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Lei WS, Chen X, Zhao L, Daley T, Phillips B, Rickels MR, Kelly A, Kindler JM. Effect of GIP and GLP-1 infusion on bone resorption in glucose intolerant, pancreatic insufficient cystic fibrosis. J Clin Transl Endocrinol 2025; 40:100392. [PMID: 40275940 PMCID: PMC12019020 DOI: 10.1016/j.jcte.2025.100392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 03/22/2025] [Accepted: 04/04/2025] [Indexed: 04/26/2025] Open
Abstract
Context Diabetes and bone disease are common in cystic fibrosis (CF) and primarily occur alongside exocrine pancreatic insufficiency (PI). "Incretins," glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), augment insulin secretion and regulate bone metabolism. In CF, PI dampens the incretin response. Loss of the insulinotropic effect of GIP in CF was recently identified, but effects on bone are unknown. Objective Determine effects of incretins on bone resorption markers in adults with PI-CF. Design Secondary analysis of a mechanistic double-blinded randomized placebo-controlled crossover trial including adults ages 18-40 years with PI-CF (n = 25). Intervention Adults with PI-CF received either GIP (4 pmol/kg/min) or GLP-1 (1.5 pmol/kg/min) infusion, followed by double-blind randomization to either incretin or placebo infusion. Non-CF healthy controls received double-blind GIP (4 pmol/kg/min) or placebo. Serum C-terminal telopeptide (CTX), a bone resorption marker, was assessed during the infusion over 80 (GIP) or 60 (GLP-1) minutes. Main Outcome Measures CTX (mg/dL) concentrations. Results In PI-CF, CTX decreased during GIP infusion, but not during placebo (time-by-treatment interaction P < 0.01). GLP-1 did not affect CTX. In non-CF healthy controls, time-by-treatment interaction was not significant (P = 0.23), but CTX decreased during GIP (P = 0.02) but not placebo (P = 0.47). Conclusions GIP evokes a bone anti-resorptive effect in people with PI-CF. Since the incretin response is perturbed in PI-CF, and an infusion of GIP lowers bone resorption, the "gut-bone axis" in CF-related bone disease requires attention.
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Affiliation(s)
- Wang Shin Lei
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
| | - XianYan Chen
- Department of Epidemiology & Biostatistics, The University of Georgia, Athens, GA, USA
| | - Lingyu Zhao
- Department of Statistics, The University of Georgia, Athens, GA, USA
| | - Tanicia Daley
- Department of Pediatrics, Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, GA, USA
| | - Bradley Phillips
- College of Pharmacy and Biomedical & Translational Sciences Institute, The University of Georgia, Athens, GA, USA
| | - Michael R. Rickels
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Joseph M. Kindler
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
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de Dreuille B, Nicolle R, Cros J, Cazals-Hatem D, Chassac A, Poté N, Le Beyec-Le Bihan J, Bado A, Le Gall M, Joly F. Identification of Pappalysin-2 (PAPP-A2), a modulator of Insulin-like Growth Factor-1 pathway, as a potential marker of teduglutide efficacy in patients with short bowel syndrome. Clin Nutr 2025; 50:128-136. [PMID: 40414050 DOI: 10.1016/j.clnu.2025.05.006] [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: 12/05/2024] [Revised: 04/04/2025] [Accepted: 05/12/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is indicated to treat short bowel syndrome (SBS) since 2015. It has been shown to reduce parenteral support (PS) in SBS patients, although patients' response is quite heterogeneous. The exact mechanisms of action of GLP-2 on intestinal cells are still poorly understood. The aim of this study was to explore the intestinal action of teduglutide to identify molecular mechanisms underlying response heterogeneity. METHODS A retrospective study was conducted in 39 SBS patients treated with teduglutide for at least 6 months. Intestinal biopsy specimens collected before and after treatment initiation were selected and analyzed by RNA sequencing to identify genes differentially expressed and pathways regulated following teduglutide treatment. RESULTS Of the 39 patients included in the study, 29 (74%) had a colon in continuity. The overall response to teduglutide was a reduction by 75% (interquartile range: 42-100) in PS volume. Among the genes differentially expressed in the small bowel during teduglutide treatment, the most significantly upregulated gene was PAPPA2 (q-value < 0.0001), encoding the metalloproteinase Pappalysin-2 (PAPPA-2) involved in Insulin-like Growth Factor (IGF) bioavailability. The best responders to teduglutide showed a lower PAPPA2 expression at baseline (p < 0.01). PAPPA2 expression at baseline also correlated positively with the percentage of remnant colon (p < 0.001). CONCLUSION We identified a new stakeholder, PAPPA-2, known to modulate IGF bioavailability, as playing a possible role in GLP-2 mechanism of action in human with SBS. We showed by association the existence of a greater spontaneous intestinal adaptation in SBS patients with a colon in continuity that could reduce sensitivity to teduglutide. Additionally, we suggest that initial PAPPA2 expression could serve as a predictive biomarker for teduglutide efficacy.
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Affiliation(s)
- Brune de Dreuille
- Centre de Recherche sur l'Inflammation (CRI), INSERM U1149, Université Paris Cité, 75018 Paris, France; Gastroenterology and Nutritional Support Department, Hôpital Beaujon (AP-HP), Clichy, France
| | - Rémy Nicolle
- Centre de Recherche sur l'Inflammation (CRI), INSERM U1149, Université Paris Cité, 75018 Paris, France
| | - Jérôme Cros
- Centre de Recherche sur l'Inflammation (CRI), INSERM U1149, Université Paris Cité, 75018 Paris, France; Pathology Department, Hôpital Beaujon (AP-HP), Clichy, France
| | | | - Anaïs Chassac
- Pathology Department, Hôpital Bichat (AP-HP), Paris, France
| | - Nicolas Poté
- Pathology Department, Hôpital Bichat (AP-HP), Paris, France
| | - Johanne Le Beyec-Le Bihan
- Centre de Recherche sur l'Inflammation (CRI), INSERM U1149, Université Paris Cité, 75018 Paris, France; Endocrine and Oncological Biochemistry Department, Hôpital Pitié-Salpêtrière (AP-HP)-Sorbonne University, Paris, France
| | - André Bado
- Centre de Recherche sur l'Inflammation (CRI), INSERM U1149, Université Paris Cité, 75018 Paris, France
| | - Maude Le Gall
- Centre de Recherche sur l'Inflammation (CRI), INSERM U1149, Université Paris Cité, 75018 Paris, France
| | - Francisca Joly
- Centre de Recherche sur l'Inflammation (CRI), INSERM U1149, Université Paris Cité, 75018 Paris, France; Gastroenterology and Nutritional Support Department, Hôpital Beaujon (AP-HP), Clichy, France.
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3
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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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Rindom E, Last KB, Svane A, Fammé A, Henriksen PG, Farup J, Jessen N, de Paoli FV, Wang T. Rapid stimulation of protein synthesis in digesting snakes: Unveiling a novel gut-pancreas-muscle axis. Acta Physiol (Oxf) 2025; 241:e70006. [PMID: 39854152 PMCID: PMC11760623 DOI: 10.1111/apha.70006] [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: 10/28/2024] [Revised: 12/17/2024] [Accepted: 01/13/2025] [Indexed: 01/26/2025]
Abstract
AIM Snakes exhibit remarkable physiological shifts when their large meals induce robust postprandial growth after prolonged fasting. To understand the regulatory mechanisms underlying this rapid metabolic transition, we examined the regulation of protein synthesis in pythons, focusing on processes driving early postprandial tissue remodeling and growth. METHODS Using the SUnSET method with puromycin labeling, we measured in vivo protein synthesis in fasting and digesting snakes at multiple post-feeding intervals. Pyloric ligation, pancreatectomy, and plasma transfusions were performed to explore the roles of gastrointestinal luminal signaling and pancreatic function across key tissues. RESULTS We observed profound and early stimulation of protein synthesis in gastrointestinal tissues and skeletal muscle already 3 h after ingestion, before any measurable rise in plasma amino acids from the meal. The gastrointestinal stimulation appears to be driven by luminal factors, while the stimulation of skeletal muscle protein synthesis is humoral with pancreatic insulin release as an integral mediator. The pre-absorptive anabolic activity is supported by the release of amino acids from the breakdown of endogenous proteins. CONCLUSIONS Our findings suggest that snakes initiate protein synthesis via distinct, tissue-specific pathways preceding nutrient absorption. This "pay before pumping" model shows how early protein synthesis prepares the digestive and muscular systems for later nutrient assimilation and growth. This intricate humoral regulation, involving a gut-pancreas-muscle axis, governs postprandial protein synthesis in snakes and provides insights into fundamental mechanisms driving metabolic adaptations and broader hyperplastic and hypertrophic responses.
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Affiliation(s)
- Emil Rindom
- Zoophysiology, Department of BiologyAarhus UniversityAarhus CDenmark
| | | | - Anja Svane
- Zoophysiology, Department of BiologyAarhus UniversityAarhus CDenmark
| | - Asger Fammé
- Zoophysiology, Department of BiologyAarhus UniversityAarhus CDenmark
| | - Per G. Henriksen
- Zoophysiology, Department of BiologyAarhus UniversityAarhus CDenmark
| | - Jean Farup
- Department of BiomedicineAarhus UniversityAarhus CDenmark
- Steno Diabetes Center AarhusAarhus University HospitalAarhus NDenmark
| | - Niels Jessen
- Department of BiomedicineAarhus UniversityAarhus CDenmark
- Steno Diabetes Center AarhusAarhus University HospitalAarhus NDenmark
| | | | - Tobias Wang
- Zoophysiology, Department of BiologyAarhus UniversityAarhus CDenmark
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Patil M, Thapa D, Warne LN, Lareu RR, Dallerba E, Lian J, Massi M, Carlessi R, Falasca M. Chronic metabolic effects of novel gut-oriented small-molecule GPR119 agonists in diet-induced obese mice. Biomed Pharmacother 2024; 181:117675. [PMID: 39566336 DOI: 10.1016/j.biopha.2024.117675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/25/2024] [Accepted: 11/07/2024] [Indexed: 11/22/2024] Open
Abstract
The pharmacological activation of G-protein coupled receptor-119 (GPR119) modulates glucose, energy, and hepatic lipid homeostasis in type-2 diabetes (T2D). We developed synthetic small-molecule GPR119 agonists targeting gastrointestinal receptors. This study investigates the chronic metabolic effects of lead candidates, ps297 and ps318, individually and in combination with sitagliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor, in high-fat diet (HFD)-induced obese (DIO) mice. In a 10-week dose-escalation protocol, DIO mice were orally treated with the investigational agents alone (10-90 mg/kg/day) and in combination with sitagliptin (20 mg/kg/day). Weekly body weight, food intake, and random blood glucose levels were monitored during the treatment phase. Post-treatment, an intraperitoneal glucose tolerance test (ipGTT), estimation of plasma biomarkers and haematological assessment were conducted. The treatment's effect on hepatic steatosis was studied by estimating liver biomarkers and histological examinations. Ten-week sitagliptin combination therapy with the investigational entities restored incretins, insulin, and other metabolic hormonal secretions, accompanied by improved glucose homeostasis and retarded weight gain. Interestingly, monotherapy with investigational agents improved liver health by reducing liver weight, liver enzymes, and inflammation. Hepatic effects were further enhanced by co-administration of sitagliptin, evident by amelioration in hepatic steatosis endpoints such as liver weight, plasma liver enzyme concentrations, hepatic triglycerides (TG), total cholesterol (CHO), hydroxyproline content, and cytokine levels. Histopathological investigations confirmed regression in hepatic steatosis in the combination groups. These findings demonstrate the therapeutic potential of novel gut-oriented GPR119 agonists in combination with a DPP-IV inhibitor to ameliorate metabolic dysfunction-associated steatohepatitis (MASH), warranting further mechanistic investigations.
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Affiliation(s)
- Mohan Patil
- Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Dinesh Thapa
- Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Leon N Warne
- Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia; College of Science, Health, Engineering, Murdoch University, Perth, WA, Australia
| | - Ricky R Lareu
- Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Elena Dallerba
- School of Molecular and Life Sciences, Curtin University, Perth, WA 6845, Australia
| | - Jerome Lian
- Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Massimiliano Massi
- School of Molecular and Life Sciences, Curtin University, Perth, WA 6845, Australia
| | - Rodrigo Carlessi
- Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia; Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Marco Falasca
- Department of Medicine and Surgery, University of Parma, Parma 43125, Italy.
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Boškoski I, Gualtieri L, Matteo MV. Small Bowel Therapies for Metabolic Disease and Obesity. Gastrointest Endosc Clin N Am 2024; 34:715-732. [PMID: 39277300 DOI: 10.1016/j.giec.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
The small bowel has a crucial role in metabolic homeostasis. Small bowel endoscopic bariatric metabolic treatments (EBMTs) include several devices aimed at providing minimally invasive approaches for the management of metabolic disorders. The aim of this review is to provide an updated and exhaustive overview of the EBMTs targeting the small bowel developed to date, including the duodenal mucosa resurfacing, the duodenal-jejunal bypass liners, gastro-jejunal bypass sleeve, and the incisioneless magnetic anastomosis system, as well as to mention the future perspectives in the field.
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Affiliation(s)
- Ivo Boškoski
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Loredana Gualtieri
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Maria Valeria Matteo
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy.
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7
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Eriksen R, White MC, Dawed AY, Perez IG, Posma JM, Haid M, Sharma S, Prehn C, Thomas EL, Koivula RW, Bizzotto R, Mari A, Giordano GN, Pavo I, Schwenk JM, De Masi F, Tsirigos KD, Brunak S, Viñuela A, Mahajan A, McDonald TJ, Kokkola T, Rutters F, Beulens J, Muilwijk M, Blom M, Elders P, Hansen TH, Fernandez-Tajes J, Jones A, Jennison C, Walker M, McCarthy MI, Pedersen O, Ruetten H, Forgie I, Holst JJ, Thomsen HS, Ridderstråle M, Bell JD, Adamski J, Franks PW, Hansen T, Holmes E, Frost G, Pearson ER. The Association of Cardiometabolic, Diet and Lifestyle Parameters With Plasma Glucagon-like Peptide-1: An IMI DIRECT Study. J Clin Endocrinol Metab 2024; 109:e1697-e1707. [PMID: 38686701 PMCID: PMC11318998 DOI: 10.1210/clinem/dgae119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 11/20/2023] [Accepted: 02/27/2024] [Indexed: 05/02/2024]
Abstract
CONTEXT The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood. OBJECTIVE We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. METHODS We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D. RESULTS Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. CONCLUSION These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D.
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Affiliation(s)
- Rebeca Eriksen
- Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
| | - Margaret C White
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee DD1 9SY, UK
| | - Adem Y Dawed
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee DD1 9SY, UK
| | - Isabel Garcia Perez
- Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
| | - Joram M Posma
- Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK
- Health Data Research UK, London NW1 2BE, UK
| | - Mark Haid
- Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), D-85764 Neuherberg, Germany
| | - Sapna Sharma
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764 Bavaria, Germany
| | - Cornelia Prehn
- Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), D-85764 Neuherberg, Germany
| | - E Louise Thomas
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London W1W 6UW, UK
| | - Robert W Koivula
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Skåne University Hospital, 221 00 Malmö, Sweden
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
| | - Roberto Bizzotto
- Institute of Neuroscience–National Research Council, 35127 Padua, Italy
| | - Andrea Mari
- Institute of Neuroscience–National Research Council, 35127 Padua, Italy
| | - Giuseppe N Giordano
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Skåne University Hospital, 221 00 Malmö, Sweden
| | - Imre Pavo
- Eli Lilly Regional Operations GmbH, 1030 Vienna, Austria
| | - Jochen M Schwenk
- Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH—Royal Institute of Technology, SE-100 44 Stockholm, Sweden
| | - Federico De Masi
- Department of Health Technology, Kgs Lyngby and The Novo Nordisk Foundation Center for Protein Research, Technical University of Denmark, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Konstantinos D Tsirigos
- Department of Health Technology, Kgs Lyngby and The Novo Nordisk Foundation Center for Protein Research, Technical University of Denmark, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Søren Brunak
- Department of Health Technology, Kgs Lyngby and The Novo Nordisk Foundation Center for Protein Research, Technical University of Denmark, University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Ana Viñuela
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Anubha Mahajan
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Timothy J McDonald
- NIHR Exeter Clinical Research Facility, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK
| | - Tarja Kokkola
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, FI-70211 Kuopio, Finland
| | - Femke Rutters
- Department of Epidemiology and data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUMC, 1007 Amsterdam, the Netherlands
| | - Joline Beulens
- Department of Epidemiology and data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUMC, 1007 Amsterdam, the Netherlands
| | - Mirthe Muilwijk
- Department of Epidemiology and data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUMC, 1007 Amsterdam, the Netherlands
| | - Marieke Blom
- Department of Epidemiology and data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUMC, 1007 Amsterdam, the Netherlands
| | - Petra Elders
- Department of Epidemiology and data Science, Amsterdam Public Health Institute, Amsterdam UMC, location VUMC, 1007 Amsterdam, the Netherlands
| | - Tue H Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, 2200 Copenhagen, Denmark
| | | | - Angus Jones
- NIHR Exeter Clinical Research Facility, Royal Devon & Exeter Hospital, Exeter EX2 5DW, UK
| | - Chris Jennison
- Department of Mathematical Sciences, University of Bath, Bath BA2 7AY, UK
| | - Mark Walker
- Institute of Cellular Medicine (Diabetes), Newcastle University, Newcastle upon Tyne NE3 1DQ, UK
| | - Mark I McCarthy
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
- NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LH, UK
| | - Oluf Pedersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Hartmut Ruetten
- Sanofi-Aventis Deutschland GmbH, R&D, 65926 Frankfurt am Main, Germany
| | - Ian Forgie
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee DD1 9SY, UK
| | - Jens J Holst
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Henrik S Thomsen
- Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | | | - Jimmy D Bell
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London W1W 6UW, UK
| | - Jerzy Adamski
- Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), D-85764 Neuherberg, Germany
- Lehrstuhl für Experimentelle Genetik, Technische Universität München, 85350 Freising-Weihenstephan, Germany
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Paul W Franks
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Skåne University Hospital, 221 00 Malmö, Sweden
- Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Elaine Holmes
- Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
| | - Gary Frost
- Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
| | - Ewan R Pearson
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee DD1 9SY, UK
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8
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Patil M, Casari I, Thapa D, Warne LN, Dallerba E, Massi M, Carlessi R, Falasca M. Preclinical pharmacokinetics, pharmacodynamics, and toxicity of novel small-molecule GPR119 agonists to treat type-2 diabetes and obesity. Biomed Pharmacother 2024; 177:117077. [PMID: 38968799 DOI: 10.1016/j.biopha.2024.117077] [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: 04/23/2024] [Revised: 06/14/2024] [Accepted: 06/29/2024] [Indexed: 07/07/2024] Open
Abstract
The escalating global prevalence of type-2 diabetes (T2D) and obesity necessitates the development of novel oral medications. Agonism at G-protein coupled receptor-119 (GPR119) has been recognized for modulation of metabolic homeostasis in T2D, obesity, and fatty liver disease. However, off-target effects have impeded the advancement of synthetic GPR119 agonist drug candidates. Non-systemic, gut-restricted GPR119 agonism is suggested as an alternative strategy that may locally stimulate intestinal enteroendocrine cells (EEC) for incretin secretion, without the need for systemic drug availability, consequently alleviating conventional class-related side effects. Herein, we report the preclinical acute safety, efficacy, and pharmacokinetics (PK) of novel GPR119 agonist compounds ps297 and ps318 that potentially target gut EEC for incretin secretion. In a proof-of-efficacy study, both compounds demonstrated glucagon-like peptide-1 (GLP-1) secretion capability during glucose and mixed-meal tolerance tests in healthy mice. Furthermore, co-administration of sitagliptin with investigational compounds in diabetic db/db mice resulted in synergism, with GLP-1 concentrations rising by three-fold. Both ps297 and ps318 exhibited low gut permeability assessed in the in-vitro Caco-2 cell model. A single oral dose PK study conducted on healthy mice demonstrated poor systemic bioavailability of both agents. PK measures (mean ± SD) for compound ps297 (Cmax 23 ± 19 ng/mL, Tmax range 0.5 - 1 h, AUC0-24 h 19.6 ± 21 h*ng/mL) and ps318 (Cmax 75 ± 22 ng/mL, Tmax range 0.25 - 0.5 h, AUC0-24 h 35 ± 23 h*ng/mL) suggest poor oral absorption. Additionally, examinations of drug excretion patterns in mice revealed that around 25 % (ps297) and 4 % (ps318) of the drugs were excreted through faeces as an unchanged form, while negligible drug concentrations (<0.005 %) were excreted in the urine. These acute PK/PD assessments suggest the gut is a primary site of action for both agents. Toxicity assessments conducted in the zebrafish and healthy mice models confirmed the safety and tolerability of both compounds. Future chronic in-vivo studies in relevant disease models will be essential to confirm the long-term safety and efficacy of these novel compounds.
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Affiliation(s)
- Mohan Patil
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, Western Australia 6102, Australia
| | - Ilaria Casari
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, Western Australia 6102, Australia
| | - Dinesh Thapa
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, Western Australia 6102, Australia
| | - Leon N Warne
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, Western Australia 6102, Australia; College of Science, Health, Engineering and Education, Murdoch University, Perth, Western Australia, Australia
| | - Elena Dallerba
- School of Molecular and Life Sciences, Curtin University, Perth, Western Australia 6845, Australia
| | - Massimiliano Massi
- School of Molecular and Life Sciences, Curtin University, Perth, Western Australia 6845, Australia
| | - Rodrigo Carlessi
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, Western Australia 6102, Australia; Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Marco Falasca
- Department of Medicine and Surgery, University of Parma, Parma 43125, Italy.
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9
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Perez PA, Wiley MB, Makriyannis A, DiPatrizio NV. Cannabinoids Block Fat-induced Incretin Release via CB 1-dependent and CB 1-independent Pathways in Intestinal Epithelium. GASTRO HEP ADVANCES 2024; 3:931-941. [PMID: 39318720 PMCID: PMC11419882 DOI: 10.1016/j.gastha.2024.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 07/11/2024] [Indexed: 09/26/2024]
Abstract
Background and Aims Glucose homeostasis is regulated by a dynamic interplay between hormones along the gastro-insular axis. For example, enteroendocrine L- and K- cells that line the intestine produce the incretins glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), respectively, which are secreted following a meal. Broadly, incretin signaling enhances insulin release from the endocrine pancreas and participates in the control of food intake, and therapeutics that mimic their activity have recently been developed for the treatment of type-2 diabetes and obesity. Notably, genes for cannabinoid subtype-1 receptor (CB1R) are expressed in these cell subpopulations; however, roles for CB1Rs in controlling fat-induced incretin release are unclear. To address this gap in our understanding, we tested the hypothesis that intestinal epithelial CB1Rs control fat-induced incretin secretion. Methods We treated mice with conditional deletion of CB1Rs in the intestinal epithelium (IntCB1-/-) or controls (IntCB1+/+) with oil gavage to stimulate incretin release in the presence of the cannabinoid receptor agonists, WIN55,212-2 or Δ9 tetrahydrocannabinol (THC), and the peripherally-restricted CB1R antagonist AM6545. Circulating incretin levels were measured in plasma. Results Oral gavage of corn oil increased levels of bioactive GLP1 and GIP in IntCB1+/+ mouse plasma. Pretreatment with the WIN55,212-2 or THC blocked this response, which was largely reversed by coadministration with AM6545. WIN55,212-2 failed to inhibit fat-induced GIP release, but not GLP1, in IntCB1-/- mice. In contrast, THC inhibited the secretion of incretins irrespective of CB1R expression in intestinal epithelial cells. Conclusion These results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB1R-dependent and CB1R-independent mechanisms.
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Affiliation(s)
- Pedro Antonio Perez
- Center for Cannabinoid Research (UCRCCR), School of Medicine, University of California, Riverside, Riverside, California
- Department of Neuroscience and The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California
| | - Mark Benjamin Wiley
- Center for Cannabinoid Research (UCRCCR), School of Medicine, University of California, Riverside, Riverside, California
| | | | - Nicholas Vincent DiPatrizio
- Center for Cannabinoid Research (UCRCCR), School of Medicine, University of California, Riverside, Riverside, California
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Abstract
PURPOSE OF REVIEW Increased morbidity seen with rising obesity rates continues to place an unheralded burden on our health system. Lack of higher bariatric surgery utilization and limitations with lifestyle modification and pharmacotherapy highlights the need for additional therapies for obesity. Endoscopic bariatric and metabolic therapies (EBMT) are effective, safe treatments for obesity. Current FDA-approved EBMT are confined to gastric modalities while small bowel directed therapies are still considered investigational. This review highlights current modalities of EBMT. RECENT FINDINGS Many randomized controlled trials have been performed, including both open label and sham-controlled, which have demonstrated safety and efficacy of EBMT over lifestyle therapy alone. In addition, emerging evidence from clinical experience further supports EBMT for treatment of obesity. Current evidence supports the safety and efficacy of EBMT for obesity treatment in conjunction with lifestyle therapy. They can also be used concurrently with weight loss medications to increase total weight loss.
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Affiliation(s)
- Fernanda Pessorrusso
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Academic Office 1, 12631 E. 17th Ave, Mail Stop B158, Aurora, CO, 80045, USA
| | - Sagar V Mehta
- Division of Gastroenterology, Geisinger Health System, Danville, PA, USA
| | - Shelby Sullivan
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Academic Office 1, 12631 E. 17th Ave, Mail Stop B158, Aurora, CO, 80045, USA.
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11
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Li P, Zhu D. Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes. J Diabetes 2024; 16:e13544. [PMID: 38664885 PMCID: PMC11045918 DOI: 10.1111/1753-0407.13544] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/12/2024] [Accepted: 01/29/2024] [Indexed: 04/29/2024] Open
Abstract
As a sensor, glucokinase (GK) controls glucose homeostasis, which progressively declines in patients with diabetes. GK maintains the equilibrium of glucose levels and regulates the homeostatic system set points. Endocrine and hepatic cells can both respond to glucose cooperatively when GK is activated. GK has been under study as a therapeutic target for decades due to the possibility that cellular GK expression and function can be recovered, hence restoring glucose homeostasis in patients with type 2 diabetes. Five therapeutic compounds targeting GK are being investigated globally at the moment. They all have distinctive molecular structures and have been clinically shown to have strong antihyperglycemia effects. The mechanics, classification, and clinical development of GK activators are illustrated in this review. With the recent approval and marketing of the first GK activator (GKA), dorzagliatin, GKA's critical role in treating glucose homeostasis disorder and its long-term benefits in diabetes will eventually become clear.
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Affiliation(s)
- Ping Li
- Department of EndocrinologyDrum Tower Hospital Affiliated to Nanjing University Medical SchoolNanjingChina
| | - Dalong Zhu
- Department of EndocrinologyDrum Tower Hospital Affiliated to Nanjing University Medical SchoolNanjingChina
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12
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Huber H, Schieren A, Holst JJ, Simon MC. Dietary impact on fasting and stimulated GLP-1 secretion in different metabolic conditions - a narrative review. Am J Clin Nutr 2024; 119:599-627. [PMID: 38218319 PMCID: PMC10972717 DOI: 10.1016/j.ajcnut.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 01/15/2024] Open
Abstract
Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide and central mediator of glucose metabolism, is secreted by L cells in the intestine in response to food intake. Postprandial secretion of GLP-1 is triggered by nutrient-sensing via transporters and G-protein-coupled receptors (GPCRs). GLP-1 secretion may be lower in adults with obesity/overweight (OW) or type 2 diabetes mellitus (T2DM) than in those with normal glucose tolerance (NGT), but these findings are inconsistent. Because of the actions of GLP-1 on stimulating insulin secretion and promoting weight loss, GLP-1 and its analogs are used in pharmacologic preparations for the treatment of T2DM. However, physiologically stimulated GLP-1 secretion through the diet might be a preventive or synergistic method for improving glucose metabolism in individuals who are OW, or have impaired glucose tolerance (IGT) or T2DM. This narrative review focuses on fasting and postprandial GLP-1 secretion in individuals with different metabolic conditions and degrees of glucose intolerance. Further, the influence of relevant diet-related factors (e.g., specific diets, meal composition, and size, phytochemical content, and gut microbiome) that could affect fasting and postprandial GLP-1 secretion are discussed. Some studies showed diminished glucose- or meal-stimulated GLP-1 response in participants with T2DM, IGT, or OW compared with those with NGT, whereas other studies have reported an elevated or unchanged GLP-1 response in T2DM or IGT. Meal composition, especially the relationship between macronutrients and interventions targeting the microbiome can impact postprandial GLP-1 secretion, although it is not clear which macronutrients are strong stimulants of GLP-1. Moreover, glucose tolerance, antidiabetic treatment, grade of overweight/obesity, and sex were important factors influencing GLP-1 secretion. The results presented in this review highlight the potential of nutritional and physiologic stimulation of GLP-1 secretion. Further research on fasting and postprandial GLP-1 concentrations and the resulting metabolic consequences under different metabolic conditions is needed.
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Affiliation(s)
- Hanna Huber
- Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology, Mölndal, Sweden; Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany
| | - Alina Schieren
- Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany
| | - Jens Juul Holst
- Department of Biomedical Sciences, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - Marie-Christine Simon
- Department Nutrition and Microbiota, University of Bonn, Institute of Nutrition and Food Science, Bonn, Germany.
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Paradiž Leitgeb E, Kerčmar J, Križančić Bombek L, Pohorec V, Skelin Klemen M, Slak Rupnik M, Gosak M, Dolenšek J, Stožer A. Exendin-4 affects calcium signalling predominantly during activation and activity of beta cell networks in acute mouse pancreas tissue slices. Front Endocrinol (Lausanne) 2024; 14:1315520. [PMID: 38292770 PMCID: PMC10826511 DOI: 10.3389/fendo.2023.1315520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/22/2023] [Indexed: 02/01/2024] Open
Abstract
Tight control of beta cell stimulus-secretion coupling is crucial for maintaining homeostasis of energy-rich nutrients. While glucose serves as a primary regulator of this process, incretins augment beta cell function, partly by enhancing cytosolic [Ca2+] dynamics. However, the details of how precisely they affect beta cell recruitment during activation, their active time, and functional connectivity during plateau activity, and how they influence beta cell deactivation remain to be described. Performing functional multicellular Ca2+ imaging in acute mouse pancreas tissue slices enabled us to systematically assess the effects of the GLP-1 receptor agonist exendin-4 (Ex-4) simultaneously in many coupled beta cells with high resolution. In otherwise substimulatory glucose, Ex-4 was able to recruit approximately a quarter of beta cells into an active state. Costimulation with Ex-4 and stimulatory glucose shortened the activation delays and accelerated beta cell activation dynamics. More specifically, active time increased faster, and the time required to reach half-maximal activation was effectively halved in the presence of Ex-4. Moreover, the active time and regularity of [Ca2+]IC oscillations increased, especially during the first part of beta cell response. In contrast, subsequent addition of Ex-4 to already active cells did not significantly enhance beta cell activity. Network analyses further confirmed increased connectivity during activation and activity in the presence of Ex-4, with hub cell roles remaining rather stable in both control experiments and experiments with Ex-4. Interestingly, Ex-4 demonstrated a biphasic effect on deactivation, slightly prolonging beta cell activity at physiological concentrations and shortening deactivation delays at supraphysiological concentrations. In sum, costimulation by Ex-4 and glucose increases [Ca2+]IC during beta cell activation and activity, indicating that the effect of incretins may, to an important extent, be explained by enhanced [Ca2+]IC signals. During deactivation, previous incretin stimulation does not critically prolong cellular activity, which corroborates their low risk of hypoglycemia.
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Affiliation(s)
- Eva Paradiž Leitgeb
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Jasmina Kerčmar
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | | | - Vilijem Pohorec
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Maša Skelin Klemen
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Marjan Slak Rupnik
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
- Alma Mater Europaea-European Center Maribor, Maribor, Slovenia
| | - Marko Gosak
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Alma Mater Europaea-European Center Maribor, Maribor, Slovenia
- Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
| | - Jurij Dolenšek
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
| | - Andraž Stožer
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
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Haddad D, Dsouza VS, Al-Mulla F, Al Madhoun A. New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment. Int J Mol Sci 2024; 25:571. [PMID: 38203742 PMCID: PMC10779250 DOI: 10.3390/ijms25010571] [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: 11/23/2023] [Revised: 12/28/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Achieving glycemic control and sustaining functional pancreatic β-cell activity remains an unmet medical need in the treatment of type 2 diabetes mellitus (T2DM). Glucokinase activators (GKAs) constitute a class of anti-diabetic drugs designed to regulate blood sugar levels and enhance β-cell function in patients with diabetes. A significant progression in GKA development is underway to address the limitations of earlier generations. Dorzagliatin, a dual-acting GKA, targets both the liver and pancreas and has successfully completed two phase III trials, demonstrating favorable results in diabetes treatment. The hepato-selective GKA, TTP399, emerges as a strong contender, displaying clinically noteworthy outcomes with minimal adverse effects. This paper seeks to review the current literature, delve into the mechanisms of action of these new-generation GKAs, and assess their efficacy and safety in treating T2DM based on published preclinical studies and recent clinical trials.
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Affiliation(s)
- Dania Haddad
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (V.S.D.); (F.A.-M.)
| | - Vanessa Sybil Dsouza
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (V.S.D.); (F.A.-M.)
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (V.S.D.); (F.A.-M.)
| | - Ashraf Al Madhoun
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (V.S.D.); (F.A.-M.)
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait
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15
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Yang SM, Myeong S, Yun SK, Kwak MH, Cho YK, Choi MG, Park JM. Duodenal mucosal resurfacing with photodynamic therapy using methylene blue in a mouse model. Photodiagnosis Photodyn Ther 2023; 44:103733. [PMID: 37536555 DOI: 10.1016/j.pdpdt.2023.103733] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND The duodenum has emerged as a key player in metabolic diseases. The objective was to evaluate the safety and efficacy of intra-duodenal PDT using methylene blue in managing glycemic control and weight reduction. METHODS Optimal concentration of methylene blue and conditions for intra-duodenal PDT were determined through in vitro experiments. After injecting methylene blue into the duodenum, we performed intra-duodenal PDT. High-fat diet rats were used to assess the efficacy of intra-duodenal PDT through measures of oral glucose tolerance, insulin sensitivity, and weight change. Immunohistochemical staining was also conducted to examine GLP-1 and GIP-producing cells in the ileum and duodenum, respectively. RESULTS Introduodenal PDT reduced villous height of duodenum at 48 h, which was fully recovered at 30 days without complications. Rats treated with PDT showed significantly lower blood glucose levels with glucose loading and improved insulin sensitivity than rats in the sham-treatment group. The PDT group also had a significant reduction in body weight compared to the sham-treatment group at 30 days after intervention, although food intake was not significantly different between the two groups. Numbers of GLP-1 and GIP producing cells in the ileum and irradiated area were significantly higher in the PDT group than in the sham-treatment group. CONCLUSIONS Intra-duodenal PDT using methylene blue showed a feasible therapeutic modality in improving metabolic parameters. However, large animal experiments and mechanism studies are needed to determine the clinical relevance. The possibility of repeating this treatment every 30 days and its accompanying complications should be further studied.
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Affiliation(s)
- Seung Mok Yang
- Catholic Photomedicine Research Institute, The Catholic University of Korea, Seoul 06591, the Republic of Korea South Korea
| | - Seokho Myeong
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-GU, Seoul 06591, the Republic of Korea South Korea
| | - Seul Ki Yun
- Catholic Photomedicine Research Institute, The Catholic University of Korea, Seoul 06591, the Republic of Korea South Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-GU, Seoul 06591, the Republic of Korea South Korea
| | - Moon Hwa Kwak
- Catholic Photomedicine Research Institute, The Catholic University of Korea, Seoul 06591, the Republic of Korea South Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, the Republic of Korea South Korea
| | - Yu Kyung Cho
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-GU, Seoul 06591, the Republic of Korea South Korea
| | - Myung-Gyu Choi
- Catholic Photomedicine Research Institute, The Catholic University of Korea, Seoul 06591, the Republic of Korea South Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-GU, Seoul 06591, the Republic of Korea South Korea
| | - Jae Myung Park
- Catholic Photomedicine Research Institute, The Catholic University of Korea, Seoul 06591, the Republic of Korea South Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-GU, Seoul 06591, the Republic of Korea South Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, the Republic of Korea South Korea.
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16
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Genchi VA, Palma G, Sorice GP, D'Oria R, Caccioppoli C, Marrano N, Biondi G, Caruso I, Cignarelli A, Natalicchio A, Laviola L, Giorgino F, Perrini S. Pharmacological modulation of adaptive thermogenesis: new clues for obesity management? J Endocrinol Invest 2023; 46:2213-2236. [PMID: 37378828 PMCID: PMC10558388 DOI: 10.1007/s40618-023-02125-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023]
Abstract
BACKGROUND Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment. PURPOSE This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. β3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.
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Affiliation(s)
- V A Genchi
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - G Palma
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - G P Sorice
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - R D'Oria
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - C Caccioppoli
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - N Marrano
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - G Biondi
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - I Caruso
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - A Cignarelli
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - A Natalicchio
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - L Laviola
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - F Giorgino
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
| | - S Perrini
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy
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17
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Darra A, Singh V, Jena A, Popli P, Nada R, Gupta P, Bhadada SK, Singh AK, Sharma V, Bhattacharya A, Agrawal A, Dutta U. Hyperglycemia is associated with duodenal dysbiosis and altered duodenal microenvironment. Sci Rep 2023; 13:11038. [PMID: 37419941 PMCID: PMC10329043 DOI: 10.1038/s41598-023-37720-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 06/26/2023] [Indexed: 07/09/2023] Open
Abstract
The gut microbiome influences the pathogenesis and course of metabolic disorders such as diabetes. While it is likely that duodenal mucosa associated microbiota contributes to the genesis and progression of increased blood sugar, including the pre-diabetic stage, it is much less studied than stool. We investigated paired stool and duodenal microbiota in subjects with hyperglycemia (HbA1c ≥ 5.7% and fasting plasma glucose > 100 mg/dl) compared to normoglycemic. We found patients with hyperglycemia (n = 33) had higher duodenal bacterial count (p = 0.008), increased pathobionts and reduction in beneficial flora compared to normoglycemic (n = 21). The microenvironment of duodenum was assessed by measuring oxygen saturation using T-Stat, serum inflammatory markers and zonulin for gut permeability. We observed that bacterial overload was correlated with increased serum zonulin (p = 0.061) and higher TNF-α (p = 0.054). Moreover, reduced oxygen saturation (p = 0.021) and a systemic proinflammatory state [increased total leukocyte count (p = 0.031) and reduced IL-10 (p = 0.015)] characterized the duodenum of hyperglycemic. Unlike stool flora, the variability in duodenal bacterial profile was associated with glycemic status and was predicted by bioinformatic analysis to adversely affect nutrient metabolism. Our findings offer new understanding of the compositional changes in the small intestine bacteria by identifying duodenal dysbiosis and altered local metabolism as potentially early events in hyperglycemia.
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Affiliation(s)
- Aarti Darra
- CSIR- Institute of Genomics and Integrative Biology, New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Vandana Singh
- CSIR- Institute of Genomics and Integrative Biology, New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Anuraag Jena
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India
| | - Priyanka Popli
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India
| | - Ritambhra Nada
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pankaj Gupta
- Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sanjay Kumar Bhadada
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Anupam Kumar Singh
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India
| | - Vishal Sharma
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India
| | - Anish Bhattacharya
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Anurag Agrawal
- CSIR- Institute of Genomics and Integrative Biology, New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Usha Dutta
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India.
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18
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Colangeli L, Escobar Marcillo DI, Simonelli V, Iorio E, Rinaldi T, Sbraccia P, Fortini P, Guglielmi V. The Crosstalk between Gut Microbiota and White Adipose Tissue Mitochondria in Obesity. Nutrients 2023; 15:nu15071723. [PMID: 37049562 PMCID: PMC10097238 DOI: 10.3390/nu15071723] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/19/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Adipose tissue (AT) dysregulation is a key process in the pathophysiology of obesity and its cardiometabolic complications, but even if a growing body of evidence has been collected over recent decades, the underlying molecular basis of adiposopathy remains to be fully understood. In this context, mitochondria, the intracellular organelles that orchestrate energy production and undergo highly dynamic adaptive changes in response to changing environments, have emerged as crucial regulators of both white (WAT) and brown adipose tissue (BAT) metabolism and function. Given that the gut microbiota and its metabolites are able to regulate host metabolism, adipogenesis, WAT inflammation, and thermogenesis, we hypothesize that their frequently observed dysregulation in obesity could affect AT metabolism by exerting direct and indirect effects on AT mitochondria. By collecting and revising the current evidence on the connections between gut microbiota and AT mitochondria in obesity, we gained insights into the molecular biology of their hitherto largely unexplored crosstalk, tracing how gut microbiota may regulate AT mitochondrial function.
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19
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Chen L, Zhang J, Sun Y, Zhao Y, Liu X, Fang Z, Feng L, He B, Zou Q, Tracey GJ. A phase I open-label clinical trial to study drug-drug interactions of Dorzagliatin and Sitagliptin in patients with type 2 diabetes and obesity. Nat Commun 2023; 14:1405. [PMID: 36918550 PMCID: PMC10014962 DOI: 10.1038/s41467-023-36946-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 02/22/2023] [Indexed: 03/16/2023] Open
Abstract
This is a phase 1, open-label, single-sequence, multiple-dose, single-center trial conducted in the US (NCT03790839), to evaluate the clinical pharmacokinetics, safety and pharmacodynamics of dorzagliatin co-administered with sitagliptin in patients with T2D and obesity. The trial has completed. 15 patients with T2D and obesity were recruited and treated with sitagliptin 100 mg QD on Day 1-5, followed by a combination of sitagliptin 100 mg QD with dorzagliatin 75 mg BID at second stage on Day 6-10 and the third stage of dorzagliatin 75 mg BID alone on Day 11-15. Primary outcomes include pharmacokinetic geometric mean ratio (GMR), safety and tolerability. Secondary outcomes include the incremental area under the curve for 4 hours post oral glucose tolerance test (iAUC) of pharmacodynamic biomarkers and glucose sensitivity. GMR for AUC0-24h and Cmax were 92.63 (90% CI, 85.61, 100.22) and 98.14 (90% CI, 83.73, 115.03) in combination/sitagliptin, and 100.34 (90% CI, 96.08, 104.79) and 102.34 (90% CI, 86.92, 120.50) in combination/dorzagliatin, respectively. Combination treatment did not increase the adverse events and well-tolerated in T2D patients. Lack of clinically meaningful pharmacokinetic interactions between dorzagliatin and sitagliptin, and an improvement of glycemic control under combination potentially support their co-administration for diabetes management.
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Affiliation(s)
- Li Chen
- Hua Medicine (Shanghai) Limited, Shanghai, China.
| | - Jiayi Zhang
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Yu Sun
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Yu Zhao
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Xiang Liu
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Zhiyin Fang
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Lingge Feng
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Bin He
- Hua Medicine (Shanghai) Limited, Shanghai, China
| | - Quanfei Zou
- Hua Medicine (Shanghai) Limited, Shanghai, China
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20
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Watkins JD, Carter S, Atkinson G, Koumanov F, Betts JA, Holst JJ, Gonzalez JT. Glucagon-like peptide-1 secretion in people with versus without type 2 diabetes: a systematic review and meta-analysis of cross-sectional studies. Metabolism 2023; 140:155375. [PMID: 36502882 DOI: 10.1016/j.metabol.2022.155375] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 12/03/2022] [Accepted: 12/04/2022] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS The aim of this systematic review was to synthesise the study findings on whether GLP-1 secretion in response to a meal tolerance test is affected by the presence of type 2 diabetes (T2D). The influence of putative moderators such as age, sex, meal type, meal form, and assay type were also explored. METHODS A literature search identified 32 relevant studies. The sample mean and SD for fasting GLP-1TOTAL and GLP-1TOTAL iAUC were extracted and used to calculate between-group standardised mean differences (SMD), which were meta-analysed using a random-effects model to derive pooled estimates of Hedges' g and 95 % prediction intervals (PI). RESULTS Pooled across 18 studies, the overall SMD in GLP-1TOTAL iAUC between individuals with T2D (n = 270, 1047 ± 930 pmol·L-1·min) and individuals without T2D (n = 402, 1204 ± 937 pmol·L-1·min) was very small, not statistically significant and heterogenous across studies (g = -0.15, p = 0.43, PI: -1.53, 1.23). Subgroup analyses demonstrated an effect of assay type whereby Hedges' g for GLP-1 iAUC was greater in individuals with, versus those without T2D when using ELISA or Mesoscale (g = 0.67 [moderate], p = 0.009), but not when using RIA (g = -0.30 [small], p = 0.10). Pooled across 30 studies, the SMD in fasting GLP-1TOTAL between individuals with T2D (n = 580, 16.2 ± 6.9 pmol·L-1) versus individuals without T2D (n = 1363, 12.4 ± 5.7 pmol·L-1) was small and heterogenous between studies (g = 0.24, p = 0.21, PI: -1.55, 2.02). CONCLUSIONS Differences in fasting GLP-1TOTAL and GLP-1TOTAL iAUC between individuals with, versus those without T2D were generally small and inconsistent between studies. Factors influencing study heterogeneity such as small sample sizes and poor matching of groups may help to explain the wide prediction intervals observed. Considerations to improve comparisons of GLP-1 secretion in T2D and potential mediating factors more important than T2D diagnosis per se are outlined. PROSPERO ID CRD42020195612.
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Affiliation(s)
- J D Watkins
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, UK.
| | - S Carter
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, UK
| | - G Atkinson
- Liverpool John Moores University, Liverpool, UK
| | - F Koumanov
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, UK
| | - J A Betts
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, UK
| | - J J Holst
- Biomedical Sciences, Endocrinology Research Section, University of Copenhagen, Denmark
| | - J T Gonzalez
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, UK.
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21
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Bonilla-Díaz A, Ordóñez-Morán P. Differentiated Epithelial Cells of the Gut. Methods Mol Biol 2023; 2650:3-16. [PMID: 37310619 DOI: 10.1007/978-1-0716-3076-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The intestine is a prime example of self-renewal where stem cells give rise to progenitor cells called transit-amplifying cells which differentiate into more specialized cells. There are two intestinal lineages: the absorptive (enterocytes and microfold cells) and the secretory (Paneth cells, enteroendocrine, goblet cells, and tuft cells). Each of these differentiated cell types has a role in creating an "ecosystem" to maintain intestinal homeostasis. Here, we summarize the main roles of each cell type.
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Affiliation(s)
- Andrea Bonilla-Díaz
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine , University of Barcelona, Barcelona, Spain
| | - Paloma Ordóñez-Morán
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK.
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22
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Elevated Glucagon-like Peptide-1 Receptor Level in the Paraventricular Hypothalamic Nucleus of Type 2 Diabetes Mellitus Patients. Int J Mol Sci 2022; 23:ijms232415945. [PMID: 36555587 PMCID: PMC9781792 DOI: 10.3390/ijms232415945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have been approved for the treatment of type 2 diabetes mellitus (T2DM); however, the brain actions of these drugs are not properly established. We used post mortem microdissected human hypothalamic samples for RT-qPCR and Western blotting. For in situ hybridization histochemistry and immunolabelling, parallel cryosections were prepared from the hypothalamus. We developed in situ hybridization probes for human GLP-1R and oxytocin. In addition, GLP-1 and oxytocin were visualized by immunohistochemistry. Radioactive in situ hybridization histochemistry revealed abundant GLP-1R labelling in the human paraventricular hypothalamic nucleus (PVN), particularly in its magnocellular subdivision (PVNmc). Quantitative analysis of the mRNA signal demonstrated increased GLP-1R expression in the PVNmc in post mortem hypothalamic samples from T2DM subjects as compared to controls, while there was no difference in the expression level of GLP-1R in the other subdivisions of the PVN, the hypothalamic dorsomedial and infundibular nuclei. Our results in the PVN were confirmed by RT-qPCR. Furthermore, we demonstrated by Western blot technique that the GLP-1R protein level was also elevated in the PVN of T2DM patients. GLP-1 fibre terminals were also observed in the PVNmc closely apposing oxytocin neurons using immunohistochemistry. The data suggest that GLP-1 activates GLP-1Rs in the PVNmc and that GLP-1R is elevated in T2DM patients, which may be related to the dysregulation of feeding behaviour and glucose homeostasis in T2DM.
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23
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Heat stress in pigs and broilers: role of gut dysbiosis in the impairment of the gut-liver axis and restoration of these effects by probiotics, prebiotics and synbiotics. J Anim Sci Biotechnol 2022; 13:126. [PMCID: PMC9673442 DOI: 10.1186/s40104-022-00783-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 09/14/2022] [Indexed: 11/19/2022] Open
Abstract
AbstractHeat stress is one of the most challenging stressors for animal production due to high economic losses resulting from impaired animal’s productivity, health and welfare. Despite the fact that all farm animal species are susceptible to heat stress, birds and pigs are particularly sensitive to heat stress due to either lacking or non-functional sweat glands. Convincing evidence in the literature exists that gut dysbiosis, a term used to describe a perturbation of commensal gut microbiota, develops in broilers and pigs under heat stress. Owing to the protective role of commensal bacteria for the gut barrier, gut dysbiosis causes a disruption of the gut barrier leading to endotoxemia, which contributes to the typical characteristics of heat stressed broilers and growing and growing-finishing pigs, such as reduced feed intake, decreased growth and reduced lean carcass weight. A substantial number of studies have shown that feeding of probiotics, prebiotics and synbiotics is an efficacious strategy to protect broilers from heat stress-induced gut barrier disruption through altering the gut microbiota and promoting all decisive structural, biochemical, and immunological elements of the intestinal barrier. In most of the available studies in heat stressed broilers, the alterations of gut microbiota and improvements of gut barrier function induced by feeding of either probiotics, prebiotics or synbiotics were accompanied by an improved productivity, health and/or welfare when compared to non-supplemented broilers exposed to heat stress. These findings indicate that the restoration of gut homeostasis and function is a key target for dietary interventions aiming to provide at least partial protection of broilers from the detrimental impact of heat stress conditions. Despite the fact that the number of studies dealing with the same feeding strategy in heat stressed pigs is limited, the available few studies suggest that feeding of probiotics might also be a suitable approach to enhance productivity, health and welfare in pigs kept under heat stress conditions.
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24
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Abstract
Modern changes in diet and lifestyle have led to an explosion of insulin resistance and metabolic diseases around the globe which, if left unchecked, will become a principal driver of morbidity and mortality in the 21st century. The nature of the metabolic homeostatic shift within the body has therefore become a topic of considerable interest. While the gut has long been recognized as an acute nutrient sensor with signaling mechanisms to the other metabolic organs of the body, its role in regulating the body's metabolic status over longer periods of time has been underappreciated. Recent insights from bariatric surgery and intestinal nutrient stimulation experiments provide a window into the adaptive role of the intestinal mucosa in a foregut/hindgut metabolic balance model that helps to define metabolic parameters within the body-informing the metabolic regulation of insulin resistance versus sensitivity, hunger versus satiety, energy utilization versus energy storage, and protection from hypoglycemia versus protection from hyperglycemia. This intestinal metabolic balance model provides an intellectual framework with which to understand the distinct roles of proximal and distal intestinal segments in metabolic regulation. The model may also aid in the development of novel disease-modifying therapies that can correct the dysregulated metabolic signals from the intestine and stem the tide of metabolic diseases in society.
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Affiliation(s)
- Harith Rajagopalan
- Fractyl Health, Inc., Lexington,
MA, USA
- Harith Rajagopalan, M.D. PhD.,
Fractyl Health, Inc., 17 Hartwell Avenue, Lexington, MA 02421, USA.
| | | | - David C. Klonoff
- Diabetes Research Institute,
Mills-Peninsula Medical Center, San Mateo, California
| | - Alan D. Cherrington
- Department of Molecular
Physiology and Biophysics, Vanderbilt University School of Medicine,
Nashville, TN, USA
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25
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Chong SC, Sukor N, Robert SA, Ng KF, Kamaruddin NA. Fasting and stimulated glucagon-like peptide-1 exhibit a compensatory adaptive response in diabetes and pre-diabetes states: A multi-ethnic comparative study. Front Endocrinol (Lausanne) 2022; 13:961432. [PMID: 36157456 PMCID: PMC9501699 DOI: 10.3389/fendo.2022.961432] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 08/22/2022] [Indexed: 12/26/2022] Open
Abstract
Background Impaired secretion of glucagon-like peptide-1 (GLP-1) among Caucasians contributes to reduced incretin effect in type 2 diabetes mellitus (T2DM) patients. However, studies emanating from East Asia suggested preserved GLP-1 levels in pre-diabetes (pre-DM) and T2DM. We aimed to resolve these conflicting findings by investigating GLP-1 levels during oral glucose tolerance test (OGTT) among Malay, Chinese, and Indian ethnicities with normal glucose tolerance (NGT), pre-DM, and T2DM. The association between total GLP-1 levels, insulin resistance, and insulin sensitivity, and GLP-1 predictors were also analyzed. Methods A total of 174 subjects were divided into NGT (n=58), pre-DM (n=54), and T2DM (n=62). Plasma total GLP-1 concentrations were measured at 0, 30, and 120 min during a 75-g OGTT. Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of insulin sensitivity (HOMA-IS), and triglyceride-glucose index (TyG) were calculated. Results Total GLP-1 levels at fasting and 30 min were significantly higher in T2DM compared with pre-DM and NGT (27.18 ± 11.56 pmol/L vs. 21.99 ± 10.16 pmol/L vs. 16.24 ± 7.79 pmol/L, p=0.001; and 50.22 ± 18.03 pmol/L vs. 41.05 ± 17.68 pmol/L vs. 31.44 ± 22.59 pmol/L, p<0.001; respectively). Ethnicity was a significant determinant of AUCGLP-1, with the Indians exhibiting higher GLP-1 responses than Chinese and Malays. Indians were the most insulin resistant, whereas Chinese were the most insulin sensitive. The GLP-1 levels were positively correlated with HOMA-IR and TyG but negatively correlated with HOMA-IS. This relationship was evident among Indians who exhibited augmented GLP-1 responses proportionately to their high insulin-resistant states. Conclusion This is the first study that showed GLP-1 responses are augmented as IR states increase. Fasting and post-OGTT GLP-1 levels are raised in T2DM and pre-DM compared to that in NGT. This raises a possibility of an adaptive compensatory response that has not been reported before. Among the three ethnic groups, the Indians has the highest IR and GLP-1 levels supporting the notion of an adaptive compensatory secretion of GLP-1.
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Affiliation(s)
- Shiau Chin Chong
- Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Kuala Lumpur, Malaysia
| | - Norlela Sukor
- Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Kuala Lumpur, Malaysia
| | - Sarah Anne Robert
- Department of Pharmacy, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Kuala Lumpur, Malaysia
| | - Kim Fong Ng
- Department of Cardiology, Hospital Sultanah Aminah Johor Bahru, Johor, Malaysia
| | - Nor Azmi Kamaruddin
- Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Kuala Lumpur, Malaysia
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26
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Firkins SA, Hart PA, Porter K, Chiang C, Cloyd J, Dillhoff M, Lara LF, Manilchuk A, Papachristou GI, Pawlik TM, Tsung A, Conwell DL, Krishna SG. Incidence and Risk Factors for New-Onset Diabetes Mellitus After Surgical Resection of Pancreatic Cystic Lesions: A MarketScan Study. Pancreas 2022; 51:427-434. [PMID: 35858183 PMCID: PMC9388590 DOI: 10.1097/mpa.0000000000002054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES There is a paucity of literature evaluating new-onset diabetes mellitus (NODM) after resection of pancreatic cystic lesions (PCLs). We sought to characterize the incidence and risk factors associated with NODM after partial pancreatectomy for PCLs. METHODS We utilized the IBM MarketScan Database (2012-2018) to identify all nondiabetic adults who underwent partial pancreatectomy for PCLs. Patients with any other pancreatic disease were excluded. We performed Kaplan-Meier analysis and multivariable Cox proportional hazards regression to define the incidence and risk factors of postoperative NODM. RESULTS Among 311 patients, the overall risk (95% confidence interval) of NODM was 9.1% (6.3-12.9%), 15.1% (11.3-20.2%), and 20.2% (15.3-26.4%) at 6, 12 and 24 months, respectively. Multivariable analysis (adjusted hazard ratio; 95% confidence interval) revealed that older age (1.97; 1.04-3.72; 55-64 vs 18-54 years), obesity (2.63; 1.35-5.12), hypertension (1.79; 1.01-3.17), and cardiovascular disease (2.54; 1.02-6.28) were independent predictors of NODM. Rates of NODM were similar after distal pancreatectomy versus pancreaticoduodenectomy. CONCLUSIONS Within 2 years, 1 in 5 patients without any other pancreatic disease will develop NODM after partial pancreatectomy for PCLs. Those with advanced age, metabolic syndrome features, and/or cardiovascular disease may benefit from preoperative counseling and intensive postoperative monitoring, education, and treatment for diabetes mellitus.
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Affiliation(s)
- Stephen A. Firkins
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Kyle Porter
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH
| | - ChienWei Chiang
- Social and Behavioral Sciences, Department of Biomedical Informatics, The Ohio State University, Columbus, OH
| | - Jordan Cloyd
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Mary Dillhoff
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Luis F. Lara
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Andrei Manilchuk
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Georgios I. Papachristou
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Timothy M. Pawlik
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Allan Tsung
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Darwin L. Conwell
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
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27
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Takagishi M, Aleogho BM, Okumura M, Ushida K, Yamada Y, Seino Y, Fujimura S, Nakashima K, Shindo A. Nutritional control of thyroid morphogenesis through gastrointestinal hormones. Curr Biol 2022; 32:1485-1496.e4. [PMID: 35196509 DOI: 10.1016/j.cub.2022.01.075] [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: 06/16/2021] [Revised: 12/08/2021] [Accepted: 01/26/2022] [Indexed: 01/27/2023]
Abstract
Developing animals absorb nutrients either through the placenta or from ingested food; however, the mechanisms by which embryos use external nutrients for individual organ morphogenesis remain to be elucidated. In this study, we assessed nutrient-dependent thyroid follicle morphogenesis in Xenopus laevis and investigated the role of secreted gastrointestinal (GI) hormones post-feeding. We found that feeding triggers thyroid follicle formation, and the thyroid cells showed transient inactivation of cell proliferation after feeding. In addition, the thyroid cells with multi-lumina were frequently observed in the fed tadpoles. The expression of the particular GI hormone incretin, glucose-dependent insulinotropic polypeptide (GIP), responded to feeding in the intestines of Xenopus tadpoles. Inhibition of dipeptidyl peptidase 4 (Dpp4), a degradative enzyme of incretin, increased the size of the thyroid follicles by facilitating follicular lumina connection, whereas inhibition of the sodium-glucose cotransporter (SGLT) reversed the effects of Dpp4 inhibition. Furthermore, injection of GIP peptide in unfed tadpoles initiated thyroid follicle formation-without requiring feeding-and injection of an incretin receptor antagonist suppressed follicle enlargement in the fed tadpoles. Lastly, GIP receptor knockout in neonatal mice showed smaller follicles in the thyroid, suggesting that the GI hormone-dependent thyroid morphogenesis is conserved in mammals. In conclusion, our study links external nutrients to thyroid morphogenesis and provides new insights into the function of GI hormone as a regulator of organ morphology in developing animals.
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Affiliation(s)
- Maki Takagishi
- Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
| | - Binta Maria Aleogho
- Division of Biological Sciences, Department of Molecular Biology, Nagoya University Graduate School of Science, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Masako Okumura
- Division of Biological Sciences, Department of Molecular Biology, Nagoya University Graduate School of Science, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
| | - Kaori Ushida
- Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Yuichiro Yamada
- Kansai Electric Power Medical Research Institute, 2-1-7 Fukushima, Fukushima-ku, Osaka 553-0003, Japan
| | - Yusuke Seino
- Department of Endocrinology, Diabetes and Metabolism, Fujita Health University, 1-98 Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
| | - Sayoko Fujimura
- Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
| | - Kaoru Nakashima
- Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
| | - Asako Shindo
- Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Division of Biological Sciences, Department of Molecular Biology, Nagoya University Graduate School of Science, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan; Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
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28
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Winquist RJ, Gribkoff VK. Cardiovascular effects of GLP-1 receptor agonism. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 94:213-254. [PMID: 35659373 DOI: 10.1016/bs.apha.2022.02.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are extensively used in type 2 diabetic patients for the effective control of hyperglycemia. It is now clear from outcomes trials that this class of drugs offers important additional benefits to these patients due to reducing the risk of developing major adverse cardiac events (MACE). This risk reduction is, in part, due to effective glycemic control in patients; however, the various outcomes trials, further validated by subsequent meta-analysis of the outcomes trials, suggest that the risk reduction in MACE is also dependent on glycemic-independent mechanisms operant in cardiovascular tissues. These glycemic-independent mechanisms are likely mediated by GLP-1 receptors found throughout the cardiovascular system and by the complex signaling cascades triggered by the binding of agonists to the G-protein coupled receptors. This heterogeneity of signaling pathways underlying different downstream effects of GLP-1 agonists, and the discovery of biased agonists favoring specific signaling pathways, may have import in the future treatment of MACE in these patients. We review the evidence supporting the glycemic-independent evidence for risk reduction of MACE by the GLP-1 receptor agonists and highlight the putative mechanisms underlying these benefits. We also comment on the different signaling pathways which appear important for mediating these effects.
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Affiliation(s)
| | - Valentin K Gribkoff
- Section on Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States; TheraStat LLC, Weston, MA, United States
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29
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Enteroendocrine System and Gut Barrier in Metabolic Disorders. Int J Mol Sci 2022; 23:ijms23073732. [PMID: 35409092 PMCID: PMC8998765 DOI: 10.3390/ijms23073732] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
With the continuous rise in the worldwide prevalence of obesity and type 2 diabetes, developing therapies regulating body weight and glycemia has become a matter of great concern. Among the current treatments, evidence now shows that the use of intestinal hormone analogs (e.g., GLP1 analogs and others) helps to control glycemia and reduces body weight. Indeed, intestinal endocrine cells produce a large variety of hormones regulating metabolism, including appetite, digestion, and glucose homeostasis. Herein, we discuss how the enteroendocrine system is affected by local environmental and metabolic signals. These signals include those arising from unbalanced diet, gut microbiota, and the host metabolic organs and their complex cross-talk with the intestinal barrier integrity.
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Abstract
With the recent urbanization and globalization, the adult obesity rate has been increasing, which was paralleled with a dramatic surge in the incidence and prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD poses a growing threat to human health as it represents the most common cause of chronic liver disease in developed countries. It encompasses a wide spectrum of conditions starting from a build-up of fat in hepatocytes (steatosis), to developing inflammation (steatohepatitis), and reaching up to cirrhosis. It is also associated with higher rates of cardiovascular mortalities. Therefore, proper timely treatment is essential and weight loss remains the cornerstone in the treatment of obesity-related liver diseases. When diet, exercise, and lifestyle changes are not successful, the current recommendation for weight loss includes antiobesity medications and bariatric endoscopic and surgical interventions. These interventions have shown to result in significant weight loss and improve liver steatosis and fibrosis. In the current literature review, we highlight the expected outcomes and side effects of the currently existing options to have a weight-centric NAFLD approach.
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Affiliation(s)
- Anas Hashem
- Division of Gastroenterology and Hepatology, Department of Medicine, Precision Medicine for Obesity Program, Mayo Clinic, Rochester, Minnesota
| | - Amani Khalouf
- Division of Gastroenterology and Hepatology, Department of Medicine, Precision Medicine for Obesity Program, Mayo Clinic, Rochester, Minnesota
| | - Andres Acosta
- Division of Gastroenterology and Hepatology, Department of Medicine, Precision Medicine for Obesity Program, Mayo Clinic, Rochester, Minnesota
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31
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Study on the Mechanism of the Blood-Glucose-Lowering Effect of Collagen Peptides from Sturgeon By-Products. Mar Drugs 2021; 19:md19100584. [PMID: 34677483 PMCID: PMC8541525 DOI: 10.3390/md19100584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/13/2021] [Accepted: 10/15/2021] [Indexed: 12/25/2022] Open
Abstract
In a previous study, we found that the collagen peptides prepared from the by-products of Bester sturgeon had an inhibitory effect on elevated blood glucose levels in a glucose tolerance test with ICR mice. In the present study, we examine the mechanism of the effect of sturgeon collagen peptides (SCPs) in detail. When glucose was orally administered to mice along with the SCPs, it was found that the glucose remained in the stomach for a longer time. In the above tests, the amount of glucose excreted in the feces of mice also increased. On the contrary, it was revealed that the SCPs have a dipeptidyl-peptidase-IV (DPP-IV) inhibitory ability in an in vitro test. In subsequent oral and intravenous glucose administration tests, glucagon-like peptide-1 (GLP-1) and insulin levels in the blood of mice were maintained at high levels. These results suggested the following three mechanisms: SCPs slow the rate of transportation of glucose from the stomach into the small intestine, resulting in delayed glucose absorption; SCPs suppress the absorption of glucose in the small intestine and excrete it from the body; SCPs inhibit DPP-IV in the blood and maintain a high GLP-1 level in blood, which in turn stimulates insulin secretion.
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32
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Zhang D, Wen Z, Jiang T, Sun Y. The incessant increase curve during oral glucose tolerance tests in Chinese adults with type 2 diabetes and its association with gut hormone levels. Peptides 2021; 143:170595. [PMID: 34116121 DOI: 10.1016/j.peptides.2021.170595] [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: 03/14/2021] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 11/20/2022]
Abstract
Glucose curve shapes during oral glucose tolerance tests (OGTTs) are mainly classified as incessant increase, monophasic and biphasic. Youth with an incessant increase curve have worse β-cell function. The aim of this paper was to investigate the incessant increase curve in Chinese adults with type 2 diabetes (T2DM), and its association with β-cell function and gut hormone levels. Eighty-nine Chinese patients (59 males and 30 females) were included in this study with a mean age of 50.56 ± 16.00 years. They were all recently diagnosed with T2DM and underwent 180-min OGTTs. Data on demographics, β-cell function, and insulin sensitivity were also collected. Gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and ghrelin, were also detected during the OGTT. A total of 39.3 % of subjects had an incessant increase in the glucose response curve, while 59.6 % had a monophasic curve. Because only one curve was classified as biphasic, patients with a biphasic curve were omitted from further research. Lower plasma C-peptide, HOMA2-β, area under the curve (AUC) of C-peptide, and ratio of AUC of insulin to AUC of glucose were found in patients with incessant increase curves compared to those with monophasic curves (P < 0.05). Higher glycated hemoglobin (HbA1c) was found in subjects with an incessant increase curve (P < 0.05). Importantly, fasting plasma ghrelin was lower and incremental ghrelin at 120 min was higher in the incessant increase group (P < 0.05), irrespective of age, sex, body mass index (BMI), fasting glucose, and fasting insulin. Time to peak is also a parameter of the OGTT curve shape. In the late-peak group, GLP-1 at 120 min and the AUC of GLP-1 were elevated compared with those in the early-peak group (P < 0.05). In Chinese adults with T2DM, the incessant increase in OGTT shape indicated impaired insulin secretion. Lower fasting ghrelin and absence of ghrelin drops after glucose load may be associated with the incessant increase OGTT shape. In addition, compensatory elevated GLP-1 dose not prevent peak delay in the OGTT curve. Gut hormones may have an effect on OGTT shapes in T2DM adults.
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Affiliation(s)
- Dongxue Zhang
- Department of Endocrinology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
| | - Zhen Wen
- Department of Endocrinology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
| | - Tao Jiang
- Department of Endocrinology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
| | - Yuyan Sun
- Department of Endocrinology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
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33
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Bandyopadhyay I, Dave S, Rai A, Nampoothiri M, Chamallamudi MR, Kumar N. Oral semaglutide in the management of type 2 DM: Clinical status and comparative analysis. Curr Drug Targets 2021; 23:311-327. [PMID: 34468297 DOI: 10.2174/1389450122666210901125420] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 06/09/2021] [Accepted: 06/24/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND In the incretin system, Glucagon-like peptide-1 (GLP-1) is a hormone that inhibits the release of glucagon and regulates glucose-dependent insulin secretion. In type 2 diabetes, correcting the impaired incretin system using GLP-1 agonist is a well-defined therapeutic strategy. OBJECTIVES This review article aims to discuss the mechanism of action, key regulatory events, clinical trials for glycaemic control and comparative analysis of semaglutide with the second-line antidiabetic drugs. DESCRIPTION Semaglutide is a glucagon-like peptide 1 (GLP 1) receptor agonist with enhanced glycaemic control in diabetes patients. In 2019, USFDA approved the first oral GLP-1 receptor agonist, semaglutide to be administered as a once-daily tablet. Further, recent studies highlight the ability of semaglutide to improve the glycaemic control in obese patients with a reduction in body weight. Still, in clinical practice, in type 2 DM treatment paradigm the impact of oral semaglutide remains unidentified. This review article discusses the mechanism of action, pharmacodynamics, key regulatory events, and clinical trials regarding glycaemic control. CONCLUSION The review highlights the comparative analysis of semaglutide with the existing second-line drugs for the management of type 2 diabetes mellitus by stressing on its benefits and adverse events.
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Affiliation(s)
- Ilora Bandyopadhyay
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Sunny Dave
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Amita Rai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Mallikarjuna Rao Chamallamudi
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Nitesh Kumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
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34
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Watkins JD, Koumanov F, Gonzalez JT. Protein- and Calcium-Mediated GLP-1 Secretion: A Narrative Review. Adv Nutr 2021; 12:2540-2552. [PMID: 34192748 PMCID: PMC8634310 DOI: 10.1093/advances/nmab078] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/31/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Glucagon-like peptide 1 (GLP-1) is an incretin hormone produced in the intestine that is secreted in response to nutrient exposure. GLP-1 potentiates glucose-dependent insulin secretion from the pancreatic β cells and promotes satiety. These important actions on glucose metabolism and appetite have led to widespread interest in GLP-1 receptor agonism. Typically, this involves pharmacological GLP-1 mimetics or targeted inhibition of dipeptidyl peptidase-IV, the enzyme responsible for GLP-1 degradation. However, nutritional strategies provide a widely available, cost-effective alternative to pharmacological strategies for enhancing hormone release. Recent advances in nutritional research have implicated the combined ingestion of protein and calcium with enhanced endogenous GLP-1 release, which is likely due to activation of receptors with high affinity and/or sensitivity for amino acids and calcium. Specifically targeting these receptors could enhance gut hormone secretion, thus providing a new therapeutic option. This narrative review provides an overview of the latest research on protein- and calcium-mediated GLP-1 release with an emphasis on human data, and a perspective on potential mechanisms that link potent GLP-1 release to the co-ingestion of protein and calcium. In light of these recent findings, potential future research directions are also presented.
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Affiliation(s)
- Jonathan D Watkins
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, United Kingdom
| | - Françoise Koumanov
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, United Kingdom
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35
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Comparative Assessment of the Acute Effects of Whey, Rice and Potato Protein Isolate Intake on Markers of Glycaemic Regulation and Appetite in Healthy Males Using a Randomised Study Design. Nutrients 2021; 13:nu13072157. [PMID: 34201703 PMCID: PMC8308460 DOI: 10.3390/nu13072157] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/15/2021] [Accepted: 06/18/2021] [Indexed: 01/16/2023] Open
Abstract
Global protein consumption has been increasing for decades due to changes in demographics and consumer shifts towards higher protein intake to gain health benefits in performance nutrition and appetite regulation. Plant-derived proteins may provide a more environmentally sustainable alternative to animal-derived proteins. This study, therefore, aimed to investigate, for the first time, the acute effects on glycaemic indices, gut hormones, and subjective appetite ratings of two high-quality, plant-derived protein isolates (potato and rice), in comparison to a whey protein isolate in a single-blind, triple-crossover design study with nine male participants (30.8 ± 9.3 yrs). Following a 12 h overnight fast, participants consumed an equal volume of the three isocaloric protein shakes on different days, with at least a one-week washout period. Glycaemic indices and gut hormones were measured at baseline, then at 30, 60, 120, 180 min at each visit. Subjective palatability and appetite ratings were measured using visual analogue scales (VAS) over the 3 h, at each visit. This data showed significant differences in insulin secretion with an increase in whey (+141.8 ± 35.1 pmol/L; p = 0.011) and rice (−64.4 ± 20.9 pmol/L; p = 0.046) at 30 min compared to potato protein. A significantly larger total incremental area under the curve (iAUC) was observed with whey versus potato and rice with p < 0.001 and p = 0.010, respectively. There was no significant difference observed in average appetite perception between the different proteins. In conclusion, this study suggests that both plant-derived proteins had a lower insulinaemic response and improved glucose maintenance compared to whey protein.
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36
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High Glucose Exposure Impairs L-Cell Differentiation in Intestinal Organoids: Molecular Mechanisms and Clinical Implications. Int J Mol Sci 2021; 22:ijms22136660. [PMID: 34206340 PMCID: PMC8268781 DOI: 10.3390/ijms22136660] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
Intestinal organoids are used to analyze the differentiation of enteroendocrine cells (EECs) and to manipulate their density for treating type 2 diabetes. EEC differentiation is a continuous process tightly regulated in the gut by a complex regulatory network. However, the effect of chronic hyperglycemia, in the modulation of regulatory networks controlling identity and differentiation of EECs, has not been analyzed. This study aimed to investigate the effect of glucotoxicity on EEC differentiation in small intestinal organoid platforms. Mouse intestinal organoids were cultured in the presence/absence of high glucose concentrations (35 mM) for 48 h to mimic glucotoxicity. Chronic hyperglycemia impaired the expression of markers related to the differentiation of EEC progenitors (Ngn3) and L-cells (NeuroD1), and it also reduced the expression of Gcg and GLP-1 positive cell number. In addition, the expression of intestinal stem cell markers was reduced in organoids exposed to high glucose concentrations. Our data indicate that glucotoxicity impairs L-cell differentiation, which could be associated with decreased intestinal stem cell proliferative capacity. This study provides the identification of new targets involved in new molecular signaling mechanisms impaired by glucotoxicity that could be a useful tool for the treatment of type 2 diabetes.
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37
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Telese A, Sehgal V, Magee CG, Naik S, Alqahtani S, Lovat L, Haidry RJ. Bariatric and Metabolic Endoscopy: A New Paradigm. Clin Transl Gastroenterol 2021; 12:e00364. [PMID: 34142665 PMCID: PMC8216681 DOI: 10.14309/ctg.0000000000000364] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 04/14/2021] [Indexed: 12/26/2022] Open
Abstract
The prevalence of obesity, type 2 diabetes mellitus, and metabolic syndromes is increasing globally. Minimally invasive metabobariatric (MB) endoscopic therapies are adjunct treatments that can potentially bridge the gap between surgical interventions and medical therapy. A growing number of MB techniques are becoming available, allowing for more personalized and patient-targeted treatment options for specific disease states. MB techniques are less invasive than surgery and can precisely target different parts of the gastrointestinal tract that may be responsible for the pathophysiology of obesity and metabolic syndromes such as type 2 diabetes mellitus. These alternatives should be selected on an individualized patient basis to balance the expected clinical outcomes and desired anatomical targets with the level of invasiveness and degree of acceptable risk. Each MB intervention presents great flexibility allowing for a tailored intervention and different levels of patient engagement. Patient awareness and motivation are essential to avoid therapy withdrawal and failure. Differences between MB procedures in terms of weight loss and metabolic benefit will be discussed in this review, along with the insights on clinical decision-making processes to evaluate the potential of further evolution and growth of bariatric and metabolic endoscopy.
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Affiliation(s)
- Andrea Telese
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
| | - Vinay Sehgal
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
| | - Cormac G. Magee
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
- Centre for Obesity research, University College London, London, UK;
| | - S. Naik
- Centre for Obesity research, University College London, London, UK;
| | - S.A. Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA;
- Liver Transplantation Unit, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - L.B. Lovat
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
- Division of Surgery and Interventional Science, University College London, London, UK.
| | - Rehan J. Haidry
- Department of Gastrointestinal Services, University College London Hospital, London, UK;
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38
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Guo X, Lv J, Xi R. The specification and function of enteroendocrine cells in Drosophila and mammals: a comparative review. FEBS J 2021; 289:4773-4796. [PMID: 34115929 DOI: 10.1111/febs.16067] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/26/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022]
Abstract
Enteroendocrine cells (EECs) in both invertebrates and vertebrates derive from intestinal stem cells (ISCs) and are scattered along the digestive tract, where they function in sensing various environmental stimuli and subsequently secrete neurotransmitters or neuropeptides to regulate diverse biological and physiological processes. To fulfill these functions, EECs are specified into multiple subtypes that occupy specific gut regions. With advances in single-cell technology, organoid culture experimental systems, and CRISPR/Cas9-mediated genomic editing, rapid progress has been made toward characterization of EEC subtypes in mammals. Additionally, studies of genetic model organisms-especially Drosophila melanogaster-have also provided insights about the molecular processes underlying EEC specification from ISCs and about the establishment of diverse EEC subtypes. In this review, we compare the regulation of EEC specification and function in mammals and Drosophila, with a focus on EEC subtype characterization, on how internal and external regulators mediate EEC subtype specification, and on how EEC-mediated intra- and interorgan communications affect gastrointestinal physiology and pathology.
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Affiliation(s)
- Xingting Guo
- National Institute of Biological Sciences, Beijing, China
| | - Jiaying Lv
- National Institute of Biological Sciences, Beijing, China.,School of Life Sciences, Tsinghua University, Beijing, China
| | - Rongwen Xi
- National Institute of Biological Sciences, Beijing, China.,Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
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39
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Angelini G, Salinari S, Castagneto-Gissey L, Bertuzzi A, Casella-Mariolo J, Ahlin S, Boskoski I, Gaggini M, Raffaelli M, Costamagna G, Casella G, Marini PL, Gastaldelli A, Bornstein S, Mingrone G. Small intestinal metabolism is central to whole-body insulin resistance. Gut 2021; 70:1098-1109. [PMID: 32994312 DOI: 10.1136/gutjnl-2020-322073] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/14/2020] [Accepted: 07/24/2020] [Indexed: 12/27/2022]
Abstract
OBJECTIVE To assess the role of jejunum in insulin resistance in humans and in experimental animals. DESIGN Twenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model.We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop.In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling. RESULTS Whole-body insulin sensitivity (SI∙104: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (Rd) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017).Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity.A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans.Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans. CONCLUSION Proximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity. TRIAL REGISTRATION NUMBER NCT03111953.
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Affiliation(s)
- Giulia Angelini
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Università Cattolica del Sacro Cuore, Rome, Italy
| | - Serenella Salinari
- Department of Computer, Control, and Management Engineering "Antonio Ruberti", Universityof Rome "Sapienza", Rome, Italy
| | | | | | | | - Sofie Ahlin
- Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Ivo Boskoski
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Università Cattolica del Sacro Cuore, Rome, Italy
| | - Melania Gaggini
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology, CNR, Pisa, Italy
| | - Marco Raffaelli
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Università Cattolica del Sacro Cuore, Rome, Italy
| | - Guido Costamagna
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Casella
- Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy
| | - Pier Luigi Marini
- Department of Surgery, Azienda Ospedaliera S. Camillo Forlanini, Rome, Italy
| | - Amalia Gastaldelli
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology, CNR, Pisa, Italy
| | - Stefan Bornstein
- Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.,Department of Medicine III, Universitätsklinikum Carl Gustav Carus an der Technischen, Universität Dresden, Dresden, Germany
| | - Geltrude Mingrone
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy .,Università Cattolica del Sacro Cuore, Rome, Italy.,Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
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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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Lu VB, Gribble FM, Reimann F. Nutrient-Induced Cellular Mechanisms of Gut Hormone Secretion. Nutrients 2021; 13:nu13030883. [PMID: 33803183 PMCID: PMC8000029 DOI: 10.3390/nu13030883] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/27/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.
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Intestinal Electrical Stimulation Enhances Release of Postprandial Incretin Hormones Via Cholinergic Mechanisms. Obes Surg 2021; 31:1957-1966. [PMID: 33469859 DOI: 10.1007/s11695-021-05228-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/05/2021] [Accepted: 01/08/2021] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Intestinal electrical stimulation (IES) has been reported to reduce body weight and improve glucose tolerance in obese and diabetic rats. Our study aimed to investigate possible IES mechanisms involving incretin hormones using intraduodenal glucose infusion in rats. We hypothesized that the enhanced release of postprandial glucagon-like peptide-1 (GLP-1) at early phase by IES was mediated through neuro/paracrine mechanisms involving the vagal nerve and glucose-dependent insulinotropic peptide (GIP). METHODS Fifteen normal male Sprague-Dawley rats chronically implanted with duodenal electrodes for IES, and an intra-duodenum catheter for the infusion of glucose were studied in a series of sessions with IES of different parameters with and without atropine and M3 receptor antagonist. Blood samples were collected via the tail vein for the measurement of blood glucose, and plasma GLP-1, and GIP. RESULTS (1) Compared to sham-IES, IES of 0.3 ms reduced blood glucose by 16.5-28.4% between 30 and 120 min (all time points p < 0.05), and IES of 3-ms reduced blood glucose at 60 (12.6%) and 90 min (11.8%). IES of 0.3 ms showed a greater hypoglycemic effect than 3 ms (p = 0.024) at 30 min. (2) IES elevated plasma GLP-1 with 0.3 ms (p = 0.001) and with 3 ms p = 0.03). (3) IES substantially elevated plasma GIP with 0.3 ms (p = 0.002) and with 3 ms (p < 0.001). (4) Pretreatment of atropine and the M3 receptor antagonist 4-DAMP blocked the effects of IES on GLP-1, GIP, and blood glucose. CONCLUSIONS IES reduces postprandial blood glucose by enhancing the release of GLP-1 and GIP mediated via the cholinergic mechanism.
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Nogal A, Valdes AM, Menni C. The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes 2021; 13:1-24. [PMID: 33764858 PMCID: PMC8007165 DOI: 10.1080/19490976.2021.1897212] [Citation(s) in RCA: 417] [Impact Index Per Article: 104.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 02/04/2023] Open
Abstract
The gut microbiota plays an important role in cardio-metabolic diseases with diet being among the strongest modulators of gut microbiota composition and function. Resistant dietary carbohydrates are fermented to short-chain fatty acids (SCFAs) by the gut bacteria. Fiber and omega-3 rich diets increase SCFAs production and abundance of SCFA-producing bacteria. Likewise, SCFAs can improve gut barrier integrity, glucose, and lipid metabolism, regulate the immune system, the inflammatory response, and blood pressure. Therefore, targeting the gut microbiota with dietary strategies leading to increased SCFA production may benefit cardio-metabolic health. In this review, we provide an overview of the association between diet, SCFAs produced by the gut microbiota and cardio-metabolic diseases. We first discuss the association between the human gut microbiota and cardio-metabolic diseases, then investigate the role of SCFAs and finally explore the beneficial effects of specific dietary interventions that can improve cardio-metabolic outcomes through boosting the SCFA production.
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Affiliation(s)
- Ana Nogal
- Department of Twin Research, King’s College London, St Thomas’ Hospital Campus, London, UK
| | - Ana M. Valdes
- Department of Twin Research, King’s College London, St Thomas’ Hospital Campus, London, UK
- School of Medicine, Nottingham City Hospital, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
| | - Cristina Menni
- Department of Twin Research, King’s College London, St Thomas’ Hospital Campus, London, UK
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Kuhre RE, Deacon CF, Holst JJ, Petersen N. What Is an L-Cell and How Do We Study the Secretory Mechanisms of the L-Cell? Front Endocrinol (Lausanne) 2021; 12:694284. [PMID: 34168620 PMCID: PMC8218725 DOI: 10.3389/fendo.2021.694284] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/11/2021] [Indexed: 12/14/2022] Open
Abstract
Synthetic glucagon-like peptide-1 (GLP-1) analogues are effective anti-obesity and anti-diabetes drugs. The beneficial actions of GLP-1 go far beyond insulin secretion and appetite, and include cardiovascular benefits and possibly also beneficial effects in neurodegenerative diseases. Considerable reserves of GLP-1 are stored in intestinal endocrine cells that potentially might be mobilized by pharmacological means to improve the body's metabolic state. In recognition of this, the interest in understanding basic L-cell physiology and the mechanisms controlling GLP-1 secretion, has increased considerably. With a view to home in on what an L-cell is, we here present an overview of available data on L-cell development, L-cell peptide expression profiles, peptide production and secretory patterns of L-cells from different parts of the gut. We conclude that L-cells differ markedly depending on their anatomical location, and that the traditional definition of L-cells as a homogeneous population of cells that only produce GLP-1, GLP-2, glicentin and oxyntomodulin is no longer tenable. We suggest to sub-classify L-cells based on their differential peptide contents as well as their differential expression of nutrient sensors, which ultimately determine the secretory responses to different stimuli. A second purpose of this review is to describe and discuss the most frequently used experimental models for functional L-cell studies, highlighting their benefits and limitations. We conclude that no experimental model is perfect and that a comprehensive understanding must be built on results from a combination of models.
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Affiliation(s)
- Rune E. Kuhre
- Department of Obesity Pharmacology, Novo Nordisk, Måløv, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Rune E. Kuhre, ;
| | - Carolyn F. Deacon
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Jens J. Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
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Kuhre RE, Modvig IM, Jepsen SL, Kizilkaya HS, Bæch-Laursen C, Smith CA, Reimann F, Gribble FM, Rosenkilde MM, Holst JJ. L-Cell Expression of Melanocortin-4-Receptor Is Marginal in Most of the Small Intestine in Mice and Humans and Direct Stimulation of Small Intestinal Melanocortin-4-Receptors in Mice and Rats Does Not Affect GLP-1 Secretion. Front Endocrinol (Lausanne) 2021; 12:690387. [PMID: 34421821 PMCID: PMC8375664 DOI: 10.3389/fendo.2021.690387] [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: 04/02/2021] [Accepted: 06/18/2021] [Indexed: 11/17/2022] Open
Abstract
The molecular sensors underlying nutrient-stimulated GLP-1 secretion are currently being investigated. Peripheral administration of melanocortin-4 receptor (MC4R) agonists have been reported to increase GLP-1 plasma concentrations in mice and humans but it is unknown whether this effect results from a direct effect on the GLP-1 secreting L-cells in the intestine, from other effects in the intestine or from extra-intestinal effects. We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion. L-cell MC4R expression was low in mouse duodenum and hardly detectable in the ileum and MC4R expression was hardly detectable in human L-cells. In isolated perfused mouse and rat intestine, neither intra-luminal nor intra-arterial administration of NDP-alpha-MSH, a potent MC4R agonist, had any effect on GLP-1 secretion (P ≥0.98, n = 5-6) from the upper or lower-half of the small intestine in mice or in the lower half in rats. Furthermore, HS014-an often used MC4R antagonist, which we found to be a partial agonist-did not affect the glucose-induced GLP-1 response in the rat, P = 0.62, n = 6). Studies on transfected COS7-cells confirmed bioactivity of the used compounds and that concentrations employed were well within in the effective range. Our combined data therefore suggest that MC4R-activated GLP-1 secretion in rodents either exclusively occurs in the colon or involves extra-intestinal signaling.
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Affiliation(s)
- Rune E. Kuhre
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Obesity Pharmacology, Novo Nordisk, Måløv, Denmark
- *Correspondence: Rune E. Kuhre, ; Jens J. Holst,
| | - Ida M. Modvig
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sara L. Jepsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hüsün S. Kizilkaya
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cecilie Bæch-Laursen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christopher A. Smith
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
| | - Frank Reimann
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
| | - Fiona M. Gribble
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
| | - Mette M. Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J. Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Rune E. Kuhre, ; Jens J. Holst,
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An alternative pathway for sweet sensation: possible mechanisms and physiological relevance. Pflugers Arch 2020; 472:1667-1691. [PMID: 33030576 DOI: 10.1007/s00424-020-02467-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/14/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022]
Abstract
Sweet substances are detected by taste-bud cells upon binding to the sweet-taste receptor, a T1R2/T1R3 heterodimeric G protein-coupled receptor. In addition, experiments with mouse models lacking the sweet-taste receptor or its downstream signaling components led to the proposal of a parallel "alternative pathway" that may serve as metabolic sensor and energy regulator. Indeed, these mice showed residual nerve responses and behavioral attraction to sugars and oligosaccharides but not to artificial sweeteners. In analogy to pancreatic β cells, such alternative mechanism, to sense glucose in sweet-sensitive taste cells, might involve glucose transporters and KATP channels. Their activation may induce depolarization-dependent Ca2+ signals and release of GLP-1, which binds to its receptors on intragemmal nerve fibers. Via unknown neuronal and/or endocrine mechanisms, this pathway may contribute to both, behavioral attraction and/or induction of cephalic-phase insulin release upon oral sweet stimulation. Here, we critically review the evidence for a parallel sweet-sensitive pathway, involved signaling mechanisms, neural processing, interactions with endocrine hormonal mechanisms, and its sensitivity to different stimuli. Finally, we propose its physiological role in detecting the energy content of food and preparing for digestion.
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Dolo PR, Huang K, Widjaja J, Li C, Zhu X, Yao L, Hong J. Distal gastric mucosa ablation induces significant weight loss and improved glycemic control in type 2 diabetes Sprague-Dawley rat model. Surg Endosc 2020; 34:4336-4346. [PMID: 31630290 DOI: 10.1007/s00464-019-07200-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/09/2019] [Indexed: 01/25/2023]
Abstract
BACKGROUND Excluding the foregut (distal stomach and duodenum) from food transit in RYGB normalizes glucose tolerance. Excluding/removing the duodenal mucosa partly improves glycemic control. So far, the effect of excluding/removing the gastric mucosa remains unknown. OBJECTIVE To observe the effect of removing the distal gastric mucosa on glucose tolerance. METHOD Thirty fatty Sprague-Dawley rats received low-dose streptozotocin (STZ) to induce type 2 diabetes (T2D), then randomly assigned to Roux-en-Y gastric bypass (RYGB, n = 8), distal gastric mucosa removal (DGMR, n = 8), duodenal-jejunal bypass (DJB, n = 8), and Sham (n = 6) groups. In the DGMR group, the distal third of the gastric mucosa was removed by thermal ablation using an electrocautery. Rats were followed for 8 weeks postoperatively. Preoperative oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and mixed-meal tolerance test (MMTT) were repeated 3 and 6 weeks postoperatively. Changes in body weight, food intake, and fasting blood glucose were also recorded. RESULTS Gastrin AUC decreased significantly (p < 0.05) in the DGMR group after surgery. A significantly increased GLP-1 AUC was found in the RYGB, DGMR, and DJB groups at week 3 and only the RYGB group at week 6 postoperatively. The improved glucose tolerance in the RYGB group was significantly greater than the improved glucose tolerance in the DGMR and DJB groups. The improved glucose tolerance 3 and 6 weeks after surgery in the DGMR group was significantly greater than the improved glucose tolerance in the DJB group. Body weight decreased significantly in the RYGB, DGMR, and DJB groups postoperatively. CONCLUSION Removing the distal gastric mucosa induced significant weight loss and improved glycemic control in T2D SD rat model. Therefore, the gastric mucosa exclusion in RYGB may be key to the weight loss and diabetes remission, which perhaps warrants a new theory.
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Affiliation(s)
- Ponnie Robertlee Dolo
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Ke Huang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Jason Widjaja
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Chao Li
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Xiaocheng Zhu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China. .,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China.
| | - Libin Yao
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China
| | - Jian Hong
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221006, Jiangsu, People's Republic of China
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Higuchi K, Futagami S, Yamawaki H, Murakami M, Kirita K, Agawa S, Ikeda G, Noda H, Kodaka Y, Ueki N, Kaneko K, Gudis K, Ohashi R, Iwakiri K. Endosonographic features in patients with non-alcoholic early chronic pancreatitis improved with treatment at one year follow up. J Clin Biochem Nutr 2020; 68:86-94. [PMID: 33536717 PMCID: PMC7844654 DOI: 10.3164/jcbn.19-130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 05/20/2020] [Indexed: 12/19/2022] Open
Abstract
Since the prevention of early chronic pancreatitis (ECP) into chronic pancreatitis might be critical for the reduction of pancreatic cancer, we tried to clarify the pathophysiology of ECP patients, focusing on ECP patients without alcoholic chronic pancreatitis. 27 ECP patients without alcoholic chronic pancreatitis and 33 patients with functional dyspepsia with pancreatic enzyme abnormalities (FD-P) were enrolled in this study. Diagnosis of ECP was made when imaging findings showed the presence of more than 2 out of 7 endoscopic ultrasound features. Duodenal degranulated eosinophils and glucagon-like peptide 1 producing cells were estimated by immunostaining. There were no significant differences in characteristics and psychogenic factors between ECP and FD-P patients. Interestingly, endoscopic ultrasound score in ECP patients significantly improved, albeit clinical symptoms in ECP patients showed no improvement at one year follow up. The extent of migration of duodenal degranulated eosinophils in FD-P patients was significantly higher compared to that in ECP patients. The levels of elastase-1 and trypsin in ECP patients with improved endoscopic ultrasound features were significantly reduced by the treatment. Further studies will be needed to clarify whether clinical symptoms and endoscopic ultrasound features in ECP patients without alcoholic chronic pancreatitis were improved in longer follow up study.
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Affiliation(s)
- Kazutoshi Higuchi
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Seiji Futagami
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Hiroshi Yamawaki
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Makoto Murakami
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Kumiko Kirita
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Shuhei Agawa
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Go Ikeda
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Hiroto Noda
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Yasuhiro Kodaka
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Nobue Ueki
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Keiko Kaneko
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Katya Gudis
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Ryuji Ohashi
- Department of Diagnostic Pathology, Nippon Medical School Musashi Kosugi Hospital, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa 211-8533, Japan
| | - Katsuhiko Iwakiri
- Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
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Koepsell H. Glucose transporters in the small intestine in health and disease. Pflugers Arch 2020; 472:1207-1248. [PMID: 32829466 PMCID: PMC7462918 DOI: 10.1007/s00424-020-02439-5] [Citation(s) in RCA: 158] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/11/2020] [Accepted: 07/17/2020] [Indexed: 12/23/2022]
Abstract
Absorption of monosaccharides is mainly mediated by Na+-D-glucose cotransporter SGLT1 and the facititative transporters GLUT2 and GLUT5. SGLT1 and GLUT2 are relevant for absorption of D-glucose and D-galactose while GLUT5 is relevant for D-fructose absorption. SGLT1 and GLUT5 are constantly localized in the brush border membrane (BBM) of enterocytes, whereas GLUT2 is localized in the basolateral membrane (BLM) or the BBM plus BLM at low and high luminal D-glucose concentrations, respectively. At high luminal D-glucose, the abundance SGLT1 in the BBM is increased. Hence, D-glucose absorption at low luminal glucose is mediated via SGLT1 in the BBM and GLUT2 in the BLM whereas high-capacity D-glucose absorption at high luminal glucose is mediated by SGLT1 plus GLUT2 in the BBM and GLUT2 in the BLM. The review describes functions and regulations of SGLT1, GLUT2, and GLUT5 in the small intestine including diurnal variations and carbohydrate-dependent regulations. Also, the roles of SGLT1 and GLUT2 for secretion of enterohormones are discussed. Furthermore, diseases are described that are caused by malfunctions of small intestinal monosaccharide transporters, such as glucose-galactose malabsorption, Fanconi syndrome, and fructose intolerance. Moreover, it is reported how diabetes, small intestinal inflammation, parental nutrition, bariatric surgery, and metformin treatment affect expression of monosaccharide transporters in the small intestine. Finally, food components that decrease D-glucose absorption and drugs in development that inhibit or downregulate SGLT1 in the small intestine are compiled. Models for regulations and combined functions of glucose transporters, and for interplay between D-fructose transport and metabolism, are discussed.
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Affiliation(s)
- Hermann Koepsell
- Institute for Anatomy and Cell Biology, University of Würzburg, Koellikerstr 6, 97070, Würzburg, Germany.
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Cornell S. A review of GLP-1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once-weekly agents. J Clin Pharm Ther 2020; 45 Suppl 1:17-27. [PMID: 32910490 PMCID: PMC7540167 DOI: 10.1111/jcpt.13230] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/24/2020] [Accepted: 05/10/2020] [Indexed: 12/16/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are one of the preferred approved treatment options for people with type 2 diabetes (T2D) and inadequate glycaemic control. The objective of this review is to provide a general clinical overview of the similarities and differences in the mechanisms of action (MoA) of the once-weekly GLP-1 RA class of medications, highlighting the role of pharmacists in providing optimal medication management, education and care for people with diabetes. METHODS This is a narrative review of the published literature regarding the MoA of the currently available once-weekly GLP-1 RAs in T2D. RESULTS AND DISCUSSION GLP-1 RAs have an established efficacy and safety profile. Their benefits derive from their blood glucose-lowering effects, which include pancreatic beta-cell-mediated glucose-dependent insulin secretion and suppressed glucagon release, and their ability to slow gastric emptying and promote satiety. GLP-1 RAs may also exert beneficial effects on multiple organ systems in which GLP-1 receptors are present, including the cardiovascular and renal systems. Differences between individual GLP-1 RAs with regard to their molecular size, structure and duration of action (short or longer acting) have led to differing pharmacodynamics and clinical effects such as degree of glycaemic control, weight loss abilities, cardiovascular effects and tolerability profiles. WHAT IS NEW AND CONCLUSION From the literature, this appears to be the first review of the evidence base supporting the MoA of once-weekly GLP-1 RAs in T2D aimed at pharmacists, with a particular emphasis on the expanding role of pharmacists in team-based diabetes management. As a class, GLP-1 RAs are an effective treatment option for people with T2D, shown to achieve multi-factorial clinical benefits. The results suggest that when selecting or advising about treatments, pharmacists should consider how the different once-weekly GLP-1 RAs and their MoA affect clinical outcomes in order to ensure optimal treatment for individuals.
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Affiliation(s)
- Susan Cornell
- Chicago College of PharmacyMidwestern UniversityDowners GroveILUSA
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