiol Behav 2021; 238:113456. [PMID: 33989649 PMCID: PMC8462672 DOI: 10.1016/j.physbeh.2021.113456] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/19/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022]
Abstract
Food intake is tightly controlled by homeostatic signals sensitive to metabolic need for the regulation of body weight. This review focuses on the peripherally-secreted gastrointestinal peptides (i.e., ghrelin, cholecystokinin, glucagon-like peptide 1, and peptide tyrosine tyrosine) that contribute to the control of appetite and discusses how these peptides or the signals arising from their release are disrupted in eating-related disorders across the weight spectrum, namely anorexia nervosa, bulimia nervosa, and obesity, and whether they are normalized following weight restoration or weight loss treatment. Further, the role of gut peptides in the pathogenesis and treatment response in human weight conditions as identified by rodent models are discussed. Lastly, we review the incretin- and hormone-based pharmacotherapies available for the treatment of obesity and eating-related disorders.
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Affiliation(s)
- Kimberly R Smith
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
| | - Timothy H Moran
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
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27
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Kahn SE, Edelstein SL, Arslanian SA, Barengolts E, Caprio S, Ehrmann DA, Hannon TS, Marcovina S, Mather KJ, Nadeau KJ, Utzschneider KM, Xiang AH, Buchanan TA. Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study. Diabetes Care 2021; 44:1948-1960. [PMID: 34135015 PMCID: PMC8740921 DOI: 10.2337/dc21-0461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/21/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. RESEARCH DESIGN AND METHODS Glucagon was measured in three randomized, parallel, clinical studies: 1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; 2) 267 adults studied at the same time points and treated with MET, G/M, or liraglutide plus metformin (L+M) or given placebo (PLAC); and 3) 88 adults studied at baseline and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose, and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs). RESULTS No change in fasting glucagon, steady-state glucagon, or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all P ≤ 0.005), which was maintained 3 months after treatment withdrawal (all P < 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months (P < 0.05 for all, except AGR at 12 months [P = 0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. CONCLUSIONS Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributable to weight loss in both interventions.
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Affiliation(s)
- Steven E Kahn
- VA Puget Sound Health Care System, Seattle, WA
- University of Washington, Seattle, WA
| | | | | | | | | | | | | | | | | | | | | | - Anny H Xiang
- Kaiser Permanente Southern California, Pasadena, CA
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Nauck MA, Wefers J, Meier JJ. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. Lancet Diabetes Endocrinol 2021; 9:525-544. [PMID: 34181914 DOI: 10.1016/s2213-8587(21)00113-3] [Citation(s) in RCA: 153] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022]
Abstract
Despite the successful development of new therapies for the treatment of type 2 diabetes, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors, the search for novel treatment options that can provide better glycaemic control and at reduce complications is a continuous effort. The present Review aims to present an overview of novel targets and mechanisms and focuses on glucose-lowering effects guiding this search and developments. We discuss not only novel developments of insulin therapy (eg, so-called smart insulin preparation with a glucose-dependent mode of action), but also a group of drug classes for which extensive research efforts have not been rewarded with obvious clinical impact. We discuss the potential clinical use of the salutary adipokine adiponectin and the hepatokine fibroblast growth factor (FGF) 21, among others. A GLP-1 peptide receptor agonist (semaglutide) is now available for oral absorption, and small molecules activating GLP-1 receptors appear on the horizon. Bariatric surgery and its accompanying changes in the gut hormonal milieu offer a background for unimolecular peptides interacting with two or more receptors (for GLP-1, glucose-dependent insulinotropic polypeptide, glucagon, and peptide YY) and provide more substantial glycaemic control and bodyweight reduction compared with selective GLP-1 receptor agonists. These and additional approaches will help expand the toolbox of effective medications needed for optimising the treatment of well delineated subgroups of type 2 diabetes or help develop personalised approaches for glucose-lowering drugs based on individual characteristics of our patients.
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Affiliation(s)
- Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.
| | - Jakob Wefers
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Juris J Meier
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital, Ruhr University Bochum, Bochum, Germany
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Trapp S, Brierley DI. Brain GLP-1 and the regulation of food intake: GLP-1 action in the brain and its implications for GLP-1 receptor agonists in obesity treatment. Br J Pharmacol 2021; 179:557-570. [PMID: 34323288 PMCID: PMC8820179 DOI: 10.1111/bph.15638] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/22/2021] [Accepted: 07/03/2021] [Indexed: 12/19/2022] Open
Abstract
This review considers the similarities and differences between the physiological systems regulated by gut-derived and neuronally produced glucagon-like peptide 1 (GLP-1). It addresses the questions of whether peripheral and central GLP-1 sources constitute separate, linked or redundant systems and whether the brain GLP-1 system consists of disparate sections or is a homogenous entity. This review also explores the implications of the answers to these questions for the use of GLP-1 receptor agonists as anti-obesity drugs.
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Affiliation(s)
- Stefan Trapp
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Daniel I Brierley
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
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30
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Craig CM, Lawler HM, Lee CJE, Tan M, Davis DB, Tong J, Glodowski M, Rogowitz E, Karaman R, McLaughlin TL, Porter L. PREVENT: A Randomized, Placebo-controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia. J Clin Endocrinol Metab 2021; 106:e3235-e3248. [PMID: 33616643 PMCID: PMC8277203 DOI: 10.1210/clinem/dgab103] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Indexed: 02/06/2023]
Abstract
CONTEXT Postbariatric hypoglycemia (PBH), characterized by enteroinsular axis overstimulation and hyperinsulinemic hypoglycemia, is a complication of bariatric surgery for which there is no approved therapy. OBJECTIVE To evaluate efficacy and safety of avexitide [exendin (9-39)], a glucagon-like peptide-1 antagonist, for treatment of PBH. METHODS A multicenter, Phase 2, randomized, placebo-controlled crossover study (PREVENT). Eighteen female patients with PBH were given placebo for 14 days followed by avexitide 30 mg twice daily and 60 mg once daily, each for 14 days in random order. The main outcome measures were glucose nadir and insulin peak during mixed-meal tolerance testing (MMTT) and hypoglycemic events captured by self-monitoring of blood glucose (SMBG), electronic diary, and blinded continuous glucose monitoring (CGM). RESULTS Compared with placebo, avexitide 30 mg twice daily and 60 mg once daily raised the glucose nadir by 21% (P = .001) and 26% (P = .0002) and lowered the insulin peak by 23% (P = .029) and 21% (P = .042), corresponding to 50% and 75% fewer participants requiring rescue during MMTT, respectively. Significant reductions in rates of Levels 1 to 3 hypoglycemia were observed, defined, respectively, as SMBG <70 mg/dL, SMBG <54 mg/dL, and a severe event characterized by altered mental and/or physical function requiring assistance. CGM demonstrated reductions in hypoglycemia without induction of clinically relevant hyperglycemia. Avexitide was well tolerated, with no increase in adverse events. CONCLUSION Avexitide administered for 28 days was well tolerated and resulted in robust and consistent improvements across multiple clinical and metabolic parameters, reinforcing the targeted therapeutic approach and demonstrating durability of effect. Avexitide may represent a first promising treatment for patients with severe PBH.
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Affiliation(s)
- Colleen M Craig
- Eiger BioPharmaceuticals, Inc., Palo Alto, CA 94306, USA
- Correspondence: Colleen M Craig, MD, 2155 Park Boulevard, Palo Alto, CA, USA 94306.
| | - Helen Margaret Lawler
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Clare Jung Eun Lee
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Marilyn Tan
- Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Dawn Belt Davis
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin, Madison, WI 53705, USA
| | - Jenny Tong
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Michele Glodowski
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Elisa Rogowitz
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Rowan Karaman
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin, Madison, WI 53705, USA
| | | | - Lisa Porter
- Eiger BioPharmaceuticals, Inc., Palo Alto, CA 94306, USA
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31
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Camacho-Ramírez A, Prada-Oliveira JA, Ribelles-García A, Almorza-Gomar D, Pérez-Arana GM. The Leading Role of Peptide Tyrosine Tyrosine in Glycemic Control After Roux-en-Y Gastric Bypass in Rats. Obes Surg 2021; 30:697-706. [PMID: 31701411 DOI: 10.1007/s11695-019-04239-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS Roux-en-Y gastric bypass (RYGB) is one of the most effective surgical therapies for the rapid resolution of type 2 diabetes. However, the mechanisms underlying the entero-hormonal response after surgery and the role of peptide tyrosine tyrosine (PYY) in the restoration of normoglycemia are still not clear. METHODS We reproduced the RYGB technique in Wistar and Goto-Kakizaki rats and performed serum hormonal, histological, and hormonal-infusion test. RESULTS Using the diabetic Goto-Kakizaki (GK) rat model, we demonstrated that PYY plasma levels showed a remarkable peak approximately 30 min earlier than GLP-1 or GIP after mixed-meal administration in RYGB-operated rats with PYY. The GLP-1 and GIP areas under the curve (AUCs) increased after RYGB in GK rats. Additionally, the findings suggested that PYY (3-36) infusion led to increased GLP-1 and GIP plasma levels close to those obtained after a meal. Finally, the number of GLP-1-positive cells appeared to increase in the three segments of the small intestine in GK-RYGB-operated rats beyond the early presence of nutrient stimulation in the ileum. Nevertheless, PYY-positive cell numbers appeared to increase only in the ileum. CONCLUSION At least in rats, these data demonstrate an earlier essential role for PYY in gut hormone regulation after RYGB. We understand that PYY contributes to GLP-1 and GIP release and there must be the existence of enteroendocrine communication routes between the distal and proximal small intestine.
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Affiliation(s)
- Alonso Camacho-Ramírez
- Puerta del Mar Hospital, University of Cadiz, Cadiz, Spain.,Asociación Gaditana de Apoyo al Investigador, Cadiz, Spain.,Biomedical Science Research and Innovation Institute (INIBICA), University of Cadiz, Cadiz, Spain
| | - J Arturo Prada-Oliveira
- Asociación Gaditana de Apoyo al Investigador, Cadiz, Spain.,Biomedical Science Research and Innovation Institute (INIBICA), University of Cadiz, Cadiz, Spain.,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, Plaza Fragela s/n, 11003, Cadiz, Spain
| | - Antonio Ribelles-García
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, Plaza Fragela s/n, 11003, Cadiz, Spain.,Sustainable Social Development Research Institute (INDESS), University of Cadiz, Cadiz, Spain
| | - David Almorza-Gomar
- Biomedical Science Research and Innovation Institute (INIBICA), University of Cadiz, Cadiz, Spain.,Operative Statistic and Research Department, University of Cadiz, Cadiz, Spain
| | - Gonzalo M Pérez-Arana
- Asociación Gaditana de Apoyo al Investigador, Cadiz, Spain. .,Biomedical Science Research and Innovation Institute (INIBICA), University of Cadiz, Cadiz, Spain. .,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Cadiz, Plaza Fragela s/n, 11003, Cadiz, Spain.
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Schalla MA, Taché Y, Stengel A. Neuroendocrine Peptides of the Gut and Their Role in the Regulation of Food Intake. Compr Physiol 2021; 11:1679-1730. [PMID: 33792904 DOI: 10.1002/cphy.c200007] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The regulation of food intake encompasses complex interplays between the gut and the brain. Among them, the gastrointestinal tract releases different peptides that communicate the metabolic state to specific nuclei in the hindbrain and the hypothalamus. The present overview gives emphasis on seven peptides that are produced by and secreted from specialized enteroendocrine cells along the gastrointestinal tract in relation with the nutritional status. These established modulators of feeding are ghrelin and nesfatin-1 secreted from gastric X/A-like cells, cholecystokinin (CCK) secreted from duodenal I-cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY) secreted from intestinal L-cells and uroguanylin (UGN) released from enterochromaffin (EC) cells. © 2021 American Physiological Society. Compr Physiol 11:1679-1730, 2021.
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Affiliation(s)
- Martha A Schalla
- Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Yvette Taché
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.,VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Andreas Stengel
- Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.,Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany
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33
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Meek CL, Lewis HB, Burling K, Reimann F, Gribble F. Expected values for gastrointestinal and pancreatic hormone concentrations in healthy volunteers in the fasting and postprandial state. Ann Clin Biochem 2021; 58:108-116. [PMID: 33175577 PMCID: PMC7961662 DOI: 10.1177/0004563220975658] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Gastrointestinal hormones regulate intestinal transit, control digestion, influence appetite and promote satiety. Altered production or action of gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY), may contribute to the biological basis of obesity and altered glucose homeostasis. However, challenges in analytical methodology and lack of clarity on expected values for healthy individuals have limited progress in this field. The aim of this study was to describe expected concentrations of gastrointestinal and pancreatic hormones in healthy volunteers following a standardized meal test (SMT) or 75 g oral glucose tolerance test (OGTT). METHODS A total of 28 healthy volunteers (12 men, 16 women; mean age 31.3 years; mean body mass index 24.9 kg/m2) were recruited to attend a hospital clinic on two occasions. Volunteers had blood sampling in the fasting state and were given, in randomized order, an oral glucose tolerance test (OGTT) and standardized mixed liquid meal test with venepuncture at timed intervals for 4 h after ingestion. Analytical methods for gut and pancreatic hormones were assessed and optimized. Concentrations of gut and pancreatic hormones were measured and used to compile ranges of expected values. RESULTS Ranges of expected values were created for glucose, insulin, glucagon, GLP-1, GIP, PYY and free fatty acids in response to a standardized mixed liquid meal or OGTT. Intact proinsulin and C-peptide levels were also measured following the OGTT. CONCLUSIONS These ranges of expected values can now be used to compare gut hormone concentrations between healthy individuals and patient groups.
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Affiliation(s)
- Claire L Meek
- Wellcome Trust-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
- Department of Clinical Biochemistry, Cambridge University Hospitals, Addenbrooke’s Hospital, Cambridge, UK
| | - Hannah B Lewis
- Wellcome Trust-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
- Department of Clinical Biochemistry, Cambridge University Hospitals, Addenbrooke’s Hospital, Cambridge, UK
| | - Keith Burling
- Department of Clinical Biochemistry, Cambridge University Hospitals, Addenbrooke’s Hospital, Cambridge, UK
- Core Biochemical Assay Laboratory, Addenbrooke’s Hospital, Hills Road, Cambridge, UK
| | - Frank Reimann
- Wellcome Trust-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
- Department of Clinical Biochemistry, Cambridge University Hospitals, Addenbrooke’s Hospital, Cambridge, UK
| | - Fiona Gribble
- Wellcome Trust-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
- Department of Clinical Biochemistry, Cambridge University Hospitals, Addenbrooke’s Hospital, Cambridge, UK
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Theilade S, Christensen MB, Vilsbøll T, Knop FK. An overview of obesity mechanisms in humans: Endocrine regulation of food intake, eating behaviour and common determinants of body weight. Diabetes Obes Metab 2021; 23 Suppl 1:17-35. [PMID: 33621414 DOI: 10.1111/dom.14270] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/21/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022]
Abstract
Obesity is one of the biggest health challenges of the 21st century, already affecting close to 700 million people worldwide, debilitating and shortening lives and costing billions of pounds in healthcare costs and loss of workability. Body weight homeostasis relies on complex biological mechanisms and the development of obesity occurs on a background of genetic susceptibility and an environment promoting increased caloric intake and reduced physical activity. The pathophysiology of common obesity links neuro-endocrine and metabolic disturbances with behavioural changes, genetics, epigenetics and cultural habits. Also, specific causes of obesity exist, including monogenetic diseases and iatrogenic causes. In this review, we provide an overview of obesity mechanisms in humans with a focus on energy homeostasis, endocrine regulation of food intake and eating behavior, as well as the most common specific causes of obesity.
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Affiliation(s)
- Simone Theilade
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Medicine, Herlev-Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Medicine, Herlev-Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective. Nutrients 2021; 13:nu13020351. [PMID: 33503878 PMCID: PMC7910956 DOI: 10.3390/nu13020351] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.
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36
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Guimarães M, Pereira SS, Monteiro MP. From Entero-Endocrine Cell Biology to Surgical Interventional Therapies for Type 2 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1307:273-297. [PMID: 32016913 DOI: 10.1007/5584_2020_480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The physiological roles of the enteroendocrine system in relation to energy and glucose homeostasis regulation have been extensively studied in the past few decades. Considerable advances were made that enabled to disclose the potential use of gastro-intestinal (GI) hormones to target obesity and type 2 diabetes (T2D). The recognition of the clinical relevance of these discoveries has led the pharmaceutical industry to design several hormone analogues to either to mitigate physiological defects or target pharmacologically T2D.Amongst several advances, a major breakthrough in the field was the unexpected observation that enteroendocrine system modulation to T2D target could be achieved by surgically induced anatomical rearrangement of the GI tract. These findings resulted from the widespread use of bariatric surgery procedures for obesity treatment, which despite initially devised to induce weight loss by limiting the systemic availably of nutrients, are now well recognized to influence GI hormone dynamics in a manner that is highly dependent on the type of anatomical rearrangement produced.This chapter will focus on enteroendocrine system related mechanisms leading to improved glycemic control in T2D after bariatric surgery interventions.
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Affiliation(s)
- Marta Guimarães
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal.,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Department of General Surgery, Centro Hospitalar de Entre o Douro e Vouga, Santa Maria da Feira, Portugal
| | - Sofia S Pereira
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal.,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Mariana P Monteiro
- Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal. .,Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
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Ramos AC, Carraso HVCJ, Bastos ELDS. Bariatric Procedures: Anatomical and Physiological Changes. MANAGEMENT OF NUTRITIONAL AND METABOLIC COMPLICATIONS OF BARIATRIC SURGERY 2021:41-67. [DOI: 10.1007/978-981-33-4702-1_4] [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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Jorsal T, Christensen MM, Mortensen B, Nygaard EB, Zhang C, Rigbolt K, Wandall E, Langholz E, Friis S, Worm D, Floyd A, Helgstrand F, Støving RK, Aldries AR, Juhl CB, Østergaard T, Rydborg T, Forman JL, Sørensen F, Schmidt T, Falkenhahn M, Musholt PB, Theis S, Larsen PJ, Rehfeld JF, Vrang N, Jelsing J, Vilsbøll T, Knop FK. Gut Mucosal Gene Expression and Metabolic Changes After Roux-en-Y Gastric Bypass Surgery. Obesity (Silver Spring) 2020; 28:2163-2174. [PMID: 33150746 DOI: 10.1002/oby.22973] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Changes in the secretion of gut-derived peptide hormones have been associated with the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. In this study, the effects of RYGB on anthropometrics, postprandial plasma hormone responses, and mRNA expression in small intestinal mucosa biopsy specimens before and after RYGB were evaluated. METHODS In a cross-sectional study, 20 individuals with obesity undergoing RYGB underwent mixed meal tests and upper enteroscopy with retrieval of small intestinal mucosa biopsy specimens 3 months before and after surgery. Concentrations of circulating gut and pancreatic hormones during mixed meal tests as well as full mRNA sequencing of biopsy specimens were evaluated. RESULTS RYGB-induced improvements of body weight and composition, insulin resistance, and circulating cholesterols were accompanied by significant changes in postprandial plasma responses of pancreatic and gut hormones. Global gene expression analysis of biopsy specimens identified 2,437 differentially expressed genes after RYGB, including changes in genes that encode prohormones and G protein-coupled receptors. CONCLUSIONS RYGB affects the transcription of a wide range of genes, indicating that the observed beneficial metabolic effects of RYGB may rely on a changed expression of several genes in the gut. RYGB-induced changes in the expression of genes encoding signaling peptides and G protein-coupled receptors may disclose new gut-derived treatment targets against obesity and diabetes.
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Affiliation(s)
- Tina Jorsal
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Marie M Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Brynjulf Mortensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | | | | | | | - Erik Wandall
- Endoscopic Unit, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Ebbe Langholz
- Endoscopic Unit, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Steffen Friis
- Endoscopic Unit, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Dorte Worm
- Department of Gastrointestinal Surgery, Zealand University Hospital, Køge, Denmark
| | - Andrea Floyd
- Department of Gastrointestinal Surgery, Zealand University Hospital, Køge, Denmark
| | - Frederik Helgstrand
- Department of Gastrointestinal Surgery, Zealand University Hospital, Køge, Denmark
| | - René K Støving
- Elite Research Center for Medical Endocrinology & Center for Eating Disorders, Odense University Hospital, Odense, Denmark
| | - Alin R Aldries
- Department of Medicine, South West Jutland Hospital, Esbjerg, Denmark
| | - Claus B Juhl
- Department of Medicine, South West Jutland Hospital, Esbjerg, Denmark
| | | | | | - Julie L Forman
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Frederik Sørensen
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | | | | | | | | | | | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, 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
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40
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Mezza T, Cefalo CMA, Cinti F, Quero G, Pontecorvi A, Alfieri S, Holst JJ, Giaccari A. Endocrine and Metabolic Insights from Pancreatic Surgery. Trends Endocrinol Metab 2020; 31:760-772. [PMID: 32830029 DOI: 10.1016/j.tem.2020.07.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/25/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023]
Abstract
Although it is well established that diabetes can also develop as a result of diseases or maneuvers on the exocrine pancreas, the complex relationship between glucose disorders and underlying pancreatic disease is still debated. There is evidence that several features linked to pancreatic diseases can modify endocrine and metabolic conditions before and after surgery. However, pancreatic surgery provides a rare opportunity to correlate in vivo endocrine and metabolic pathways with ex vivo pancreatic samples, to examine the endocrine and metabolic effects of acute islet removal, and finally to clarify the pathogenesis of diabetes. This approach could therefore represent a unique method to shed light on the molecular mechanisms, predicting factors, and metabolic consequences of insulin resistance, islet plasticity, β cell failure, and type 2 diabetes.
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Affiliation(s)
- Teresa Mezza
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara M A Cefalo
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Cinti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giuseppe Quero
- Chirurgia Digestiva, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alfredo Pontecorvi
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Sergio Alfieri
- Chirurgia Digestiva, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Jens J Holst
- Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Andrea Giaccari
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
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Iqbal Z, Adam S, Ho JH, Syed AA, Ammori BJ, Malik RA, Soran H. Metabolic and cardiovascular outcomes of bariatric surgery. Curr Opin Lipidol 2020; 31:246-256. [PMID: 32618731 DOI: 10.1097/mol.0000000000000696] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
PURPOSE OF REVIEW Bariatric surgery is an effective therapy for morbid obesity that also improves weight-related metabolic parameters and reduces morbidity and mortality. The purpose of this review is to consolidate our current understanding of metabolic, macrovascular and microvascular benefits of bariatric surgery and to provide an update. RECENT FINDINGS Early resolution of insulin resistance and type 2 diabetes mellitus (T2DM) varies by type of bariatric surgery and appears to be mediated by changes in secretion of gut hormones, metabolism of bile acids, expression of glucose transporters and the gut microbiome. Dyslipidaemia, atherosclerosis, microvascular complications of obesity and diabetes, systemic and tissue-level inflammation show evidence of regression and hypertension improves significantly after bariatric surgery. SUMMARY Bariatric surgery leads to improvements in obesity-related metabolic comorbidities such as dyslipidaemia, HDL functionality, hypertension, T2DM, insulin resistance and inflammation. It slows the atherosclerotic process and reduces cardiovascular and all-cause mortality. Recent data have demonstrated regression of the microvascular complications of obesity and diabetes including the regeneration of small nerve fibres. The magnitude of change in short-term metabolic effects depends on the surgical procedure whilst longer term effects are related to the amount of sustained excess weight loss.
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Affiliation(s)
- Zohaib Iqbal
- Faculty of Biology, Medicine and Health, University of Manchester
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust
| | - Safwaan Adam
- Faculty of Biology, Medicine and Health, University of Manchester
- The Christie Hospital NHS Foundation Trust, Manchester
| | - Jan H Ho
- Faculty of Biology, Medicine and Health, University of Manchester
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust
| | - Akheel A Syed
- Faculty of Biology, Medicine and Health, University of Manchester
- Department of Diabetes, Endocrinology and Obesity Medicine
| | - Basil J Ammori
- Faculty of Biology, Medicine and Health, University of Manchester
- Department of Surgery, Salford Royal NHS Foundation Trust, Salford, UK
| | - Rayaz A Malik
- Faculty of Biology, Medicine and Health, University of Manchester
- Weill-Cornell Medicine-Qatar, Doha, Qatar
| | - Handrean Soran
- Faculty of Biology, Medicine and Health, University of Manchester
- The Christie Hospital NHS Foundation Trust, Manchester
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Arakawa R, Febres G, Cheng B, Krikhely A, Bessler M, Korner J. Prospective study of gut hormone and metabolic changes after laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass. PLoS One 2020; 15:e0236133. [PMID: 32687546 PMCID: PMC7371190 DOI: 10.1371/journal.pone.0236133] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Background Laparoscopic sleeve gastrectomy (SG) has surpassed Roux-en-Y gastric bypass (RYGB) as the most prevalent bariatric procedure worldwide. While RYGB and SG demonstrate equivalent short-term weight loss, long-term weight loss tends to be greater after RYGB. Differences in the effect of these procedures on gastrointestinal hormones that regulate energy homeostasis are felt to partially underlie differences in outcomes. The objective of this study was to prospectively quantify blood levels of gut hormones of energy and glucose homeostasis at one year follow up to delineate possible reasons for greater efficacy of RYGB over SG in achieving weight loss. Methods Patients undergoing SG (n = 19) and RYGB (n = 40) were studied before surgery and at 2,12, 26, and 52 weeks postoperatively. Blood samples drawn in the fasted state and after a liquid mixed meal were assayed at baseline, 26, and 52 weeks for peptide YY (PYY), glucagon-like peptide-1 (GLP-1), ghrelin, insulin, glucose, and leptin. Fasting and postprandial appetitive sensations were assessed by visual analog scale. Results At 1 year there was greater weight loss in RYGB compared with SG patients (30% vs 27%; P = 0.03). Area under the curve (AUC) after the mixed meal for PYY was greater in RYGB patients (P<0.001). RYGB patients had significant increases in GLP-1 AUC compared to baseline (P = 0.002). Ghrelin levels decreased only after SG compared to baseline (P<0.001) but were not significantly different from RYGB. There was a trend toward decreased sweet cravings in RYGB patients (P = 0.056). Conclusions Differences in gastrointestinal hormones that regulate energy and glucose homeostasis are a possible mechanism for greater efficacy of RYGB compared to SG.
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Affiliation(s)
- Rachel Arakawa
- Division of Endocrinology & Metabolism, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Gerardo Febres
- Division of Endocrinology & Metabolism, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Bin Cheng
- Department of Biostatistics, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Abraham Krikhely
- Division of Minimal Access/Bariatric Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Marc Bessler
- Division of Minimal Access/Bariatric Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Judith Korner
- Division of Endocrinology & Metabolism, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
- * E-mail:
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Berthoud HR, Morrison CD, Münzberg H. The obesity epidemic in the face of homeostatic body weight regulation: What went wrong and how can it be fixed? Physiol Behav 2020; 222:112959. [PMID: 32422162 DOI: 10.1016/j.physbeh.2020.112959] [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] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 04/23/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022]
Abstract
Ever since the pioneering discoveries in the mid nineteen hundreds, the hypothalamus was recognized as a crucial component of the neural system controlling appetite and energy balance. The new wave of neuron-specific research tools has confirmed this key role of the hypothalamus and has delineated many other brain areas to be part of an expanded neural system sub serving these crucial functions. However, despite significant progress in defining this complex neural circuitry, many questions remain. One of the key questions is why the sophisticated body weight regulatory system is unable to prevent the rampant obesity epidemic we are experiencing. Why are pathologically obese body weight levels defended, and what can we do about it? Here we try to find answers to these questions by 1) reminding the reader that the neural controls of ingestive behavior have evolved in a demanding, restrictive environment and encompass much of the brain's major functions, far beyond the hypothalamus and brainstem, 2) hypothesizing that the current obesogenic environment impinges mainly on a critical pathway linking hypothalamic areas with the motivational and reward systems to produce uncompensated hyperphagia, and 3) proposing adequate strategies for prevention and treatment.
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Affiliation(s)
- Hans-Rudolf Berthoud
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA.
| | - Christopher D Morrison
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
| | - Heike Münzberg
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
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Saad R, Habli D, El Sabbagh R, Chakhtoura M. Bone Health Following Bariatric Surgery: An Update. J Clin Densitom 2020; 23:165-181. [PMID: 31519474 DOI: 10.1016/j.jocd.2019.08.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 08/02/2019] [Accepted: 08/05/2019] [Indexed: 12/13/2022]
Abstract
Obesity rates are increasing rapidly, and bariatric surgery is currently the most effective tool for weight loss. Recently, bariatric surgery induced bone loss has gained attention. Such detrimental effect on bone is multifactorial and causes may include nutrient deficiencies, gut and gonadal hormonal changes, mechanical unloading, loss of lean mass, increased bone marrow fat, and increased risk of fall. This review describes the available evidence on bone loss and fracture risk following bariatric surgery and summarizes the guidelines on the topic. Increased bone resorption starts early postsurgery, and bone markers peak at 1-2 yr. Across studies, the drop in areal bone mineral density is inconsistent at the lumbar spine, while a 2%-5% drop at 6 mo and a 6%-10.5% at 9-12 mo are observed at the total hip. Conversely, studies using quantitative CT showed a 6%-7% decrease in volumetric bone mineral density at the lumbar spine at 6-12 mo postsurgery. These studies also report significant bone loss at the radius and tibia, in addition to alteration in bone microarchitecture. Fracture risk increases 2 yr after surgery, more so following malabsorptive procedures. Fractures were reported at axial, weight bearing sites and at appendicular sites. The available evidence is very heterogeneous, and mostly derived from studies on Roux-en-y gastric bypass in premenopausal women. Data on restrictive procedures is scarce. Our findings suggest that the early postoperative phase represents the "golden window" to intervene and promote bone health. More research is needed to determine the effect of different bariatric procedures on bone, to identify optimal interventions to prevent bone loss and to characterize high risk individuals who should be targeted.
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Affiliation(s)
- Randa Saad
- Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, Division of Endocrinology and Metabolism, Department of Internal Medicine-American University of Beirut Medical Center, Beirut, Lebanon
| | - Dalal Habli
- Department of Internal Medicine - American University of Beirut Medical Center, Beirut, Lebanon
| | - Rawaa El Sabbagh
- Department of Internal Medicine - American University of Beirut Medical Center, Beirut, Lebanon
| | - Marlene Chakhtoura
- Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, Division of Endocrinology and Metabolism, Department of Internal Medicine-American University of Beirut Medical Center, Beirut, Lebanon.
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Alexiadou K, Cuenco J, Howard J, Wewer Albrechtsen NJ, Ilesanmi I, Kamocka A, Tharakan G, Behary P, Bech PR, Ahmed AR, Purkayastha S, Wheller R, Fleuret M, Holst JJ, Bloom SR, Khoo B, Tan TMM. Proglucagon peptide secretion profiles in type 2 diabetes before and after bariatric surgery: 1-year prospective study. BMJ Open Diabetes Res Care 2020; 8:8/1/e001076. [PMID: 32209584 PMCID: PMC7103850 DOI: 10.1136/bmjdrc-2019-001076] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 01/20/2020] [Accepted: 02/07/2020] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Hyperglucagonemia is a key pathophysiological driver of type 2 diabetes. Although Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for diabetes, it is presently unclear how surgery alters glucagon physiology. The aim of this study was to characterize the behavior of proglucagon-derived peptide (glucagon, glucagon-like peptide-1 (GLP-1), oxyntomodulin, glicentin) secretion after RYGB surgery. RESEARCH DESIGN AND METHODS Prospective study of 19 patients with obesity and pre-diabetes/diabetes undergoing RYGB. We assessed the glucose, insulin, GLP-1, glucose-dependent insulinotropic peptide (GIP), oxyntomodulin, glicentin and glucagon responses to a mixed-meal test (MMT) before and 1, 3 and 12 months after surgery. Glucagon was measured using a Mercodia glucagon ELISA using the 'Alternative' improved specificity protocol, which was validated against a reference liquid chromatography combined with mass spectrometry method. RESULTS After RYGB, there were early improvements in fasting glucose and glucose tolerance and the insulin response to MMT was accelerated and amplified, in parallel to significant increases in postprandial GLP-1, oxyntomodulin and glicentin secretion. There was a significant decrease in fasting glucagon levels at the later time points of 3 and 12 months after surgery. Glucagon was secreted in response to the MMT preoperatively and postoperatively in all patients and there was no significant change in this postprandial secretion. There was no significant change in GIP secretion. CONCLUSIONS There is a clear difference in the dynamics of secretion of proglucagon peptides after RYGB. The reduction in fasting glucagon secretion may be one of the mechanisms driving later improvements in glycemia after RYGB. TRIAL REGISTRATION NUMBER NCT01945840.
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Affiliation(s)
- Kleopatra Alexiadou
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Joyceline Cuenco
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - James Howard
- Drug Development Solutions, LGC Bioscience, Fordham, Cambridgeshire, UK
| | - Nicolai Jacob Wewer Albrechtsen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
- NNF Center for Protein Research, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - Ibiyemi Ilesanmi
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Anna Kamocka
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - George Tharakan
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Preeshila Behary
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Paul R Bech
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Ahmed R Ahmed
- Department of Surgery and Cancer, Imperial College London, London, UK
| | | | - Robert Wheller
- Drug Development Solutions, LGC Bioscience, Fordham, Cambridgeshire, UK
| | - Matthieu Fleuret
- Drug Development Solutions, LGC Bioscience, Fordham, Cambridgeshire, UK
| | - Jens Juul Holst
- Department of Biomedical Sciences and the NNF Center for Basic Metabolic Research, University of Copenhagen Panum Institute, Copenhagen, Denmark
| | - Stephen R Bloom
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Bernard Khoo
- Division of Medicine, University College London, London, UK
| | - Tricia M-M Tan
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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Bailey CJ. GIP analogues and the treatment of obesity-diabetes. Peptides 2020; 125:170202. [PMID: 31756366 DOI: 10.1016/j.peptides.2019.170202] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/09/2019] [Accepted: 11/11/2019] [Indexed: 12/18/2022]
Abstract
The potential application of glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide, GIP) in the management of obesity and type 2 diabetes has been controversial. Initial interest in the therapeutic use of GIP was dampened by evidence that its insulinotropic activity was reduced in type 2 diabetes and by reports that it increased glucagon secretion and adipose deposition in non-diabetic individuals. Also, attention was diverted away from GIP by the successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, and a therapeutic strategy for GIP became uncertain when evidence emerged that both inhibition and enhancement of GIP action could prevent or reverse obese non-insulin dependent forms of diabetes in rodents. Species differences in GIP receptor responsiveness complicated the extrapolation of evidence from rodents to humans, but initial clinical studies are investigating the effect of a GIP antagonist in non-diabetic individuals. A therapeutic role for GIP agonists was reconsidered when clinical studies noted that the insulinotropic effect of GIP was increased if near-normal glycaemia was re-established, and GIP was found to have little effect on glucagon secretion or adipose deposition in obese type 2 diabetes patients. This encouraged the development of designer peptides that act as GIP receptor agonists, including chimeric peptides that mimic the incretin partnership of GIP with GLP-1, where the two agents exert complementary and often additive effects to improve glycaemic control and facilitate weight loss. Polyagonist peptides that exert agonism at GIP, GLP-1 and glucagon receptors are also under investigation as potential treatments for obese type 2 diabetes.
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Affiliation(s)
- Clifford J Bailey
- School of Life and Health Sciences, Aston University, B4 7ET, Birmingham, UK.
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Korakas E, Kountouri A, Raptis A, Kokkinos A, Lambadiari V. Bariatric Surgery and Type 1 Diabetes: Unanswered Questions. Front Endocrinol (Lausanne) 2020; 11:525909. [PMID: 33071965 PMCID: PMC7531037 DOI: 10.3389/fendo.2020.525909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 08/20/2020] [Indexed: 01/19/2023] Open
Abstract
In recent decades there has been an alarming increase in the prevalence of obesity in patients with type 1 diabetes leading to the development of insulin resistance and cardiometabolic complications, with mechanisms poorly clarified. While bariatric surgery has long been considered an effective treatment option for patients with type 2 diabetes, the evidence regarding its benefits on weight loss and the prevention of complications in T1DM patients is scarce, with controversial outcomes. Bariatric surgery has been associated with a significant reduction in daily insulin requirement, along with a considerable reduction in body mass index, results which were sustained in the long term. Furthermore, studies suggest that bariatric surgery in type 1 diabetes results in the improvement of comorbidities related to obesity including hypertension and dyslipidemia. However, regarding glycemic control, the reduction of mean glycosylated hemoglobin was modest or statistically insignificant in most studies. The reasons for these results are yet to be elucidated; possible explanations include preservation of beta cell mass and increased residual function post-surgery, improvement in insulin action, altered GLP-1 function, timing of surgery, and association with residual islet cell mass. A number of concerns regarding safety issues have arisen due to the reporting of peri-operative and post-operative adverse events. The most significant complications are metabolic and include diabetic ketoacidosis, severe hypoglycemia and glucose fluctuations. Further prospective clinical studies are required to provide evidence for the effect of bariatric surgery on T1DM patients. The results may offer a better knowledge for the selection of people living with diabetes who will benefit more from a metabolic surgery.
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Affiliation(s)
- Emmanouil Korakas
- Second Department of Internal Medicine, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini Kountouri
- Second Department of Internal Medicine, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios Raptis
- Second Department of Internal Medicine, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Vaia Lambadiari
- Second Department of Internal Medicine, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
- *Correspondence: Vaia Lambadiari
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Grandl G, Novikoff A, DiMarchi R, Tschöp MH, Müller TD. Gut Peptide Agonism in the Treatment of Obesity and Diabetes. Compr Physiol 2019; 10:99-124. [PMID: 31853954 DOI: 10.1002/cphy.c180044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism. © 2020 American Physiological Society. Compr Physiol 10:99-124, 2020.
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Affiliation(s)
- Gerald Grandl
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Richard DiMarchi
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | - Matthias H Tschöp
- German Center for Diabetes Research (DZD), Neuherberg, Germany.,Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany
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Perakakis N, Kokkinos A, Peradze N, Tentolouris N, Ghaly W, Pilitsi E, Upadhyay J, Alexandrou A, Mantzoros CS. Circulating levels of gastrointestinal hormones in response to the most common types of bariatric surgery and predictive value for weight loss over one year: Evidence from two independent trials. Metabolism 2019; 101:153997. [PMID: 31672446 DOI: 10.1016/j.metabol.2019.153997] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 09/29/2019] [Accepted: 10/01/2019] [Indexed: 01/22/2023]
Abstract
AIMS Bariatric surgery leads to profound and sustainable weight loss. Gastrointestinal hormones are involved in energy and glucose homeostasis, thus postoperative changes of their circulating levels may be mediating future weight loss. To investigate how the circulating concentrations of gastrointestinal hormones change in response to the most common types of bariatric operation and whether these changes can predict future weight loss. MATERIALS AND METHODS We measured circulating GLP-1, GLP-2, oxyntomodulin, glicentin, glucagon, major proglucagon fragment (MPGF), ghrelin, GIP, PYY after overnight fasting and/or after a mixed meal test (MMT) in: a) 14 subjects that have undergone either an adjustable gastric banding [AGB] (n = 9) or a Roux-en-Y bypass (RYGB) (n = 5) (Pilot study 1), b) 28 subjects that have undergone either a vertical sleeve gastrectomy (n = 17) or a RYGB (n = 11) before and three, six and twelve months after surgery. RESULTS In addition to the expected associations with GLP-1, the most robust increases were observed in postprandial levels of oxyntomodulin and glicentin three months after VSG or RYGB (but not after AGB) and are associated with degree of weight loss. Oxyntomodulin and glicentin levels at the third and sixth month postoperative visit are positively associated with feeling of satiety which may be underlying the observed associations with future weight loss. CONCLUSION Beyond GLP-1, early postprandial changes in circulating oxyntomodulin and glicentin are predictors of weight loss after bariatric surgery, possibly through regulation of satiety. Further studies should focus on underlying mechanisms, and their potential as attractive therapeutic tools against obesity and related comorbidities.
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Affiliation(s)
- Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Natia Peradze
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Nikolaos Tentolouris
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Wael Ghaly
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Physiology, Fayoum University, Fayoum, Egypt
| | - Eleni Pilitsi
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jagriti Upadhyay
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Andreas Alexandrou
- First Department of Surgery, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, 150 South Huntington Avenue, Boston, MA 02130, USA
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Sanches E, Timmermans M, Topal B, Celik A, Sundbom M, Ribeiro R, Parmar C, Ugale S, Proczko M, Stepaniak PS, Pujol Rafols J, Mahawar K, Buise MP, Neimark A, Severin R, Pouwels S. Cardiac remodeling in obesity and after bariatric and metabolic surgery; is there a role for gastro-intestinal hormones? Expert Rev Cardiovasc Ther 2019; 17:771-790. [PMID: 31746657 DOI: 10.1080/14779072.2019.1690991] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Obesity is associated with various diseases such as type 2 diabetes, hypertension, obstructive sleep apnea syndrome (OSAS), metabolic syndrome, and cardiovascular diseases. It affects several organ systems, including the pulmonary and cardiac systems. Furthermore, it induces pulmonary and cardiac changes that can result in right and/or left heart failure.Areas covered: In this review, authors provide an overview of obesity and cardiovascular remodeling, the individual actions of the gut hormones (like GLP-1 and PYY), the effects after bariatric/metabolic surgery and its influence on cardiac remodeling. In this review, we focussed and searched for literature in Pubmed and The Cochrane library (from the earliest date until April 2019), regarding cardiac function changes before and after bariatric surgery and literature regarding changes in gastrointestinal hormones.Expert opinion: Regarding the surgical treatment of obesity and metabolic diseases there is recognition of the importance of both weight loss (bariatric surgery) and improvement in metabolic milieu (metabolic surgery). A growing body of evidence further suggests that bariatric surgical procedures [like the Sleeve Gastrectomy (SG), Roux-en Y Gastric Bypass (RYGB), or One Anastomosis Gastric Bypass (OAGB)] have can improve outcomes of patients suffering from a number of cardiovascular diseases, including heart failure.
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Affiliation(s)
- Elijah Sanches
- Department of Surgery, Haaglanden Medical Center, The Hague, The Netherlands
| | - Marieke Timmermans
- Department of Surgery, Haaglanden Medical Center, The Hague, The Netherlands
| | - Besir Topal
- Department of Cardiothoracic Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Alper Celik
- Department of Bariatric and Metabolic Surgery, Metabolic Surgery Clinic, Sisli, Turkey
| | - Magnus Sundbom
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Rui Ribeiro
- Centro Multidisciplinar da Doença Metabólica, Clínica de Santo António, Lisbon, Portugal
| | - Chetan Parmar
- Department of Surgery, Whittington Hospital, London, UK
| | - Surendra Ugale
- Bariatric & Metabolic Surgery Clinic, Kirloskar Hospital, Hyderabad, India
| | - Monika Proczko
- Department of General, Endocrine and Transplant Surgery, University Medical Center, Gdansk University, Gdansk, Poland
| | - Pieter S Stepaniak
- Department of Operating Rooms, Catharina Hospital, Eindhoven, The Netherlands
| | | | - Kamal Mahawar
- Bariatric Unit, Sunderland Royal Hospital, Sunderland, UK
| | - Marc P Buise
- Department of Anesthesiology, Intensive Care and Pain Medicine, Catharina Hospital, Eindhoven, The Netherlands
| | - Aleksandr Neimark
- Department of Surgery, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Rich Severin
- Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA.,Doctor of Physical Therapy Program, Robbins College of Health and Human Sciences, Baylor University, Waco, TX, USA
| | - Sjaak Pouwels
- Department of Surgery, Haaglanden Medical Center, The Hague, The Netherlands
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