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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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Yang Y, Yamane S, Harada N, Ikeguchi-Ogura E, Yamamoto K, Wada N, Fauzi M, Murakami T, Yabe D, Hayashi Y, Inagaki N. Voltage-gated calcium channel α 2δ-1 subunit is involved in the regulation of glucose-stimulated GLP-1 secretion in mice. Am J Physiol Gastrointest Liver Physiol 2025; 328:G243-G251. [PMID: 39918794 DOI: 10.1152/ajpgi.00279.2024] [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: 09/03/2024] [Revised: 10/01/2024] [Accepted: 02/03/2025] [Indexed: 02/26/2025]
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin produced by enteroendocrine preproglucagon (PPG)-expressing cells in response to nutrient ingestion that potentiates insulin secretion. The voltage-gated Ca2+ channel has been reported previously to be involved in glucose-stimulated GLP-1 secretion; in this study, we show that PPG-cells in upper and lower small intestine substantially express the voltage-gated Ca2+ channel α2δ-1 subunit (CaVα2δ-1). In vitro experiments using NCI-H716 cells demonstrate that inhibition of CaVα2δ-1 by gabapentin (GBP), an inhibitory ligand of the α2δ subunit, attenuates glucose-stimulated intracellular calcium elevation and reduces GLP-1 secretion. In addition, systemic administration of gabapentin significantly reduces glucose-stimulated GLP-1 secretion without affecting blood glucose levels in wild-type mice. Furthermore, knockout mice of intestine-specific Cacna2d1, a gene encoding CaVα2δ-1, exhibit reduced GLP-1 secretion in response to oral glucose administration regardless of sex. These results demonstrate that CaVα2δ-1 expressed in PPG-cells plays an important role in glucose-stimulated GLP-1 secretion and represents a potential target in the treatment of diabetes and obesity.NEW & NOTEWORTHY In this study, we establish high expression of the voltage-gated Ca2+ channel α2δ-1 subunit (CaVα2δ-1) subunit in enteroendocrine glucagon-like peptide-1 (GLP-1) producing cells and elucidate its role in GLP-1 secretion, providing a more detailed understanding of the mechanism of GLP-1 secretion.
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Affiliation(s)
- Yuhan Yang
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Endocrinology and Metabolism, School of Medical Sciences, University of Fukui, Fukui, Japan
| | - Eri Ikeguchi-Ogura
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kana Yamamoto
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naoki Wada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Muhammad Fauzi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takaaki Murakami
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshitaka Hayashi
- Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Medical Research Institute Kitano Hospital, P.I.I.F. Tazuke-kofukai, Osaka, Japan
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Lewandowski SL, El K, Campbell JE. Evaluating glucose-dependent insulinotropic polypeptide and glucagon as key regulators of insulin secretion in the pancreatic islet. Am J Physiol Endocrinol Metab 2024; 327:E103-E110. [PMID: 38775725 PMCID: PMC11390117 DOI: 10.1152/ajpendo.00360.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/27/2024] [Accepted: 05/09/2024] [Indexed: 06/04/2024]
Abstract
The incretin axis is an essential component of postprandial insulin secretion and glucose homeostasis. There are two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert multiple actions throughout the body. A key cellular target for the incretins are pancreatic β-cells, where they potentiate nutrient-stimulated insulin secretion. This feature of incretins has made this system an attractive target for therapeutic interventions aimed at controlling glycemia. Here, we discuss the role of GIP in both β-cells and α-cells within the islet, to stimulate insulin and glucagon secretion, respectively. Moreover, we discuss how glucagon secretion from α-cells has important insulinotropic actions in β-cells through an axis termed α- to β-cell communication. These recent advances have elevated the potential of GIP and glucagon as a therapeutic targets, coinciding with emerging compounds that pharmacologically leverage the actions of these two peptides in the context of diabetes and obesity.
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Affiliation(s)
- Sophie L Lewandowski
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
| | - Kimberley El
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
- Division of Endocrinology, Department of Medicine, Duke University, Durham, North Carolina, United States
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, United States
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Sun B, Chen H, Xue J, Li P, Fu X. The role of GLUT2 in glucose metabolism in multiple organs and tissues. Mol Biol Rep 2023; 50:6963-6974. [PMID: 37358764 PMCID: PMC10374759 DOI: 10.1007/s11033-023-08535-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 05/17/2023] [Indexed: 06/27/2023]
Abstract
The glucose transporter family has an important role in the initial stage of glucose metabolism; Glucose transporters 2 (GLUTs, encoded by the solute carrier family 2, SLC2A genes) is the major glucose transporter in β-cells of pancreatic islets and hepatocytes but is also expressed in the small intestine, kidneys, and central nervous system; GLUT2 has a relatively low affinity to glucose. Under physiological conditions, GLUT2 transports glucose into cells and allows the glucose concentration to reach balance on the bilateral sides of the cellular membrane; Variation of GLUT2 is associated with various endocrine and metabolic disorders; In this study, we discussed the role of GLUT2 in participating in glucose metabolism and regulation in multiple organs and tissues and its effects on maintaining glucose homeostasis.
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Affiliation(s)
- Bo Sun
- Endorcrine and Metabolism Department, Lanzhou University Second Hospital, Lanzhou, 730000, China
- Department of Infantile Endocrine Genetic Metabolism, Gansu Maternal and child Health Care Hospital, Lanzhou, 730000, China
| | - Hui Chen
- Endorcrine and Metabolism Department, Lanzhou University Second Hospital, Lanzhou, 730000, China.
| | - Jisu Xue
- EndEnorcrine and Metabolism Department, Shenzhen Bao 'an People's Hospital (Group), Shenzhen, 518100, China
| | - Peiwu Li
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, 730000, China
| | - Xu Fu
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, 730000, China
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5
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De Siqueira MK, Andrade-Oliveira V, Stacy A, Pedro Tôrres Guimarães J, Wesley Alberca-Custodio R, Castoldi A, Marques Santos J, Davoli-Ferreira M, Menezes-Silva L, Miguel Turato W, Han SJ, Glatman Zaretsky A, Hand TW, Olsen Saraiva Câmara N, Russo M, Jancar S, Morais da Fonseca D, Belkaid Y. Infection-elicited microbiota promotes host adaptation to nutrient restriction. Proc Natl Acad Sci U S A 2023; 120:e2214484120. [PMID: 36652484 PMCID: PMC9942920 DOI: 10.1073/pnas.2214484120] [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] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 12/14/2022] [Indexed: 01/19/2023] Open
Abstract
The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent.
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Affiliation(s)
- Mirian Krystel De Siqueira
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Vinicius Andrade-Oliveira
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
- National Institute of Allergy and Infectious Diseases Microbiome Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
| | - Apollo Stacy
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
- National Institute of Allergy and Infectious Diseases Microbiome Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
| | - João Pedro Tôrres Guimarães
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | | | - Angela Castoldi
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Jaqueline Marques Santos
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Marcela Davoli-Ferreira
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Luísa Menezes-Silva
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Walter Miguel Turato
- Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Seong-Ji Han
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
- National Institute of Allergy and Infectious Diseases Microbiome Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
| | - Arielle Glatman Zaretsky
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
- National Institute of Allergy and Infectious Diseases Microbiome Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
| | - Timothy Wesley Hand
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
| | - Niels Olsen Saraiva Câmara
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Momtchilo Russo
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Sonia Jancar
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Denise Morais da Fonseca
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP05508-000, Brazil
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
- National Institute of Allergy and Infectious Diseases Microbiome Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD20892
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Murata Y, Harada N, Kishino S, Iwasaki K, Ikeguchi-Ogura E, Yamane S, Kato T, Kanemaru Y, Sankoda A, Hatoko T, Kiyobayashi S, Ogawa J, Hirasawa A, Inagaki N. Medium-chain triglycerides inhibit long-chain triglyceride-induced GIP secretion through GPR120-dependent inhibition of CCK. iScience 2021; 24:102963. [PMID: 34466786 PMCID: PMC8382997 DOI: 10.1016/j.isci.2021.102963] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 01/14/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Long-chain triglycerides (LCTs) intake strongly stimulates GIP secretion from enteroendocrine K cells and induces obesity and insulin resistance partly due to GIP hypersecretion. In this study, we found that medium-chain triglycerides (MCTs) inhibit GIP secretion after single LCT ingestion and clarified the mechanism underlying MCT-induced inhibition of GIP secretion. MCTs reduced the CCK effect after single LCT ingestion in wild-type (WT) mice, and a CCK agonist completely reversed MCT-induced inhibition of GIP secretion. In vitro studies showed that medium-chain fatty acids (MCFAs) inhibit long-chain fatty acid (LCFA)-stimulated CCK secretion and increase in intracellular Ca2+ concentrations through inhibition of GPR120 signaling. Long-term administration of MCTs reduced obesity and insulin resistance in high-LCT diet-fed WT mice, but not in high-LCT diet-fed GIP-knockout mice. Thus, MCT-induced inhibition of GIP hypersecretion reduces obesity and insulin resistance under high-LCT diet feeding condition.
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Affiliation(s)
- Yuki Murata
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shigenobu Kishino
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Kanako Iwasaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Eri Ikeguchi-Ogura
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomoko Kato
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yoshinori Kanemaru
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akiko Sankoda
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tomonobu Hatoko
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Sakura Kiyobayashi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Jun Ogawa
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
| | - Akira Hirasawa
- Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
- Corresponding author
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7
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Ahrén B, Yamada Y, Seino Y. The Insulin Response to Oral Glucose in GIP and GLP-1 Receptor Knockout Mice: Review of the Literature and Stepwise Glucose Dose Response Studies in Female Mice. Front Endocrinol (Lausanne) 2021; 12:665537. [PMID: 34122340 PMCID: PMC8190331 DOI: 10.3389/fendo.2021.665537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/21/2021] [Indexed: 12/31/2022] Open
Abstract
A key factor for the insulin response to oral glucose is the pro-glucagon derived incretin hormone glucagon-like peptide-1 (GLP-1), together with the companion incretin hormone, glucose-dependent insulinotropic polypeptide (GIP). Studies in GIP and GLP-1 receptor knockout (KO) mice have been undertaken in several studies to examine this role of the incretin hormones. In the present study, we reviewed the literature on glucose and insulin responses to oral glucose in these mice. We found six publications with such studies reporting results of thirteen separate study arms. The results were not straightforward, since glucose intolerance in GIP or GLP-1 receptor KO mice were reported only in eight of the arms, whereas normal glucose tolerance was reported in five arms. A general potential weakness of the published study is that each of them have examined effects of only one single dose of glucose. In a previous study in mice with genetic deletion of both GLP-1 and GIP receptors we showed that these mice have impaired insulin response to oral glucose after large but not small glucose loads, suggesting that the relevance of the incretin hormones may be dependent on the glucose load. To further test this hypothesis, we have now performed a stepwise glucose administration through a gastric tube (from zero to 125mg) in model experiments in anesthetized female wildtype, GLP-1 receptor KO and GIP receptor KO mice. We show that GIP receptor KO mice exhibit glucose intolerance in the presence of impaired insulin response after 100 and 125 mg glucose, but not after lower doses of glucose. In contrast, GLP-1 receptor KO mice have normal glucose tolerance after all glucose loads, in the presence of a compensatory increase in the insulin response. Therefore, based on these results and the literature survey, we suggest that GIP and GLP-1 receptor KO mice retain normal glucose tolerance after oral glucose, except after large glucose loads in GIP receptor KO mice, and we also show an adaptive mechanism in GLP-1 receptor KO mice, which needs to be further examined.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Yuichiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Graduate School of Medicine, Akita University, Akita, Japan
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Ahrén B, Yamada Y, Seino Y. The Incretin Effect in Female Mice With Double Deletion of GLP-1 and GIP Receptors. J Endocr Soc 2019; 4:bvz036. [PMID: 32010875 PMCID: PMC6984998 DOI: 10.1210/jendso/bvz036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 12/19/2019] [Indexed: 12/19/2022] Open
Abstract
To establish the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) for the incretin effect after oral glucose, studies were undertaken in female mice with genetic deletion of receptors for GIP and GLP-1 (double incretin receptor knockout [DIRKO] mice) and their wild-type (WT) counterparts. Insulin secretion was explored after oral glucose (doses ranging from 0 to 100 mg), after intravenous glucose (doses ranging from 0 to 0.75 g/kg), and after oral and intravenous glucose at matching circulating glucose. DIRKO mice had glucose intolerance after oral glucose challenges in association with impaired beta-cell function. Suprabasal area under the curve for C-peptide (AUCC-peptide) correlated linearly with suprabasal AUCglucose both in WT (r = 0.942, P = .017) and DIRKO mice (r = 0.972, P = .006). The slope of this regression was lower in DIRKO than in WT mice (0.012 ± 0.006 vs 0.031 ± 0.006 nmol C-peptide/mmol glucose, P = .042). In contrast, there was no difference in the insulin response to intravenous glucose between WT and DIRKO mice. Furthermore, oral and intravenous glucose administration at matching glucose levels showed that the augmentation of insulin secretion after oral glucose (the incretin effect) in WT mice (11.8 ± 2.3 nmol/L min) was entirely absent in DIRKO mice (3.3 ± 1.2 nmol/L min). We conclude that GIP and GLP-1 are required for normal glucose tolerance and beta-cell function after oral glucose in mice, that they are the sole incretin hormones after oral glucose at higher dose levels, and that they contribute by 65% to insulin secretion after oral glucose.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Yuichiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Graduate School of Medicine, Akita University, Akita, Japan
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Fujii M, Murakami Y, Karasawa Y, Sumitomo Y, Fujita S, Koyama M, Uda S, Kubota H, Inoue H, Konishi K, Oba S, Ishii S, Kuroda S. Logical design of oral glucose ingestion pattern minimizing blood glucose in humans. NPJ Syst Biol Appl 2019; 5:31. [PMID: 31508240 PMCID: PMC6718521 DOI: 10.1038/s41540-019-0108-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 08/06/2019] [Indexed: 12/22/2022] Open
Abstract
Excessive increase in blood glucose level after eating increases the risk of macroangiopathy, and a method for not increasing the postprandial blood glucose level is desired. However, a logical design method of the dietary ingestion pattern controlling the postprandial blood glucose level has not yet been established. We constructed a mathematical model of blood glucose control by oral glucose ingestion in three healthy human subjects, and predicted that intermittent ingestion 30 min apart was the optimal glucose ingestion patterns that minimized the peak value of blood glucose level. We confirmed with subjects that this intermittent pattern consistently decreased the peak value of blood glucose level. We also predicted insulin minimization pattern, and found that the intermittent ingestion 30 min apart was optimal, which is similar to that of glucose minimization pattern. Taken together, these results suggest that the glucose minimization is achieved by suppressing the peak value of insulin concentration, rather than by enhancing insulin concentration. This approach could be applied to design optimal dietary ingestion patterns.
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Affiliation(s)
- Masashi Fujii
- Molecular Genetic Research Laboratory, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033 Japan
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033 Japan
- Present Address: Department of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8526 Japan
| | - Yohei Murakami
- Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, 606-8501 Japan
| | - Yasuaki Karasawa
- Department of Neurosurgery, The University of Tokyo Hospital, The University of Tokyo, Tokyo, 113-0033 Japan
- Department of Rehabilitation, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033 Japan
| | - Yohei Sumitomo
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033 Japan
| | - Suguru Fujita
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033 Japan
| | - Masanori Koyama
- Department of Mathematics, Graduate School of Science and Engineering, Ritsumeikan University, Shiga, 525-8577 Japan
| | - Shinsuke Uda
- Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582 Japan
| | - Hiroyuki Kubota
- Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582 Japan
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Ishikawa, 920-8640 Japan
| | - Katsumi Konishi
- Faculty of Computer and Information Sciences, Hosei University, Tokyo, 184-8584 Japan
| | - Shigeyuki Oba
- Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, 606-8501 Japan
| | - Shin Ishii
- Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, 606-8501 Japan
- CREST, Japan Science and Technology Agency, Tokyo, 113-0033 Japan
| | - Shinya Kuroda
- Molecular Genetic Research Laboratory, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033 Japan
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033 Japan
- CREST, Japan Science and Technology Agency, Tokyo, 113-0033 Japan
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10
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Perez KM, Curley KL, Slaughter JC, Shoemaker AH. Glucose Homeostasis and Energy Balance in Children With Pseudohypoparathyroidism. J Clin Endocrinol Metab 2018; 103:4265-4274. [PMID: 30085125 PMCID: PMC6194807 DOI: 10.1210/jc.2018-01067] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/31/2018] [Indexed: 01/20/2023]
Abstract
Context Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterized by early-onset obesity and multihormone resistance. To treat abnormal weight gain and prevent complications such as diabetes, we must understand energy balance and glucose homeostasis in PHP types 1A and 1B. Objective The aim of this study was to evaluate food intake, energy expenditure, and glucose homeostasis in children with PHP. Design Assessments included resting energy expenditure (REE), physical activity, food intake, sucrose preference, questionnaires, endocrine status, and auxological status. All patients underwent an oral glucose tolerance test (OGTT). Setting Vanderbilt University Medical Center. Patients We assessed 16 children with PHP1A, three with PHP1B, and 15 healthy controls. Main Outcome Measures Food intake during an ad lib buffet meal and glucose at five time points during OGTT. Results PHP1A and control groups were well matched. Participants with PHP1A had significantly lower REE without concomitant change in food intake or physical activity. At baseline, participants with PHP1A had significantly lower fasting glucose and insulin resistance. During OGTT, participants with PHP1A had significantly delayed peak glucose and a slower rate of glucose decline despite similar oral glucose insulin sensitivity. Participants with PHP1A had 0.46% lower HbA1c levels than controls from a clinic database after adjustment for OGTT 2-hour glucose. The PHP1B group was similar to the PHP1A group. Conclusions In contrast to other monogenic obesity syndromes, our results support reduced energy expenditure, not severe hyperphagia, as the primary cause of abnormal weight gain in PHP. Patients with PHP are at high risk for dysglycemia without reduced insulin sensitivity.
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Affiliation(s)
- Katia M Perez
- Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Kathleen L Curley
- The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - James C Slaughter
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ashley H Shoemaker
- Department of Pediatrics, Division of Pediatric Endocrinology, Vanderbilt University Medical Center, Nashville, Tennessee
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11
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Oakie A, Wang R. β-Cell Receptor Tyrosine Kinases in Controlling Insulin Secretion and Exocytotic Machinery: c-Kit and Insulin Receptor. Endocrinology 2018; 159:3813-3821. [PMID: 30239687 PMCID: PMC6202852 DOI: 10.1210/en.2018-00716] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 09/13/2018] [Indexed: 12/25/2022]
Abstract
Insulin secretion from pancreatic β-cells is initiated through channel-mediated depolarization, cytoskeletal remodeling, and vesicle tethering at the cell membrane, all of which can be regulated through cell surface receptors. Receptor tyrosine kinases (RTKs) promote β-cell development and postnatal signaling to improve β-cell mass and function, yet their activation has also been shown to initiate exocytotic events in β-cells. This review examines the role of RTK signaling in insulin secretion, with a focus on RTKs c-Kit and insulin receptor (IR). Pathways that control insulin release and the potential interplay between c-Kit and IR signaling are discussed, along with clinical implications of RTK therapy on insulin secretion.
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Affiliation(s)
- Amanda Oakie
- Children’s Health Research Institute, Victoria Research Laboratories, London, Ontario, Canada
- Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada
| | - Rennian Wang
- Children’s Health Research Institute, Victoria Research Laboratories, London, Ontario, Canada
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
- Correspondence: Rennian Wang, MD, PhD, Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, Ontario N6C 2V5, Canada. E-mail:
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Terauchi Y, Yamada Y, Watada H, Nakatsuka Y, Shiosakai K, Washio T, Taguchi T. Efficacy and safety of the G protein-coupled receptor 119 agonist DS-8500a in Japanese type 2 diabetes mellitus patients with inadequate glycemic control on sitagliptin: A phase 2 randomized placebo-controlled study. J Diabetes Investig 2018; 9:1333-1341. [PMID: 29607623 PMCID: PMC6215943 DOI: 10.1111/jdi.12846] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 02/16/2018] [Accepted: 03/19/2018] [Indexed: 02/06/2023] Open
Abstract
Introduction We evaluated the efficacy and safety of DS‐8500a as add‐on therapy to sitagliptin in Japanese type 2 diabetes mellitus patients. Materials and Methods This multicenter, randomized, double‐blind, placebo‐controlled, phase 2 trial randomized patients aged ≥20 years with hemoglobin A1c ≥7.0% and <9.0%, and inadequate glycemic control with sitagliptin 50‐mg monotherapy to receive 25 or 75 mg DS‐8500a, or a placebo, orally. The primary end‐point was change from baseline to day 28 in 24‐h weighted mean glucose. Secondary end‐points included change from baseline in fasting plasma glucose, 2‐h postprandial plasma glucose and lipid profiles. Results Overall, 29, 28 and 27 patients in the placebo, 25‐ and 75‐mg groups, respectively, were analyzed. A significant dose‐dependent reduction was observed in 24‐h weighted mean glucose (linear: P = 0.0006, saturated at 25 mg: P = 0.0003, responded from 75 mg: P = 0.0176) when compared with the placebo (25 mg: −13.19 mg/dL [−0.73 mmol/L], P = 0.0044 vs placebo and 75 mg: −16.12 mg/dL [−0.89 mmol/L], P = 0.0006 vs placebo). A significant reduction in fasting plasma glucose at 75 mg vs placebo was observed (P < 0.001). At 25 and 75 mg, significant reductions of 2‐h postprandial plasma glucose (after breakfast), total cholesterol, low‐cholesterol and triglycerides were observed (all P < 0.05), with a (non‐significant) trend towards increased high‐density lipoprotein cholesterol. Both doses of DS‐8500a were well tolerated. There were no significant treatment‐emergent adverse events leading to discontinuation during the study. Conclusions DS‐8500a was well tolerated, and showed significant glycemic benefits and favorable changes in lipid profile in Japanese type 2 diabetes mellitus patients with inadequate glycemic control with sitagliptin therapy.
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Affiliation(s)
- Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Yuichiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | | | - Takuo Washio
- Asia Development Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Takashi Taguchi
- Clinical Development Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan
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Biggs EK, Liang L, Naylor J, Madalli S, Collier R, Coghlan MP, Baker DJ, Hornigold DC, Ravn P, Reimann F, Gribble FM. Development and characterisation of a novel glucagon like peptide-1 receptor antibody. Diabetologia 2018; 61:711-721. [PMID: 29119245 PMCID: PMC5890879 DOI: 10.1007/s00125-017-4491-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 10/05/2017] [Indexed: 02/06/2023]
Abstract
AIMS/HYPOTHESIS Glucagon like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion by binding to GLP-1 receptors (GLP1Rs) on pancreatic beta cells. GLP-1 mimetics are used in the clinic for the treatment of type 2 diabetes, but despite their therapeutic success, several clinical effects of GLP-1 remain unexplained at a mechanistic level, particularly in extrapancreatic tissues. The aim of this study was to generate and characterise a monoclonal antagonistic antibody for the GLP1R for use in vivo. METHODS A naive phage display selection strategy was used to isolate single-chain variable fragments (ScFvs) that bound to GLP1R. The ScFv with the highest affinity, Glp1R0017, was converted into a human IgG1 and characterised further. In vitro antagonistic activity was assessed in a number of assays: a cAMP-based homogenous time-resolved fluorescence assay in GLP1R-overexpressing cell lines, a live cell cAMP imaging assay and an insulin secretion assay in INS-1 832/3 cells. Glp1R0017 was further tested in immunostaining of mouse pancreas, and the ability of Glp1R0017 to block GLP1R in vivo was assessed by both IPGTT and OGTT in C57/Bl6 mice. RESULTS Antibodies to GLP1R were selected from naive antibody phage display libraries. The monoclonal antibody Glp1R0017 antagonised mouse, human, rat, cynomolgus monkey and dog GLP1R. This antagonistic activity was specific to GLP1R; no antagonistic activity was found in cells overexpressing the glucose-dependent insulinotropic peptide receptor (GIPR), glucagon like peptide-2 receptor or glucagon receptor. GLP-1-stimulated cAMP and insulin secretion was attenuated in INS-1 832/3 cells by Glp1R0017 incubation. Immunostaining of mouse pancreas tissue with Glp1R0017 showed specific staining in the islets of Langerhans, which was absent in Glp1r knockout tissue. In vivo, Glp1R0017 reversed the glucose-lowering effect of liraglutide during IPGTTs, and reduced glucose tolerance by blocking endogenous GLP-1 action in OGTTs. CONCLUSIONS/INTERPRETATION Glp1R0017 is a monoclonal antagonistic antibody to the GLP1R that binds to GLP1R on pancreatic beta cells and blocks the actions of GLP-1 in vivo. This antibody holds the potential to be used in investigating the physiological importance of GLP1R signalling in extrapancreatic tissues where cellular targets and signalling pathways activated by GLP-1 are poorly understood.
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Affiliation(s)
- Emma K Biggs
- Department of Cardiovascular and Metabolic Disease, MedImmune Ltd, Granta Park, Cambridge, UK
- Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Cambridge, CB21 6GH, UK
- University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK
| | - Lihuan Liang
- Department of Cardiovascular and Metabolic Disease, MedImmune Ltd, Granta Park, Cambridge, UK
| | - Jacqueline Naylor
- Department of Cardiovascular and Metabolic Disease, MedImmune Ltd, Granta Park, Cambridge, UK
| | - Shimona Madalli
- Department of Cardiovascular and Metabolic Disease, MedImmune Ltd, Granta Park, Cambridge, UK
| | - Rachel Collier
- In Vivo Sciences - UK, AstraZeneca, The Babraham Institute, Cambridge, UK
| | - Matthew P Coghlan
- Department of Cardiovascular and Metabolic Disease, MedImmune Ltd, Granta Park, Cambridge, UK
| | - David J Baker
- Department of Cardiovascular and Metabolic Disease, MedImmune Ltd, Granta Park, Cambridge, UK
| | - David C Hornigold
- Department of Cardiovascular and Metabolic Disease, MedImmune Ltd, Granta Park, Cambridge, UK
| | - Peter Ravn
- Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Cambridge, CB21 6GH, UK.
| | - Frank Reimann
- University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
| | - Fiona M Gribble
- University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
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14
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Kolodziejski PA, Sassek M, Chalupka D, Leciejewska N, Nogowski L, Mackowiak P, Jozefiak D, Stadnicka K, Siwek M, Bednarczyk M, Szwaczkowski T, Pruszynska-Oszmalek E. GLP1 and GIP are involved in the action of synbiotics in broiler chickens. J Anim Sci Biotechnol 2018; 9:13. [PMID: 29416857 PMCID: PMC5785812 DOI: 10.1186/s40104-017-0227-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 12/22/2017] [Indexed: 12/25/2022] Open
Abstract
Background In order to discover new strategies to replace antibiotics in the post-antibiotic era in meat-type chicken production, two new synbiotics were tested: (Lactobacillus salivarius IBB3154 plus galactooligosaccharide (Syn1) and Lactobacillus plantarum IBB3036 plus raffinose family oligosaccharides (Syn2). Methods The synbiotics were administered via syringe, using a special automatic system, into the egg air chamber of Cobb 500 broiler chicks on the 12th day of egg incubation (2 mg of prebiotics + 105 cfu bacteria per egg). Hatched roosters (total 2,400) were reared on an experimental farm, kept in pens (75 animals per pen), with free access to feed and water. After 42 d animals were slaughtered. Blood serum, pancreas, duodenum and duodenum content were collected. Results Syn2 increased trypsin activity by 2.5-fold in the pancreas and 1.5-fold in the duodenal content. In the duodenum content, Syn2 resulted in ca 30% elevation in lipase activity and 70% reduction in amylase activity. Syn1 and Syn2 strongly decreased expression of mRNA for GLP-1 and GIP in the duodenum and for GLP-1 receptors in the pancreas. Simultaneously, concentrations of the incretins significantly diminished in the blood serum (P < 0.05). The decreased expression of incretins coincides with changed activity of digestive enzymes in the pancreas and in the duodenal content. The results indicate that incretins are involved in the action of Syn1 and Syn2 or that they may even be their target. No changes were observed in key hormones regulating metabolism (insulin, glucagon, corticosterone, thyroid hormones, and leptin) or in metabolic indices (glucose, NEFA, triglycerides, cholesterol). Additionally, synbiotics did not cause significant changes in the activities of alanine and aspartate aminotransferases in broiler chickens. Simultaneously, the activity of alkaline phosphatase and gamma glutamyl transferase diminished after Syn2 and Syn1, respectively. Conclusion The selected synbiotics may be used as in ovo additives for broiler chickens, and Syn2 seems to improve their potential digestive proteolytic and lipolytic ability. Our results suggest that synbiotics can be directly or indirectly involved in incretin secretion and reception.
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Affiliation(s)
- Pawel Antoni Kolodziejski
- 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland
| | - Maciej Sassek
- 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland
| | - Daniela Chalupka
- 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland
| | - Natalia Leciejewska
- 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland
| | - Leszek Nogowski
- 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland
| | - Pawel Mackowiak
- 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland
| | - Damian Jozefiak
- 2Department of Animal Nutrition and Feed Management, Poznan University of Life Sciences, Wolynska 33, 60-637 Poznan, Poland
| | - Katarzyna Stadnicka
- 4Department of Animal Biochemistry and Biotechnology, UTP University of Science and Technology, 85-084 Bydgoszcz, Poland
| | - Maria Siwek
- 4Department of Animal Biochemistry and Biotechnology, UTP University of Science and Technology, 85-084 Bydgoszcz, Poland
| | - Marek Bednarczyk
- 4Department of Animal Biochemistry and Biotechnology, UTP University of Science and Technology, 85-084 Bydgoszcz, Poland
| | - Tomasz Szwaczkowski
- 3Department of Genetics and Animal Breeding, Poznan University of Life Sciences, Wolynska 33, 60-637 Poznan, Poland
| | - Ewa Pruszynska-Oszmalek
- 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland
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15
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Normand E, Franco A, Moreau A, Marcil V. Dipeptidyl Peptidase-4 and Adolescent Idiopathic Scoliosis: Expression in Osteoblasts. Sci Rep 2017; 7:3173. [PMID: 28600546 PMCID: PMC5466660 DOI: 10.1038/s41598-017-03310-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 04/25/2017] [Indexed: 12/25/2022] Open
Abstract
It has been proposed that girls with adolescent idiopathic scoliosis (AIS) tend to have a taller stature and a lower body mass index. Energy homeostasis, that is known to affect bone growth, could contribute to these characteristics. In circulation, dipeptidyl peptidase-4 (DPP-4) inactivates glucagon-like peptide-1 (GLP-1), an incretin that promotes insulin secretion and sensitivity. Our objectives were to investigate DPP-4 status in plasma and in osteoblasts of AIS subjects and controls and to evaluate the regulatory role of metabolic effectors on DPP-4 expression. DPP-4 activity was assessed in plasma of 113 girls and 62 age-matched controls. Osteoblasts were isolated from bone specimens of AIS patients and controls. Human cells were incubated with glucose, insulin, GLP-1 and butyrate. Gene and protein expressions were evaluated by RT-qPCR and Western blot. Our results showed 14% inferior plasma DPP-4 activity in AIS patients when compared to healthy controls (P = 0.0357). Similarly, osteoblasts derived from AIS subjects had lower DPP-4 gene and protein expression than controls by 90.5% and 57.1% respectively (P < 0.009). DPP-4 expression was regulated in a different manner in osteoblasts isolated from AIS participants compared to controls. Our results suggest a role for incretins in AIS development and severity.
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Affiliation(s)
- Emilie Normand
- Research Center of the Sainte-Justine University Hospital, Montreal, Quebec, H3T 1C5, Canada
- Department of Nutrition, Faculty of Medicine, Université de Montreal, Montreal, Quebec, H3T 1J4, Canada
| | - Anita Franco
- Research Center of the Sainte-Justine University Hospital, Montreal, Quebec, H3T 1C5, Canada
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Research Center of the Sainte-Justine University Hospital, Montreal, Quebec, H3T 1C5, Canada
| | - Alain Moreau
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Research Center of the Sainte-Justine University Hospital, Montreal, Quebec, H3T 1C5, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montreal, Montreal, Quebec, H3T 1J4, Canada
- Department of Stomatology, Faculty of Dentistry, Université de Montréal, Montreal, Quebec, H3A 1J4, Canada
| | - Valérie Marcil
- Research Center of the Sainte-Justine University Hospital, Montreal, Quebec, H3T 1C5, Canada.
- Department of Nutrition, Faculty of Medicine, Université de Montreal, Montreal, Quebec, H3T 1J4, Canada.
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Taha O, Abdelaal M, Abozeid M, Askalany A, Alaa M. Outcomes of One Anastomosis Gastric Bypass in 472 Diabetic Patients. Obes Surg 2017; 27:2802-2810. [PMID: 28534188 DOI: 10.1007/s11695-017-2711-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The positive impact of Roux-en-Y gastric bypass (RYGB) on metabolic syndrome and glycemic control has been proven in obese patients. One anastomosis gastric bypass (OAGB) is a simple, effective and easy to learn procedure. OAGB provides encouraging results for the treatment of diabetes obese patients, but does it have the ability to be an alternative procedure to RYGB in the treatment of these patients? The aim of this study is to evaluate the outcomes of OAGB on diabetic obese patients at the bariatric centre of our university hospital. By extension, we evaluated the possibility of BMI and the preoperative antidiabetic medication usage to be predictive factors for postoperative diabetes resolution. METHODS This is a retrospective single-centre study of 472 diabetic patients who underwent OAGB from November 2009 to December 2015. All patients were followed-up for at least 1 year, and up to 3 years, where available. Weight, HbA1c, and anti-diabetic medications were recorded at baseline, 3, 6, 12, 24 and 36 months. RESULTS A total of 472 patients have been followed-up for 1 year and 361 for 3 years. The mean BMI decreased from 46.8 ± 7.2 to 29.5 ± 2.8 kg/m2 and HbA1c from 9.6 ± 1.3 to 5.7 ± 1.5% at the 12-month follow-up. At the 3-year follow-up, the mean BMI was 32.1 ± 3.3 and HbA1c mean was 5.8 ± 0.9%. Diabetes remission was achieved by 84.1% of patients. CONCLUSIONS OAGB can be an excellent alternative to RYGB for the treatment of diabetes and obesity. Pre-operative medications may be used to predict postoperative diabetes remission, but not BMI.
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Affiliation(s)
- Osama Taha
- Plastic and Obesity Surgery Department, Assiut University Hospital, Assiut, Egypt.,Overweight Clinics, Cairo, Egypt
| | - Mahmoud Abdelaal
- Plastic and Obesity Surgery Department, Assiut University Hospital, Assiut, Egypt.
| | - Mohamed Abozeid
- General Surgery Department, Ain Shams University hospital, Cairo, Egypt
| | - Awny Askalany
- Plastic and Obesity Surgery Department, Assiut University Hospital, Assiut, Egypt
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Dror E, Dalmas E, Meier DT, Wueest S, Thévenet J, Thienel C, Timper K, Nordmann TM, Traub S, Schulze F, Item F, Vallois D, Pattou F, Kerr-Conte J, Lavallard V, Berney T, Thorens B, Konrad D, Böni-Schnetzler M, Donath MY. Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol 2017; 18:283-292. [PMID: 28092375 DOI: 10.1038/ni.3659] [Citation(s) in RCA: 281] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 12/06/2016] [Indexed: 12/12/2022]
Abstract
The deleterious effect of chronic activation of the IL-1β system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1β in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1β, in a glucose-dependent manner. Subsequently, IL-1β contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1β signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1β and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1β mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1β and insulin in the regulation of both metabolism and immunity.
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Affiliation(s)
- Erez Dror
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Elise Dalmas
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Daniel T Meier
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Stephan Wueest
- Deptartment of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Julien Thévenet
- Inserm, University Lille, Centre Hospitalier Universitaire, Lille, France, and Translational Research for Diabetes, European Genomic Institute for Diabetes, Lille, France
| | - Constanze Thienel
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Katharina Timper
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Thierry M Nordmann
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Shuyang Traub
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Friederike Schulze
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Flurin Item
- Deptartment of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - David Vallois
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Francois Pattou
- Inserm, University Lille, Centre Hospitalier Universitaire, Lille, France, and Translational Research for Diabetes, European Genomic Institute for Diabetes, Lille, France
| | - Julie Kerr-Conte
- Inserm, University Lille, Centre Hospitalier Universitaire, Lille, France, and Translational Research for Diabetes, European Genomic Institute for Diabetes, Lille, France
| | - Vanessa Lavallard
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland, and University of Geneva School of Medicine, Geneva, Switzerland
| | - Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland, and University of Geneva School of Medicine, Geneva, Switzerland
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Daniel Konrad
- Deptartment of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Marianne Böni-Schnetzler
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marc Y Donath
- Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland
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Farkas I, Vastagh C, Farkas E, Bálint F, Skrapits K, Hrabovszky E, Fekete C, Liposits Z. Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways. Front Cell Neurosci 2016; 10:214. [PMID: 27672360 PMCID: PMC5018486 DOI: 10.3389/fncel.2016.00214] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 08/26/2016] [Indexed: 12/25/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM-5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9-39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N(5)-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid pathway indicating an anandamide-TRPV1-sensitive control of 2-arachidonoylglycerol (2-AG) production. Furthermore, GLP-1 immunoreactive (IR) axons innervated GnRH neurons in the hypothalamus suggesting that GLP-1 of both peripheral and neuronal sources can modulate GnRH neurons. RT-qPCR study confirmed the expression of GLP-1R and neuronal NO synthase (nNOS) mRNAs in GnRH-GFP neurons. Immuno-electron microscopic analysis revealed the presence of nNOS protein in GnRH neurons. These results indicate that GLP-1 exerts direct facilitatory actions via GLP-1R on GnRH neurons and modulates NO and 2-AG retrograde signaling mechanisms that control the presynaptic excitatory GABAergic inputs to GnRH neurons.
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Affiliation(s)
- Imre Farkas
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
| | - Csaba Vastagh
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
| | - Erzsébet Farkas
- Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Hungarian Academy of SciencesBudapest, Hungary; Roska Tamás Doctoral School of Sciences and Technology, Faculty of Information Technology and Bionics, Pázmány Péter Catholic UniversityBudapest, Hungary
| | - Flóra Bálint
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of SciencesBudapest, Hungary; Roska Tamás Doctoral School of Sciences and Technology, Faculty of Information Technology and Bionics, Pázmány Péter Catholic UniversityBudapest, Hungary
| | - Katalin Skrapits
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
| | - Erik Hrabovszky
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
| | - Csaba Fekete
- Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Hungarian Academy of SciencesBudapest, Hungary; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical CenterBoston, MA, USA
| | - Zsolt Liposits
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of SciencesBudapest, Hungary; Department of Neuroscience, Faculty of Information Technology and Bionics, Pázmány Péter Catholic UniversityBudapest, Hungary
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Wang J, Dai G, Li W. [Berberine regulates glycemia via local inhibition of intestinal dipeptidyl peptidase-Ⅳ]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2016; 45:486-492. [PMID: 28087908 PMCID: PMC10397012 DOI: 10.3785/j.issn.1008-9292.2016.09.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 06/08/2016] [Indexed: 06/06/2023]
Abstract
Objective: To investigate the effect of berberine on glycemia regulation in rats with diabetes and the related mechanisms. Methods: Diabetic-like rat model was successfully induced by intraperitoneal injection of streptozotocin in 50 out of 60 male SD rats, which were then randomly divided into 5 groups with 10 rats in each:control group (received vehicle only), positive drug control group (sitagliptin 10 mg·kg-1·d-1), low-dose berberine group (30 mg·kg-1·d-1), moderate-dose berberine group (60 mg·kg-1·d-1), and high-dose berberine group (120 mg·kg-1·d-1). All animals were fed for 3 d, and fasting blood sampling was performed on day 3 of administration. Rats were given glucose (2 g/kg) by gavage 30 min after the last dose. Blood and intestinal samples were obtained 2 h after glucose loading. Fasting blood glucose (FBG) and 2-h postprandial plasma glucose (2h-PPG) were detected by using biochemical analyzer, and insulin, glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-Ⅳ(DPP-Ⅳ) were measured by using ELISA kit. Results: No significant difference in FBG and serum DPP-Ⅳ level were found between berberine groups and control group (all P>0.05). Compared with control group, serum levels of GLP-1 and insulin were increased in high-and moderate-dose berberine groups, while 2h-PPG was decreased (all P<0.05); GLP-1 levels in the intestinal samples were increased, while DPP-Ⅳ levels were decreased in all berberine groups (all P<0.05). Conclusions: Short-term berberine administration can decrease 2h-PPG level in streptozotocin-induced diabetic rat model through local inhibition of intestinal DPP-Ⅳ. The efficacy of DPP-Ⅳ inhibitor may be associated with its intestinal pharmacokinetics.
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Affiliation(s)
- Jiesheng Wang
- Department of Cadre Health, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Guanhai Dai
- Basic Laboratory, Institute of Traditional Chinese Medicine of Zhejiang Province, Hangzhou 310007, China
| | - Weijia Li
- Department of Endocrinology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China.
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Surgical cure for type 2 diabetes by foregut or hindgut operations: a myth or reality? A systematic review. Surg Endosc 2016; 31:25-37. [PMID: 27194257 DOI: 10.1007/s00464-016-4952-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 04/18/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bariatric surgery results in remission of type 2 diabetes mellitus in a significant proportion of patients. Animal research has proposed the foregut and hindgut hypotheses as possible mechanisms of remission of T2DM independent of weight loss. These hypotheses have formed the basis of investigational procedures designed to treat T2DM in non-obese (in addition to obese) patients. The aim of this study was to review the procedures that utilise the foregut and hindgut hypotheses to treat T2DM in humans. METHODS A systematic review was conducted to identify the investigational procedures performed in humans that are based on the foregut and hindgut hypotheses and then to assess their outcomes. RESULTS Twenty-four studies reported novel procedures to treat T2DM in humans; only ten utilised glycated haemoglobin A1c (HbA1c) in their definition of remission. Reported remission rates were 20-40 % for duodenal-jejunal bypass (DJB), 73-93 % for duodenal-jejunal bypass with sleeve gastrectomy (DJB-SG), 62.5-100 % for duodenal-jejunal bypass sleeve (DJBS) and 47-95.7 % for ileal interposition with sleeve gastrectomy (II-SG). When using a predetermined level of HbA1c to define remission, the remission rates were lower (27, 63, 0 and 65 %) for DJB, DJB-SG, DJBS and II-SG. CONCLUSIONS The outcomes of the foregut- and hindgut-based procedures are not better than the outcomes of just one of their components, namely sleeve gastrectomy. The complexity of these procedures in addition to their comparable outcomes to a simpler operation questions their utility.
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Röder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 2016; 48:e219. [PMID: 26964835 PMCID: PMC4892884 DOI: 10.1038/emm.2016.6] [Citation(s) in RCA: 519] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 12/03/2015] [Accepted: 12/06/2015] [Indexed: 12/11/2022] Open
Abstract
In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
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Affiliation(s)
- Pia V Röder
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore. E-mail: or
| | - Bingbing Wu
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
| | - Yixian Liu
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
| | - Weiping Han
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore. E-mail: or
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Wang F, Yang Q, Huesman S, Xu M, Li X, Lou D, Woods SC, Marziano C, Tso P. The role of apolipoprotein A-IV in regulating glucagon-like peptide-1 secretion. Am J Physiol Gastrointest Liver Physiol 2015; 309:G680-7. [PMID: 26294669 PMCID: PMC4609932 DOI: 10.1152/ajpgi.00075.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 08/14/2015] [Indexed: 01/31/2023]
Abstract
Both glucagon-like peptide-1 (GLP-1) and apolipoprotein A-IV (apoA-IV) are produced from the gut and enhance postprandial insulin secretion. This study investigated whether apoA-IV regulates nutrient-induced GLP-1 secretion and whether apoA-IV knockout causes compensatory GLP-1 release. Using lymph-fistula-mice, we first determined lymphatic GLP-1 secretion by administering apoA-IV before an intraduodenal Ensure infusion. apoA-IV changed neither basal nor Ensure-induced GLP-1 secretion relative to saline administration. We then assessed GLP-1 in apoA-IV-/- and wild-type (WT) mice administered intraduodenal Ensure. apoA-IV-/- mice had comparable lymph flow, lymphatic triglyceride, glucose, and protein outputs as WT mice. Intriguingly, apoA-IV-/- mice had higher lymphatic GLP-1 concentration and output than WT mice 30 min after Ensure administration. Increased GLP-1 was also observed in plasma of apoA-IV-/- mice at 30 min. apoA-IV-/- mice had comparable total gut GLP-1 content relative to WT mice under fasting, but a lower GLP-1 content 30 min after Ensure administration, suggesting that more GLP-1 was secreted. Moreover, an injection of apoA-IV protein did not reverse the increased GLP-1 secretion in apoA-IV-/- mice. Finally, we assessed gene expression of GLUT-2 and the lipid receptors, including G protein-coupled receptor (GPR) 40, GPR119, and GPR120 in intestinal segments. GLUT-2, GPR40 and GPR120 mRNAs were unaltered by apoA-IV knockout. However, ileal GPR119 mRNA was significantly increased in apoA-IV-/- mice. GPR119 colocalizes with GLP-1 in ileum and stimulates GLP-1 secretion by sensing OEA, lysophosphatidylcholine, and 2-monoacylglycerols. We suggest that increased ileal GPR119 is a potential mechanism by which GLP-1 secretion is enhanced in apoA-IV-/- mice.
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Affiliation(s)
- Fei Wang
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Qing Yang
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Sarah Huesman
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Min Xu
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Xiaoming Li
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Danwen Lou
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Stephen C. Woods
- 2Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio
| | - Corina Marziano
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
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Murovets VO, Bachmanov AA, Zolotarev VA. Impaired Glucose Metabolism in Mice Lacking the Tas1r3 Taste Receptor Gene. PLoS One 2015; 10:e0130997. [PMID: 26107521 PMCID: PMC4479554 DOI: 10.1371/journal.pone.0130997] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 05/27/2015] [Indexed: 01/12/2023] Open
Abstract
The G-protein-coupled sweet taste receptor dimer T1R2/T1R3 is expressed in taste bud cells in the oral cavity. In recent years, its involvement in membrane glucose sensing was discovered in endocrine cells regulating glucose homeostasis. We investigated importance of extraorally expressed T1R3 taste receptor protein in age-dependent control of blood glucose homeostasis in vivo, using nonfasted mice with a targeted mutation of the Tas1r3 gene that encodes the T1R3 protein. Glucose and insulin tolerance tests, as well as behavioral tests measuring taste responses to sucrose solutions, were performed with C57BL/6ByJ (Tas1r3+/+) inbred mice bearing the wild-type allele and C57BL/6J-Tas1r3tm1Rfm mice lacking the entire Tas1r3 coding region and devoid of the T1R3 protein (Tas1r3-/-). Compared with Tas1r3+/+ mice, Tas1r3-/- mice lacked attraction to sucrose in brief-access licking tests, had diminished taste preferences for sucrose solutions in the two-bottle tests, and had reduced insulin sensitivity and tolerance to glucose administered intraperitoneally or intragastrically, which suggests that these effects are due to absence of T1R3. Impairment of glucose clearance in Tas1r3-/- mice was exacerbated with age after intraperitoneal but not intragastric administration of glucose, pointing to a compensatory role of extraoral T1R3-dependent mechanisms in offsetting age-dependent decline in regulation of glucose homeostasis. Incretin effects were similar in Tas1r3+/+ and Tas1r3-/- mice, which suggests that control of blood glucose clearance is associated with effects of extraoral T1R3 in tissues other than the gastrointestinal tract. Collectively, the obtained data demonstrate that the T1R3 receptor protein plays an important role in control of glucose homeostasis not only by regulating sugar intake but also via its extraoral function, probably in the pancreas and brain.
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Affiliation(s)
- Vladimir O. Murovets
- Department of physiology of digestion, Pavlov Institute of Physiology, Saint-Petersburg, Russia
| | | | - Vasiliy A. Zolotarev
- Department of physiology of digestion, Pavlov Institute of Physiology, Saint-Petersburg, Russia
- * E-mail:
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Kim MJ, Hur KY. Short-term outcomes of laparoscopic single anastomosis gastric bypass (LSAGB) for the treatment of type 2 diabetes in lower BMI (<30 kg/m(2)) patients. Obes Surg 2015; 24:1044-51. [PMID: 24566662 DOI: 10.1007/s11695-014-1202-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Bariatric surgery is an efficient procedure for remission of type 2 diabetes (T2DM) in morbid obesity. However, in Asian countries, mean body mass index (BMI) of T2DM patients is about 25 kg/m(2). Various data on patients undergoing gastric bypass surgery showed that control of T2DM after surgery occurs rapidly and somewhat independent to weight loss. We hypothesized that in non-obese patients with T2DM, the glycemic control would be achieved as a consequence of gastric bypass surgery. METHODS From September 2009, the 172 patients have had laparoscopic single anastomosis gastric bypass (LSAGB) surgery. Among them, 107 patients have been followed up more than 1 year. We analyzed the dataset of these patients. Values related to diabetes were measured before and 1, 2, and 3 years after the surgery. RESULTS The mean BMI decreased during the first year after the surgery but plateaued after that. The mean glycosylated hemoglobin level decreased continuously. The mean fasting and postglucose loading plasma glucose level also decreased. CONCLUSION After LSAGB surgery in non-obese T2DM patients, the control of T2DM was possible safely and effectively. However, longer follow-up with matched control group is essential.
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Affiliation(s)
- Myung Jin Kim
- Department of Surgery, Soonchunhyang University College of Medicine, 59, Daesagwan-ro (657, Hannam-dong), Yongsan-gu, Seoul, South Korea
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Abstract
The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In humans, inactivating mutations in GLUT2 cause Fanconi-Bickel syndrome, which is characterised by hepatomegaly and kidney disease; defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology.
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Affiliation(s)
- Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Genopode Building, 1015, Lausanne, Switzerland,
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Mieczkowska A, Mansur S, Bouvard B, Flatt PR, Thorens B, Irwin N, Chappard D, Mabilleau G. Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength. Osteoporos Int 2015; 26:209-18. [PMID: 25127672 DOI: 10.1007/s00198-014-2845-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 08/07/2014] [Indexed: 12/25/2022]
Abstract
UNLABELLED A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone--and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. INTRODUCTION The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. METHODS Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. RESULTS As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. CONCLUSIONS This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.
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Affiliation(s)
- A Mieczkowska
- GEROM-LHEA UPRES EA 4658, Institut de Biologie en Santé, LUNAM Université, 4 rue larrey, 49933, Angers Cedex 09, France
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Cătoi AF, Pârvu A, Mureşan A, Busetto L. Metabolic Mechanisms in Obesity and Type 2 Diabetes: Insights from Bariatric/Metabolic Surgery. Obes Facts 2015; 8:350-63. [PMID: 26584027 PMCID: PMC5644813 DOI: 10.1159/000441259] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 09/17/2015] [Indexed: 12/11/2022] Open
Abstract
Obesity and the related diabetes epidemics represent a real concern worldwide. Bariatric/metabolic surgery emerged in last years as a valuable therapeutic option for obesity and related diseases, including type 2 diabetes mellitus (T2DM). The complicated network of mechanisms involved in obesity and T2DM have not completely defined yet. There is still a debate on which would be the first metabolic defect leading to metabolic deterioration: insulin resistance or hyperinsulinemia? Insight into the metabolic effects of bariatric/metabolic surgery has revealed that, beyond weight loss and food restriction, other mechanisms can be activated by the rearrangements of the gastrointestinal tract, such as the incretinic/anti-incretinic system, changes in bile acid composition and flow, and modifications of gut microbiota; all of them possibly involved in the remission of T2DM. The complete elucidation of these mechanisms will lead to a better understanding of the pathogenesis of this disease. Our aim was to review some of the metabolic mechanisms involved in the development of T2DM in obese patients as well as in the remission of this condition in patients submitted to bariatric/metabolic surgery.
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Affiliation(s)
- Adriana Florinela Cătoi
- Department of Functional Biosciences, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, Cluj-Napoca, Romania, Italy
| | - Alina Pârvu
- Department of Functional Biosciences, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, Cluj-Napoca, Romania, Italy
| | - Adriana Mureşan
- Department of Functional Biosciences, Faculty of Medicine, ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, Cluj-Napoca, Romania, Italy
| | - Luca Busetto
- Department of Medicine, University of Padova, Padova, Italy
- *Dr. Luca Busetto, Clinica Medica 3, Policlinico Universitario, Via Giustiniani 2, 30100 Padova, Italy
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Pabreja K, Mohd MA, Koole C, Wootten D, Furness SGB. Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation. Br J Pharmacol 2014; 171:1114-28. [PMID: 23889512 DOI: 10.1111/bph.12313] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 07/10/2013] [Accepted: 07/19/2013] [Indexed: 12/22/2022] Open
Abstract
The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long-term limitation being the eventual need for insulin replacement therapy (Table 1). Since 2007, drugs targeting the glucagon-like peptide-1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterized even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand-dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary for future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide.
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Affiliation(s)
- K Pabreja
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic., Australia
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Vallois D, Niederhäuser G, Ibberson M, Nagaray V, Marselli L, Marchetti P, Chatton JY, Thorens B. Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression. PLoS One 2014; 9:e103277. [PMID: 25058609 PMCID: PMC4110016 DOI: 10.1371/journal.pone.0103277] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 06/28/2014] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND/AIMS Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms. METHODS We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO) mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed. RESULTS Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation. CONCLUSIONS/INTERPRETATION Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes.
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Affiliation(s)
- David Vallois
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Guy Niederhäuser
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Mark Ibberson
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
- Vital-IT group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | | | - Lorella Marselli
- Department of Endocrinology and Metabolism, Ospedale di Cisanello, Pisa, Italy
| | - Piero Marchetti
- Department of Endocrinology and Metabolism, Ospedale di Cisanello, Pisa, Italy
| | - Jean-Yves Chatton
- Department of Cell Biology and Morphology, University of Lausanne, Lausanne, Switzerland
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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Role of endogenous GLP-1 and GIP in beta cell compensatory responses to insulin resistance and cellular stress. PLoS One 2014; 9:e101005. [PMID: 24967820 PMCID: PMC4072716 DOI: 10.1371/journal.pone.0101005] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 06/02/2014] [Indexed: 12/15/2022] Open
Abstract
Role of GLP-1 and GIP in beta cell compensatory responses to beta cell attack and insulin resistance were examined in C57BL/6 mice lacking functional receptors for GLP-1 and GIP. Mice were treated with multiple low dose streptozotocin or hydrocortisone. Islet parameters were assessed by immunohistochemistry and hormone measurements were determined by specific enzyme linked immunoassays. Wild-type streptozotocin controls exhibited severe diabetes, irregularly shaped islets with lymphocytic infiltration, decreased Ki67/TUNEL ratio with decreased beta cell and increased alpha cell areas. GLP-1 and GIP were co-expressed with glucagon and numbers of alpha cells mainly expressing GLP-1 were increased. In contrast, hydrocortisone treatment and induction of insulin resistance increased islet numbers and area, with enhanced beta cell replication, elevated mass of beta and alpha cells, together with co-expression of GLP-1 and GIP with glucagon in islets. The metabolic responses to streptozotocin in GLP-1RKO and GIPRKO mice were broadly similar to C57BL/6 controls, although decreases in islet numbers and size were more severe. In contrast, both groups of mice lacking functional incretin receptors displayed substantially impaired islet adaptations to insulin resistance induced by hydrocortisone, including marked curtailment of expansion of islet area, beta cell mass and islet number. Our observations cannot be explained by simple changes in circulating incretin concentrations, suggesting that intra-islet GLP-1 and GIP make a significant contribution to islet adaptation, particularly expansion of beta cell mass and compensatory islet compensation to hydrocortisone and insulin resistance.
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Abstract
Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β cells. GIP and GLP‐1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which belong to the G‐protein coupled receptor family. Receptor binding activates and increases the level of intracellular cyclic adenosine monophosphate in pancreatic β cells, thereby stimulating insulin secretion glucose‐dependently. In addition to their insulinotropic effects, GIP and GLP‐1 play critical roles in various biological processes in different tissues and organs that express GIPR and GLP‐1R, including the pancreas, fat, bone and the brain. Within the pancreas, GIP and GLP‐1 together promote β cell proliferation and inhibit apoptosis, thereby expanding pancreatic β cell mass, while GIP enhances postprandial glucagon response and GLP‐1 suppresses it. In adipose tissues, GIP but not GLP‐1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP‐1 inhibits bone absorption. In the brain, both GIP and GLP‐1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP‐1 and their insulinotropic effects on β cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects. We summarize here the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic action on pancreatic β cells, and their non‐insulinotropic effects, and discuss their potential in treatment of type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00022.x, 2010)
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Affiliation(s)
- Yutaka Seino
- The Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
| | - Mitsuo Fukushima
- The Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka ; The Department of Nutritional Science, Okayama Prefectural University, Okayama, Japan
| | - Daisuke Yabe
- The Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
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Moffett RC, Vasu S, Thorens B, Drucker DJ, Flatt PR. Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy. PLoS One 2014; 9:e96863. [PMID: 24927416 PMCID: PMC4057070 DOI: 10.1371/journal.pone.0096863] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 04/12/2014] [Indexed: 12/25/2022] Open
Abstract
Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 and PC1/3 together with significant amounts of GLP-1 and GIP were detected in alpha cells. Knockout of GLP-1R abolished these islet adaptations and paradoxically decreased pancreatic insulin, GLP-1 and GIP. This was associated with abolition of normal pregnancy-induced increases in plasma GIP, L-cell numbers, and intestinal GIP and GLP-1 stores. These data indicate that GLP-1 but not GIP is a key mediator of beta cell mass expansion and related adaptations in pregnancy, triggered in part by generation of intra-islet GLP-1.
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Affiliation(s)
- R. Charlotte Moffett
- SAAD centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, Northern Ireland
| | - Srividya Vasu
- SAAD centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, Northern Ireland
- * E-mail:
| | - Bernard Thorens
- Centre for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Daniel J. Drucker
- The Lunenfield – Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Peter R. Flatt
- SAAD centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, Northern Ireland
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Tarussio D, Metref S, Seyer P, Mounien L, Vallois D, Magnan C, Foretz M, Thorens B. Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis. J Clin Invest 2014; 124:413-24. [PMID: 24334455 PMCID: PMC3871223 DOI: 10.1172/jci69154] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 10/11/2013] [Indexed: 01/19/2023] Open
Abstract
How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function.
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Affiliation(s)
- David Tarussio
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Salima Metref
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Pascal Seyer
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Lourdes Mounien
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - David Vallois
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Christophe Magnan
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Marc Foretz
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne (UNIL), Lausanne, Switzerland.
Institut de Génomique Fonctionnelle, Montpellier, France.
Laboratoire de Physiologie et Physiopathologie du Système Nerveux Somato-Moteur et Neurovégétatif, Université EA4674 Aix-Marseille — Faculté Saint Jérôme, Marseille, France.
CNRS-University Paris Diderot, Paris, France.
Institut Cochin — INSERM U1016 — CNRS UMR8104 — Université Paris Descartes, Paris, France
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Shi Z, Tang S, Chen Y, Yang J, Jiang B, Liu X, Zhou X, Pan X, Yang J, Wu J, Hu H, Ji B, Lin X, Chen S, Zhang J. Prevalence of stress hyperglycemia among hepatopancreatobiliary postoperative patients. Int J Clin Exp Med 2013; 6:799-803. [PMID: 24179574 PMCID: PMC3798216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 09/13/2013] [Indexed: 06/02/2023]
Abstract
OBJECTIVE The aim of this study was to determine the prevalence of stress hyperglycemia and its association with mortality among hepatopancreatobiliary postoperative patients admitted. METHODS Retrospectively analysis was made on 706 cases of the hepatopancreatobiliary postoperative patients from three Grade A hospitals in Hunan province from November 2011 to June 2012, including the incidence and risk factors of patients with stress hyperglycemia. RESULTS The incidence of stress hyperglycemia of pancreatic postoperative patients was 34.28%. The incidence of pancreatic surgery, simple cholecystectomy and biliary tract and liver surgery in patients with stress hyperglycemia was 63.08%, 20.83% and 32.21%, respectively. Stress hyperglycemia was associated with the first postoperative glucose values, duration of surgery, whether the anemia and the presence or absence of hypoproteinemia (P<0.05), but was no related with sex, weight and previous history (P>0.05). CONCLUSION Stress hyperglycemia is common among emergency admissions and these patients have significantly higher mortality rate compared to other patients (P=0.001). Postoperative first blood glucose levels, duration of surgery, whether the anemia and the presence or absence of hypoproteinemia were stress hyperglycemia risk factors for patients.
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Affiliation(s)
- Zeya Shi
- School of Nursing Central South UniversityChangsha 410013, China
- People’s Hospital of Hunan ProvinceChangsha 410005, China
| | - Siyuan Tang
- School of Nursing Central South UniversityChangsha 410013, China
| | - Yuxiang Chen
- Biomedical Engineering Institute Central South UniversityChangsha 410008, China
| | - Jinxu Yang
- Luohe Medical CollegeLuohe, Henan 462002, China
| | - Bo Jiang
- People’s Hospital of Hunan ProvinceChangsha 410005, China
| | - Xiaoming Liu
- People’s Hospital of Hunan ProvinceChangsha 410005, China
| | - Xu Zhou
- People’s Hospital of Hunan ProvinceChangsha 410005, China
| | - Xiaoji Pan
- People’s Hospital of Hunan ProvinceChangsha 410005, China
| | - Juan Yang
- People’s Hospital of Hunan ProvinceChangsha 410005, China
| | - Jinshu Wu
- People’s Hospital of Hunan ProvinceChangsha 410005, China
| | - Hongjuan Hu
- School of Nursing Central South UniversityChangsha 410013, China
| | - Binbin Ji
- School of Nursing Central South UniversityChangsha 410013, China
| | - Xiaolin Lin
- School of Nursing Central South UniversityChangsha 410013, China
| | - Sanmei Chen
- School of Nursing Central South UniversityChangsha 410013, China
| | - Juan Zhang
- People’s Hospital of Hunan ProvinceChangsha 410005, China
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Taylor BL, Liu FF, Sander M. Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Rep 2013; 4:1262-75. [PMID: 24035389 DOI: 10.1016/j.celrep.2013.08.010] [Citation(s) in RCA: 232] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 07/11/2013] [Accepted: 08/05/2013] [Indexed: 02/06/2023] Open
Abstract
Recently, loss of beta-cell-specific traits has been proposed as an early cause of beta cell failure in diabetes. However, the molecular mechanisms that underlie the loss of beta cell features remain unclear. Here, we identify an Nkx6.1-controlled gene regulatory network as essential for maintaining the functional and molecular traits of mature beta cells. Conditional Nkx6.1 inactivation in adult mice caused rapid-onset diabetes and hypoinsulinemia. Genome-wide analysis of Nkx6.1-regulated genes and functional assays further revealed a critical role for Nkx6.1 in the control of insulin biosynthesis, insulin secretion, and beta cell proliferation. Over time, Nkx6.1-deficient beta cells acquired molecular characteristics of delta cells, revealing a molecular link between impaired beta cell functional properties and loss of cell identity. Given that Nkx6.1 levels are reduced in human type 2 diabetic beta cells, our study lends support to the concept that loss of beta cell features could contribute to the pathogenesis of diabetes.
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Affiliation(s)
- Brandon L Taylor
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093-0695, USA
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Terasaki M, Nagashima M, Nohtomi K, Kohashi K, Tomoyasu M, Sinmura K, Nogi Y, Katayama Y, Sato K, Itoh F, Watanabe T, Hirano T. Preventive effect of dipeptidyl peptidase-4 inhibitor on atherosclerosis is mainly attributable to incretin's actions in nondiabetic and diabetic apolipoprotein E-null mice. PLoS One 2013; 8:e70933. [PMID: 23967137 PMCID: PMC3742603 DOI: 10.1371/journal.pone.0070933] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 06/25/2013] [Indexed: 12/11/2022] Open
Abstract
Aim Several recent reports have revealed that dipeptidyl peptidase (DPP)-4 inhibitors have suppressive effects on atherosclerosis in apolipoprotein E-null (Apoe−/−) mice. It remains to be seen, however, whether this effect stems from increased levels of the two active incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Methods Nontreated Apoe−/− mice, streptozotocin-induced diabetic Apoe−/− mice, and db/db diabetic mice were administered the DPP-4 inhibitor vildagliptin in drinking water and co-infused with either saline, the GLP-1 receptor blocker, exendin(9–39), the GIP receptor blocker, (Pro3)GIP, or both via osmotic minipumps for 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages were determined. Results Vildagliptin increased plasma GLP-1 and GIP levels without affecting food intake, body weight, blood pressure, or plasma lipid profile in any of the animals tested, though it reduced HbA1c in the diabetic mice. Diabetic Apoe−/− mice exhibited further-progressed atherosclerotic lesions and foam cell formation compared with nondiabetic counterparts. Nondiabetic and diabetic Apoe−/− mice showed a comparable response to vildagliptin, namely, remarkable suppression of atherosclerotic lesions with macrophage accumulation and foam cell formation in peritoneal macrophages. Exendin(9–39) or (Pro3)GIP partially attenuated the vildagliptin-induced suppression of atherosclerosis. The two blockers in combination abolished the anti-atherosclerotic effect of vildagliptin in nondiabetic mice but only partly attenuated it in diabetic mice. Vildagliptin suppressed macrophage foam cell formation in nondiabetic and diabetic mice, and this suppressive effect was abolished by infusions with exendin(9–39)+(Pro3)GIP. Incubation of DPP-4 or vildagliptin in vitro had no effect on macrophage foam cell formation. Conclusions Vildagliptin confers a substantial anti-atherosclerotic effect in both nondiabetic and diabetic mice, mainly via the action of the two incretins. However, the partial attenuation of atherosclerotic lesions by the dual incretin receptor antagonists in diabetic mice implies that vildagliptin confers a partial anti-atherogenic effect beyond that from the incretins.
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Affiliation(s)
- Michishige Terasaki
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
| | - Masaharu Nagashima
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
| | - Kyoko Nohtomi
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
| | - Kyoko Kohashi
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
| | - Masako Tomoyasu
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
| | - Kyoko Sinmura
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
| | - Yukinori Nogi
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
| | - Yuki Katayama
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Hachioji-City, Tokyo, Japan
| | - Kengo Sato
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Hachioji-City, Tokyo, Japan
| | - Fumiko Itoh
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Hachioji-City, Tokyo, Japan
| | - Takuya Watanabe
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Hachioji-City, Tokyo, Japan
| | - Tsutomu Hirano
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
- * E-mail:
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Affiliation(s)
- Marc Y Donath
- Clinic of Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland.
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38
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Zhang C, Suckow AT, Chessler SD. Altered pancreatic islet function and morphology in mice lacking the Beta-cell surface protein neuroligin-2. PLoS One 2013; 8:e65711. [PMID: 23776533 PMCID: PMC3679192 DOI: 10.1371/journal.pone.0065711] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 05/03/2013] [Indexed: 11/24/2022] Open
Abstract
Neuroligin-2 is a transmembrane, cell-surface protein originally identified as an inhibitory synapse-associated protein in the central nervous system. Neuroligin-2 is also present on the pancreatic beta-cell surface, and there it engages in transcellular interactions that drive functional maturation of the insulin secretory machinery; these are necessary for normal insulin secretion. The effects of neuroligin-2 deficiency on brain and neuronal function and morphology and on behavior and coordination have been extensively characterized using neuroligin-2 knockout mice. The effects of absent neuroligin-2 expression on islet development and function, however, are unknown. Here, to help test whether neuroligin-2 is necessary for normal islet development, we characterized islet morphology in mice lacking neuroligin-2. To test whether–as predicted by our earlier co-culture studies–absence of neuroligin-2 impairs beta cell function, we compared glucose-stimulated insulin secretion by islets from mutant and wild-type mice. Our results show that while islets from neuroligin-2-deficient mice do not to appear to differ architecturally from wild-type islets, they are smaller, fewer in number, and contain beta cells with lower insulin content. Evaluation of transcript levels suggests that upregulation of neuroligin-1 helps compensate for loss of neuroligin-2. Surprisingly, under both basal and stimulating glucose levels, isolated islets from the knockout mice secreted more of their intracellular insulin content. Rat islets with shRNA-mediated neuroligin-2 knockdown also exhibited increased insulin secretion. Neurexin transcript levels were lower in the knockout mice and, consistent with our prior finding that neurexin is a key constituent of the insulin granule docking machinery, insulin granule docking was reduced. These results indicate that neuroligin-2 is not necessary for the formation of pancreatic islets but that neuroligin-2 influences islet size and number. Neuroligin-2–perhaps through its effects on the expression and/or activity of its binding partner neurexin–promotes insulin granule docking, a known constraint on insulin secretion.
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Affiliation(s)
- Charles Zhang
- Department of Medicine, University of California Irvine, School of Medicine, Irvine, California, United States of America
| | - Arthur T. Suckow
- Pediatric Diabetes Research Center, University of California San Diego, La Jolla, California, United States of America
| | - Steven D. Chessler
- Department of Medicine, University of California Irvine, School of Medicine, Irvine, California, United States of America
- * E-mail:
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39
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Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in β-cells. Proc Natl Acad Sci U S A 2013; 110:10004-9. [PMID: 23720317 DOI: 10.1073/pnas.1220009110] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
NHA2 is a sodium/hydrogen exchanger with unknown physiological function. Here we show that NHA2 is present in rodent and human β-cells, as well as β-cell lines. In vivo, two different strains of NHA2-deficient mice displayed a pathological glucose tolerance with impaired insulin secretion but normal peripheral insulin sensitivity. In vitro, islets of NHA2-deficient and heterozygous mice, NHA2-depleted Min6 cells, or islets treated with an NHA2 inhibitor exhibited reduced sulfonylurea- and secretagogue-induced insulin secretion. The secretory deficit could be rescued by overexpression of a wild-type, but not a functionally dead, NHA2 transporter. NHA2 deficiency did not affect insulin synthesis or maturation and had no impact on basal or glucose-induced intracellular Ca(2+) homeostasis in islets. Subcellular fractionation and imaging studies demonstrated that NHA2 resides in transferrin-positive endosomes and synaptic-like microvesicles but not in insulin-containing large dense core vesicles in β-cells. Loss of NHA2 inhibited clathrin-dependent, but not clathrin-independent, endocytosis in Min6 and primary β-cells, suggesting defective endo-exocytosis coupling as the underlying mechanism for the secretory deficit. Collectively, our in vitro and in vivo studies reveal the sodium/proton exchanger NHA2 as a critical player for insulin secretion in the β-cell. In addition, our study sheds light on the biological function of a member of this recently cloned family of transporters.
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40
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Li B, Zhou X, Wu J, Zhou H. From gut changes to type 2 diabetes remission after gastric bypass surgeries. Front Med 2013; 7:191-200. [PMID: 23553469 DOI: 10.1007/s11684-013-0258-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 01/14/2013] [Indexed: 12/18/2022]
Abstract
Increasing evidence suggests that the gut may influence the host's metabolism and ultimately change the outcomes of type 2 diabetes mellitus (T2DM). We review the evidence on the relationship between the gut and T2DM remission after gastric bypass surgery, and discuss the potential mechanisms underlying the above relationship: gut anatomical rearrangement, microbial composition changes, altered gut cells, and gut hormone modulation. However, the exact changes and their relative importance in the metabolic improvements after gastric bypass surgery remain to be further clarified. Elucidating the precise metabolic mechanisms of T2DM resolution after bypass surgery will help to reveal the molecular mechanisms of pathogenesis, and facilitate the development of novel diagnoses and preventative interventions for this common disease.
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Affiliation(s)
- Bing Li
- Key Laboratory of Systems Biology, SIBS-Novo Nordisk Translational Research Centre for PreDiabetes, Shanghai Institutes for Biological Sciences, CAS, Shanghai, China
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41
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Seyer P, Vallois D, Poitry-Yamate C, Schütz F, Metref S, Tarussio D, Maechler P, Staels B, Lanz B, Grueter R, Decaris J, Turner S, da Costa A, Preitner F, Minehira K, Foretz M, Thorens B. Hepatic glucose sensing is required to preserve β cell glucose competence. J Clin Invest 2013; 123:1662-76. [PMID: 23549084 DOI: 10.1172/jci65538] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 01/24/2013] [Indexed: 12/31/2022] Open
Abstract
Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr(-/-) mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link.
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Affiliation(s)
- Pascal Seyer
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
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42
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Harcourt BE, Penfold SA, Forbes JM. Coming full circle in diabetes mellitus: from complications to initiation. Nat Rev Endocrinol 2013; 9:113-23. [PMID: 23296171 DOI: 10.1038/nrendo.2012.236] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Glycaemic control, reduction of blood pressure using agents that block the renin-angiotensin system and control of dyslipidaemia are the major strategies used in the clinical management of patients with diabetes mellitus. Each of these approaches interrupts a number of pathological pathways, which directly contributes to the vascular complications of diabetes mellitus, including renal disease, blindness, neuropathy and cardiovascular disease. However, research published over the past few years has indicated that many of the pathological pathways important in the development of the vascular complications of diabetes mellitus are equally relevant to the initiation of diabetes mellitus itself. These pathways include insulin signalling, generation of cellular energy, post-translational modifications and redox imbalances. This Review will examine how the development of diabetes mellitus has come full circle from initiation to complications and suggests that the development of diabetes mellitus and the progression to chronic complications both require the same mechanistic triggers.
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Affiliation(s)
- Brooke E Harcourt
- Glycation and Diabetes Complications, Mater Medical Research Institute, Raymond Terrace, South Brisbane, QLD, Australia
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43
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Xie R, Everett LJ, Lim HW, Patel NA, Schug J, Kroon E, Kelly OG, Wang A, D'Amour KA, Robins AJ, Won KJ, Kaestner KH, Sander M. Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell 2013; 12:224-37. [PMID: 23318056 DOI: 10.1016/j.stem.2012.11.023] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 10/30/2012] [Accepted: 11/30/2012] [Indexed: 02/06/2023]
Abstract
Embryonic development is characterized by dynamic changes in gene expression, yet the role of chromatin remodeling in these cellular transitions remains elusive. To address this question, we profiled the transcriptome and select chromatin modifications at defined stages during pancreatic endocrine differentiation of human embryonic stem cells. We identify removal of Polycomb group (PcG)-mediated repression on stage-specific genes as a key mechanism for the induction of developmental regulators. Furthermore, we discover that silencing of transitory genes during lineage progression associates with reinstatement of PcG-dependent repression. Significantly, in vivo- but not in vitro-differentiated endocrine cells exhibit close similarity to primary human islets in regard to transcriptome and chromatin structure. We further demonstrate that endocrine cells produced in vitro do not fully eliminate PcG-mediated repression on endocrine-specific genes, probably contributing to their malfunction. These studies reveal dynamic chromatin remodeling during developmental lineage progression and identify possible strategies for improving cell differentiation in culture.
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Affiliation(s)
- Ruiyu Xie
- Department of Pediatrics and Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA 92093-0695, USA
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44
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Javorský M, Babjaková E, Klimčáková L, Schroner Z, Židzik J, Štolfová M, Šalagovič J, Tkáč I. Association between TCF7L2 Genotype and Glycemic Control in Diabetic Patients Treated with Gliclazide. Int J Endocrinol 2013; 2013:374858. [PMID: 23509454 PMCID: PMC3590634 DOI: 10.1155/2013/374858] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 01/20/2013] [Indexed: 12/25/2022] Open
Abstract
Previous studies showed associations between variants in TCF7L2 gene and the therapeutic response to sulfonylureas. All sulfonylureas stimulate insulin secretion by the closure of ATP-sensitive potassium (KATP) channel. The aim of the present study was to compare TCF7L2 genotype specific effect of gliclazide binding to KATP channel A-site (Group 1) with sulfonylureas binding to AB-site (Group 2). A total of 101 patients were treated with sulfonylureas for 6 months as an add-on therapy to the previous metformin treatment. TCF7L2 rs7903146 C/T genotype was identified by real-time PCR with subsequent melting curve analysis. Analyses using the dominant genetic model showed significantly higher effect of gliclazide in the CC genotype group in comparison with combined CT + TT genotype group (1.32 ± 0.15% versus 0.73 ± 0.11%, P (adj) = 0.005). No significant difference in ΔHbA1c between the patients with CC genotype and the T-allele carriers was observed in Group 2. In the multivariate analysis, only the TCF7L2 genotype (P = 0.006) and the baseline HbA1c (P < 0.001) were significant predictors of ΔHbA1c. After introducing an interaction term between the TCF7L2 genotype and the sulfonylurea type into multivariate model, the interaction became a significant predictor (P = 0.023) of ΔHbA1c. The results indicate significantly higher difference in ΔHbA1c among the TCF7L2 genotypes in patients treated with gliclazide than in patients treated with glimepiride, glibenclamide, or glipizide.
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Affiliation(s)
- Martin Javorský
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
| | - Eva Babjaková
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
| | - Lucia Klimčáková
- Department of Medical Biology, Faculty of Medicine, P. J. Šafárik University in Košice, 040 66 Košice, Slovakia
| | - Zbynek Schroner
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
| | - Jozef Židzik
- Department of Medical Biology, Faculty of Medicine, P. J. Šafárik University in Košice, 040 66 Košice, Slovakia
| | - Mária Štolfová
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
| | - Ján Šalagovič
- Department of Medical Biology, Faculty of Medicine, P. J. Šafárik University in Košice, 040 66 Košice, Slovakia
| | - Ivan Tkáč
- Department of Internal Medicine 4, Faculty of Medicine, L. Pasteur University Hospital, P. J. Šafárik University in Košice, 041 90 Košice, Slovakia
- *Ivan Tkáč:
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45
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Yang Y, Chang BHJ, Chan L. Sustained expression of the transcription factor GLIS3 is required for normal beta cell function in adults. EMBO Mol Med 2012. [PMID: 23197416 PMCID: PMC3569656 DOI: 10.1002/emmm.201201398] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Genome-wide association studies identified GLIS3 as a susceptibility locus for type 1 and type 2 diabetes. Global Glis3 deficiency in mice leads to congenital diabetes and neonatal lethality. In this study, we explore the role of Glis3 in adulthood using Glis3+/− and conditional knockout animals. We challenged Glis3+/− mice with high fat diet for 20 weeks and found that they developed diabetes because of impaired beta cell mass expansion. GLIS3 controls beta cell proliferation in response to high-fat feeding at least partly by regulating Ccnd2 transcription. To determine if sustained Glis3 expression is essential to normal beta cell function, we generated Glis3fl/fl/Pdx1CreERT+ animal by intercrossing Glis3fl/fl mice with Pdx1CreERT+ mice and used tamoxifen (TAM) to induce Glis3 deletion in adults. Adult Glis3fl/fl/Pdx1CreERT+ mice are euglycaemic. TAM-mediated beta cell-specific inactivation of Glis3 in adult mice downregulates insulin expression, leading to hyperglycaemia and subsequently enhanced beta cell apoptosis. We conclude that normal Glis3 expression is required for pancreatic beta cell function and mass maintenance during adulthood, which impairment leads to diabetes in adults.
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Affiliation(s)
- Yisheng Yang
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine, Houston, TX, USA
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46
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Geraedts MCP, Takahashi T, Vigues S, Markwardt ML, Nkobena A, Cockerham RE, Hajnal A, Dotson CD, Rizzo MA, Munger SD. Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery. Am J Physiol Endocrinol Metab 2012; 303:E464-74. [PMID: 22669246 PMCID: PMC3423100 DOI: 10.1152/ajpendo.00163.2012] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 06/05/2012] [Indexed: 01/06/2023]
Abstract
The glucose-dependent secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) is a critical step in the regulation of glucose homeostasis. Two molecular mechanisms have separately been suggested as the primary mediator of intestinal glucose-stimulated GLP-1 secretion (GSGS): one is a metabotropic mechanism requiring the sweet taste receptor type 2 (T1R2) + type 3 (T1R3) while the second is a metabolic mechanism requiring ATP-sensitive K(+) (K(ATP)) channels. By quantifying sugar-stimulated hormone secretion in receptor knockout mice and in rats receiving Roux-en-Y gastric bypass (RYGB), we found that both of these mechanisms contribute to GSGS; however, the mechanisms exhibit different selectivity, regulation, and localization. T1R3(-/-) mice showed impaired glucose and insulin homeostasis during an oral glucose challenge as well as slowed insulin granule exocytosis from isolated pancreatic islets. Glucose, fructose, and sucralose evoked GLP-1 secretion from T1R3(+/+), but not T1R3(-/-), ileum explants; this secretion was not mimicked by the K(ATP) channel blocker glibenclamide. T1R2(-/-) mice showed normal glycemic control and partial small intestine GSGS, suggesting that T1R3 can mediate GSGS without T1R2. Robust GSGS that was K(ATP) channel-dependent and glucose-specific emerged in the large intestine of T1R3(-/-) mice and RYGB rats in association with elevated fecal carbohydrate throughout the distal gut. Our results demonstrate that the small and large intestines utilize distinct mechanisms for GSGS and suggest novel large intestine targets that could mimic the improved glycemic control seen after RYGB.
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Affiliation(s)
- Maartje C P Geraedts
- Division of Endocrinology, Diabetes, and Nutrition, Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
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47
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Physiology and emerging biochemistry of the glucagon-like peptide-1 receptor. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:470851. [PMID: 22666230 PMCID: PMC3359799 DOI: 10.1155/2012/470851] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2011] [Accepted: 01/25/2012] [Indexed: 12/16/2022]
Abstract
The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators.
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Roy SAB, Langlois MJ, Carrier JC, Boudreau F, Rivard N, Perreault N. Dual regulatory role for phosphatase and tensin homolog in specification of intestinal endocrine cell subtypes. World J Gastroenterol 2012; 18:1579-89. [PMID: 22529686 PMCID: PMC3325523 DOI: 10.3748/wjg.v18.i14.1579] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Revised: 02/06/2012] [Accepted: 02/26/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the impact of phosphatase and tensin homolog (Pten) in the specification of intestinal enteroendocrine subpopulations.
METHODS: Using the Cre/loxP system, a mouse with conditional intestinal epithelial Pten deficiency was generated. Pten mutant mice and controls were sacrificed and small intestines collected for immunofluorescence and quantitative real-time polymerase chain reaction. Blood was collected on 16 h fasted mice by cardiac puncture. Enzyme-linked immunosorbent assay was used to measure blood circulating ghrelin, somatostatin (SST) and glucose-dependent insulinotropic peptide (GIP) levels.
RESULTS: Results show an unexpected dual regulatory role for epithelial Pten signalling in the specification/differentiation of enteroendocrine cell subpopulations in the small intestine. Our data indicate that Pten positively regulates chromogranin A (CgA) expressing subpopulations, including cells expressing secretin, ghrelin, gastrin and cholecystokinin (CCK). In contrast, Pten negatively regulates the enteroendocrine subtype specification of non-expressing CgA cells such as GIP and SST expressing cells.
CONCLUSION: The present results demonstrate that Pten signalling favours the enteroendocrine progenitor to specify into cells expressing CgA including those producing CCK, gastrin and ghrelin.
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49
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Laferrère B. Gut feelings about diabetes. ACTA ACUST UNITED AC 2012; 59:254-60. [PMID: 22386248 DOI: 10.1016/j.endonu.2012.01.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 01/09/2012] [Indexed: 01/14/2023]
Abstract
Studies of patients going into diabetes remission after gastric bypass surgery have demonstrated the important role of the gut in glucose control. The improvement of type 2 diabetes after gastric bypass surgery occurs via weight dependent and weight independent mechanisms. The rapid improvement of glucose levels within days after the surgery, in relation to change of meal pattern, rapid nutrient transit, enhanced incretin release and improved incretin effect on insulin secretion, suggest mechanisms independent of weight loss. Alternatively, insulin sensitivity improves over time as a function of weight loss. The role of bile acids and microbiome in the metabolic improvement after bariatric surgery remains to be determined. While most patients after bariatric surgery experienced sustained weight loss and improved metabolism, small scale studies have shown weight regain and diabetes relapse, the mechanisms of which remain unknown.
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Affiliation(s)
- Blandine Laferrère
- Obesity Nutrition Research Center, St. Luke's/Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
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50
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Abstract
Gastric bypass surgery (GBP) results in important and sustained weight loss and remarkable improvement of Type 2 diabetes. The favorable change in the incretin gut hormones is thought to be responsible, in part, for diabetes remission after GBP, independent of weight loss. However, the relative role of the change in incretins and of weight loss is difficult to differentiate. After GBP, the plasma concentrations of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide increase postprandially by three- to fivefold. The postprandial incretin effect on insulin secretion, blunted in diabetes, improves rapidly after the surgery. In addition to the change in incretins, the pattern of insulin secretion in response to oral glucose changes after GBP, with recovery of the early phase and significant decrease in postprandial glucose levels. These changes were not seen after an equivalent weight loss by diet. The improved insulin release and glucose tolerance after GBP were shown by others to be blocked by the administration of a GLP-1 antagonist, demonstrating that the favorable metabolic changes after GBP are, in part, GLP-1 dependent. The improved incretin levels and effect persist years after GBP, but their long-term effect on glucose metabolism, and on hypoglycemia post GBP are yet unknown. Understanding the mechanisms by which incretin release is exaggerated postprandially after GBP may help develop new less invasive treatment options for obesity and diabetes. Changes in rate of eating, gastric emptying, intestinal transit time, nutrient absorption and sensing, as well as bile acid metabolism, may all be implicated.
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Affiliation(s)
- B Laferrère
- New York Obesity Nutrition Research Center, Division of Endocrinology and Diabetes, Department of Medicine, St Luke's Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 10025, USA.
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