DOCSLIB.ORG

Pvhl Is a Regulator of Glucose Metabolism and Insulin Secretion in Pancreatic ␤ Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pvhl Is a Regulator of Glucose Metabolism and Insulin Secretion in Pancreatic ␤ Cells Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic ␤ cells Jens Zehetner,1 Carsten Danzer,1,5 Stephan Collins,2,5 Katrin Eckhardt,1 Philipp A. Gerber,1 Pia Ballschmieter,1 Juris Galvanovskis,2 Kenju Shimomura,3 Frances M. Ashcroft,3 Bernard Thorens,4 Patrik Rorsman,2 and Wilhelm Krek1,6 1Institute of Cell Biology and Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, 8093 Zurich, Switzerland; 2Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; 3Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom; 4Department of Physiology and Center for Integrative Genomics, University Lausanne, 1015 Lausanne, Switzerland Insulin secretion from pancreatic ␤ cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1␣, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL–HIF1␣ pathway in the control of ␤-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in ␤ cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca2+ concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1␣ rescued these phenotypes, implying that they are the result of HIF1␣ activation. Together, these results identify pVHL and HIF1␣ as key regulators of insulin secretion from pancreatic ␤ cells. They further suggest that changes in the metabolic strategy of glucose metabolism in ␤ cells have profound effects on whole-body glucose homeostasis. [Keywords: HIF; VHL; glucose intolerance; islet; pancreas] Supplemental material is available at http://www.genesdev.org. Received July 14, 2008; revised version accepted September 5, 2008. During adulthood, cell type-specific growth that exceeds oxygen supply provided by the vasculature. An immedi- the normal physiological constraints is a common fea- ate consequence of decreased tissue oxygen availability ture of adaptive processes of tissues to changes in meta- is that cells shift cellular fuel metabolism from mito- bolic homeostasis and underlies the development of chondrial respiration to glycolysis and activate an angio- many human diseases, including cancer, heart disease, genic program to increase oxygen delivery in order to and diabetes (De Boer et al. 2003; Bouwens and Rooman overcome the imbalance between tissue mass and vas- 2005). Adaptive cell mass expansion, whether neoplastic cularization (Semenza 2001; Brahimi-Horn et al. 2007). or nonneoplastic, creates a requirement for compensa- In this way, tissue function is supported and further tory neovascularization to supply oxygen, metabolic mass expansion can occur. substances, and growth/survival factors to the growing At the molecular level, the central regulators of the tissue (Marti 2005). Therefore, adaptive cell growth re- cellular response to low-oxygen availability are the hyp- sponses are generally accompanied, at least initially, by oxia-inducible transcription factors (HIF). HIF are het- relative states of hypoxia as a result of a mismatch be- erodimeric transcription factors composed of HIF1␣, tween oxygen demand caused by tissue expansion and HIF2␣, or HIF3␣ (collectively HIF␣) and HIF␤/ARNT (Aryl hydrocarbon receptor nuclear translocator) sub- units. While the latter is constitutively expressed and stable, HIF␣ subunits are rapidly degraded under nor- 5These authors contributed equally to this work. moxia due to prolylhydroxylase activity, which marks 6Corresponding author. E-MAIL [email protected]; FAX 41-44-633-1357. them for recognition by the von Hippel-Lindau (VHL) Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.496908. tumor suppressor ubiquitin ligase complex, targeting GENES & DEVELOPMENT 22:3135–3146 © 2008 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/08; www.genesdev.org 3135 Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Zehetner et al. them for ubiquitination and proteasomal degradation mouse models in which the Vhlh and Hif1␣ genes are (Schofield and Ratcliffe 2004). Hypoxia leads to a stabi- conditionally inactivated (singly or in combination) in ␤ lization of HIF␣, dimerization with constitutively ex- cells. Our results suggest that HIF1␣ activation mediates pressed HIF␤/ARNT subunits, and the activation of hyp- metabolic reprogramming of ␤ cells to a glycolytic form oxia-inducible genes, whose products play key roles in of ATP production, causing a switch from regulated to the regulation of diverse processes including angiogene- constitutive increased basal and impaired glucose-stimu- sis, glucose uptake, and the conversion of cellular me- lated insulin secretion, hallmarks of type 2 diabetes. tabolism from a mitochondrial oxidative toward a glyco- lytic form of ATP production (Fantin et al. 2006; Kim et al. 2006; Papandreou et al. 2006). There is evidence to Results suggest that HIF1␣ preferentially activates genes impor- tant for glycolysis, while HIF2␣ favors genes involved in Deletion of Vhlh leads to the accumulation angiogenesis (Hu et al. 2003; Rankin et al. 2008). Finally, of transcriptionally active HIF1␣ in ␤ cells in addition to the well-established activation of HIF␣ in response to oxygen availability, there is accumulating The mRNAs of Vhlh and Hif1␣ are highly enriched in evidence for hypoxia-independent mechanisms of HIF1␣ islets of wild-type (wt) mice (hereafter referred to as con- expression. For example, high levels of HIF1␣ expression trol) compared with total pancreas as evidenced by real- have been observed under well-oxygenated conditions in time PCR analysis (Fig. 1A). Also, the heterodimeriza- response to growth factor stimulation (Hellwig-Burgel et tion partner of Hif1␣, Hif1␤/ARNT, is expressed in pan- al. 2005). Growth factor-mediated up-regulation of creatic ␤ cells (Supplemental Fig. S1). In addition, HIF1␣ expression has been implicated to promote glu- confocal immunofluorescence (IF) microscopy demon- cose uptake and a form of metabolism that is referred to strated that pVHL colocalizes predominantly with the as “aerobic glycolysis” to better meet the bioenergetic insulin-producing ␤ cells (Fig. 1B). ARNT colocalizes as needs associated with growth and proliferation (Lum et well with ␤ cells (Supplemental Fig. S1). Thus, Vhlh, al. 2007). Hif1␣, and Arnt are principally expressed in mouse is- Pancreatic ␤ cells display significant plasticity in re- lets. To investigate the physiological effects of Vhlh de- sponse to changes in metabolic homeostasis (Bouwens and letion in pancreatic ␤ cells, mice with a loxP-flanked Rooman 2005). The mass of ␤ cells is known to increase Vhlh allele were crossed to Rip2-Cre transgenic mice during pregnancy, to compensate for the increased meta- carrying the Cre-recombinase under the rat insulin pro- bolic load of a developing fetus (Van Assche et al. 1978), moter (Herrera 2000). This transgene induces Cre-medi- and in nondiabetic obese individuals, as part of an adap- ated recombination specifically in pancreatic ␤ cells. De- tive response to increased metabolic load and obesity- letion of Vhlh in pancreatic islets of Rip2-Cre; Vhlhfl/fl associated insulin resistance (Prentki and Nolan 2006), mice (hereafter referred to as Vhlh−/−) was confirmed by thereby maintaining a balance between metabolic de- PCR-mediated detection of the recombined Vhlh allele, mand and insulin supply. Conversely, when ␤ cells fail as identical sized bands were generated by these PCR to respond to the body’s insulin demand, type 2 diabetes reactions as from kidney DNA derived from a kidney- results (Rhodes 2005). Thus, adaptive changes in func- specific Vhlh−/− mouse model (Fig. 1C; Frew et al. 2008). tional ␤-cell mass is key to maintaining systemic eugly- Immunohistochemical analysis of islets of 26-wk-old cemia. Vhlh−/− mice revealed strong nuclear accumulation of In this regard, gene expression analysis of prediabetic HIF1␣ (Fig. 1D, insert). High levels of the HIF␣ target and diabetic Zucker diabetic fatty (ZDF) rats, which protein glucose transporter 1 (SLC2A1; also referred to as carry a mutation in the leptin receptor gene and serve as GLUT1) were also observed (Fig. 1D). Neither the overall a model for ␤-cell mass adaptation and decompensation morphology nor staining for insulin or glucagon was de- during progression of type 2 diabetes, revealed that cer- tectably affected by deletion of Vhlh (Fig. 1D). Immuno- tain hypoxia-inducible target genes become activated at blotting of purified islets of Vhlh−/− mice confirmed that the prediabetic stage, coinciding with adaptive ␤-cell Vhlh was efficiently deleted and that HIF1␣ and SLC2A1 mass expansion (Li et al. 2006). The hypoxia-inducible
Load more

Recommended publications
  • Benjamin Woodworth & Cameron Rhode Designer Daniel Grove Cover Photographer
    UMBC REVIEW JOURNAL OF UNDERGRADUATE RESEARCH 2015 vol.16 Sand (12 cm) (12 (15 cm) (15 Gravel (12 cm) (12 (15 cm) (15 Gravel Sand (15 cm) Sand 27 cm ↕ © Copyright 2015 University of Maryland, 27 cm 27 BaltimoreGravel County All rights reserved cm 27 (12EDITORS cm) Benjamin Woodworth & Cameron Rhode DESIGNER Daniel Grove COVER PHOTOGRAPHER Katrina Janson (12 cm) (12 (15 cm) (15 (12 cm) (12 Gravel (15 cm) (15 Gravel Sand Sand 27 cm 27 27 cm 27 Sand (15 cm) 27 cm 16 vol. 2015 GravelSand (15(12 cm)cm) 27 cm RESEARCH UNDERGRADUATE UNDERGRADUATE JOURNAL OF OF JOURNAL UMBC REVIEW UMBC GravelSand ↕ (15(12 cm) ↕ 27 cm Gravel (12 cm) TABLE OF CONTENTS Kendall Queen Modeling the Building Blocks of the Pancreatic Islet: 10 Connecting a-, b-, and d-cells Hollie Adejumo Evaluating the Ability of Low-Tech Processes to Remove 36 Bacterial Contaminants from Drinking Water in Kenya Sarah Klimek The Tragedy of Reluctant Compassion: Jewish Child Refugees 48 and Britain’s Kindertransport Program before the Second World War Boris Tizenberg 78 Darwinism and Moral Realism Alexis Rubin Effects of Social Skills on Hearing-Impaired Children’s 90 Academic Achievement: A Mediation Analysis Hannah Jones Philanthropy and Reputation in the Lives of Joseph 108 Townsend and Baltimore’s “public spirited citizens” Ryan Kotowski Reanalysis of Modern Colloquial French Subject Clitics 138 as Agreement Features Alexa White Residential Waste Analysis and Achieving Understanding 168 of Waste Management Infrastructure for Improving Sustainability at a University Caitlyn Leiter-Mason Evaluating the Success of Question 6: 190 A Case Study of Abortion Politics in Maryland, 1990-1992 Alana Lescure The Role of RpS9 in Ribosome Assembly and rRNA 210 Processing in Saccharomyces cerevisiae 6 UMBC REVIEW 2015 vol.16 EDITORS’ INTRODUCTION Since 2000, the UMBC Review: Journal of Undergraduate Research has been a unique outlet to showcase research from UMBC students working with UMBC faculty.
    [Show full text]
  • Women Physiologists
    Women physiologists: Centenary celebrations and beyond physiologists: celebrations Centenary Women Hodgkin Huxley House 30 Farringdon Lane London EC1R 3AW T +44 (0)20 7269 5718 www.physoc.org • journals.physoc.org Women physiologists: Centenary celebrations and beyond Edited by Susan Wray and Tilli Tansey Forewords by Dame Julia Higgins DBE FRS FREng and Baroness Susan Greenfield CBE HonFRCP Published in 2015 by The Physiological Society At Hodgkin Huxley House, 30 Farringdon Lane, London EC1R 3AW Copyright © 2015 The Physiological Society Foreword copyright © 2015 by Dame Julia Higgins Foreword copyright © 2015 by Baroness Susan Greenfield All rights reserved ISBN 978-0-9933410-0-7 Contents Foreword 6 Centenary celebrations Women in physiology: Centenary celebrations and beyond 8 The landscape for women 25 years on 12 "To dine with ladies smelling of dog"? A brief history of women and The Physiological Society 16 Obituaries Alison Brading (1939-2011) 34 Gertrude Falk (1925-2008) 37 Marianne Fillenz (1924-2012) 39 Olga Hudlická (1926-2014) 42 Shelagh Morrissey (1916-1990) 46 Anne Warner (1940–2012) 48 Maureen Young (1915-2013) 51 Women physiologists Frances Mary Ashcroft 56 Heidi de Wet 58 Susan D Brain 60 Aisah A Aubdool 62 Andrea H. Brand 64 Irene Miguel-Aliaga 66 Barbara Casadei 68 Svetlana Reilly 70 Shamshad Cockcroft 72 Kathryn Garner 74 Dame Kay Davies 76 Lisa Heather 78 Annette Dolphin 80 Claudia Bauer 82 Kim Dora 84 Pooneh Bagher 86 Maria Fitzgerald 88 Stephanie Koch 90 Abigail L. Fowden 92 Amanda Sferruzzi-Perri 94 Christine Holt 96 Paloma T. Gonzalez-Bellido 98 Anne King 100 Ilona Obara 102 Bridget Lumb 104 Emma C Hart 106 Margaret (Mandy) R MacLean 108 Kirsty Mair 110 Eleanor A.
    [Show full text]
  • Phosphatidylinositol 4-Kinase Serves As a Metabolic Sensor and Regulates Priming of Secretory Granules in Pancreatic ␤ Cells
    Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic ␤ cells Hervør L. Olsen*, Marianne Høy*, Wei Zhang†, Alejandro M. Bertorello‡, Krister Bokvist*§, Kirsten Capito¶, Alexander M. Efanov‡§, Bjo¨ rn Meister†, Peter Thams¶, Shao-Nian Yang‡, Patrik Rorsmanʈ, Per-Olof Berggren‡, and Jesper Gromada*§** *Islet Cell Physiology, Novo Nordisk A͞S, Novo Alle, DK-2880 Bagsvaerd, Denmark; †Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden; ‡The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; ¶Department of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark; and ʈDepartment of Physiological Sciences, Lund University, BMC F11, SE-22184 Lund, Sweden Communicated by Rolf Luft, Karolinska Hospital, Stockholm, Sweden, March 5, 2003 (received for review November 15, 2002) Insulin secretion is controlled by the ␤ cell؅s metabolic state, and uting to the acquisition of fusion competence (6, 7). The the ability of the secretory granules to undergo exocytosis in- activities of these kinases, which lead to the sequential synthesis creases during glucose stimulation in a membrane potential-inde- of PI 4-phosphate [PI(4)P] and PI 4,5-bisphosphate [PI(4,5)P2], pendent fashion. Here, we demonstrate that exocytosis of insulin- have been proposed to account for at least part of the require- containing secretory granules depends on phosphatidylinositol ment for Mg-ATP in the priming process (6, 7). PI(4,5)P2 binds 4-kinase (PI 4-kinase) activity and that inhibition of this enzyme specifically to the Ca2ϩ-dependent activator protein for secretion suppresses glucose-stimulated insulin secretion.
    [Show full text]
  • Glucagon Secretion from Pancreatic A-Cells
    UPSALA JOURNAL OF MEDICAL SCIENCES, 2016 VOL. 121, NO. 2, 113–119 http://dx.doi.org/10.3109/03009734.2016.1156789 REVIEW ARTICLE Glucagon secretion from pancreatic a-cells Linford Brianta, Albert Salehib, Elisa Vergaria, Quan Zhanga and Patrik Rorsmana,b aOxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; bMetabolic Research, Department of Physiology, Institute of Neuroscience and Physiology, University of G€oteborg, G€oteborg, Sweden ABSTRACT ARTICLE HISTORY Type 2 diabetes involves a menage a trois of impaired glucose regulation of pancreatic hormone Received 3 February 2016 release: in addition to impaired glucose-induced insulin secretion, the release of the hyperglycaemic Accepted 16 February 2016 hormone glucagon becomes dysregulated; these last-mentioned defects exacerbate the metabolic con- sequences of hypoinsulinaemia and are compounded further by hypersecretion of somatostatin (which KEYWORDS inhibits both insulin and glucagon secretion). Glucagon secretion has been proposed to be regulated by diabetes; electrophysiology; experimental diabetes; either intrinsic or paracrine mechanisms, but their relative significance and the conditions under which glucagon; intrinsic they operate are debated. Importantly, the paracrine and intrinsic modes of regulation are not mutually mechanisms; pancreatic exclusive; they could operate in parallel to control glucagon secretion. Here we have applied mathemat- alpha-cells; paracrine ical modelling of a-cell electrical activity as a novel means of dissecting the processes that underlie metabolic regulation of glucagon secretion. Our analyses indicate that basal hypersecretion of somato- statin and/or increased activity of somatostatin receptors may explain the loss of adequate counter- regulation under hypoglycaemic conditions, as well as the physiologically inappropriate stimulation of glucagon secretion during hyperglycaemia seen in diabetic patients.
    [Show full text]
  • Pancreatic Beta Cells Results from Glucose Insensitivity Of
    Proc. Nati. Acad. Sci. USA Vol. 86, pp. 4505-4509, June 1989 Cell Biology Failure of glucose to elicit a normal secretory response in fetal pancreatic beta cells results from glucose insensitivity of the ATP-regulated K+ channels PATRIK RORSMAN*, PER ARKHAMMARt, KRISTER BOKVIST*, CLAES HELLERSTROMt, THOMAS NILSSONtt, MICHAEL WELSHt, NILS WELSHt, AND PER-OLOF BERGGRENt* *Department of Medical Physics, Box 33031, Gothenburg University, S-400 33, Gothenburg, Sweden; tDepartment of Medical Cell Biology, Box 571, Biomedicum, University of Uppsala, S-751 23, Uppsala, Sweden; and tDepartment of Endocrinology, Box 60500, Karolinska Institute, Karolinska Hospital, S-104 01, Stockholm, Sweden Communicated by Jan G. Waldenstrom, February 27, 1989 (receivedfor review December 22, 1988) ABSTRACT Fetal pancreatic beta cells demonstrate a MATERIALS AND METHODS deficient insulin release in response to glucose, but the under- lying mechanism at the cellular level is unknown. By using beta Preparation and Dispersion ofFetal Pancreatic Islets as Well cells from 21-day fetal rats we made an attempt to clarify the as Measurements of Insulin Release. Fetal rat islets were mechanism(s) behind this reduced glucose response. In addi- isolated from 21-day pregnant rats as in Hellerstrom et al. tion to measuring insulin release, glucose metabolism, and (21). The islets were collected after 1 day of culture in RPMI cellular ATP content, ATP-regulated K+ channels (G channels) 1640 medium containing 11 mM glucose, 10%o (vol/vol) fetal and voltage-activated Ca2+ currents were investigated with the bovine serum, 100 international units of penicillin per ml, 100 patch-clamp technique. It was thus demonstrated that the ,ug of streptomycin per ml, and 50 ,ug of gentamycin per ml.
    [Show full text]
  • Patrik Rorsman Its Early-Career Fellowship Programme
    CAREERS SWEDEN TURNING POINT Basic-research boost One of Sweden’s largest private research funders has awarded the first 30 grants in Patrik Rorsman its early-career fellowship programme. The Wallenberg Academy Fellows initiative of the Knut and Alice Wallenberg Foundation Physiologist Patrik Rorsman accepted a in Stockholm aims to “kick-start” Swedish prestigious 7-year, Can$10-million (US$10- science, especially basic research, says million) grant to serve as the Canadian Göran Sandberg, the foundation’s executive Excellence in Research Chair in Diabetes at director. “Sweden is still performing well, the University of Alberta in Edmonton. But but we need young people to focus on last autumn, after seven months in the post, science,” he says. At least 250 fellows across he returned to the University of Oxford, UK, all disciplines will be funded. Researchers forgoing the generous funding. in and outside Sweden are nominated by Swedish universities, which will hire them What persuaded you to accept the Canadian as faculty members if they are selected. Excellence in Research Chair? Grantees receive 7.5 million kronor I’m a bit of a gypsy as a scientist. I had made (US$1.1 million) over 5 years, with the two other big moves before settling at Oxford. potential for a 5-year renewal. Applications So when Alberta approached me with sig- for the next round are due by 1 March. nificant funding and plans to spend mil- lions expanding their facilities, I was easily seduced. A former postdoc and valued col- UNITED KINGDOM league of mine, Patrick McDonald, is now a was in Canada.
    [Show full text]
  • År 2017 Årgång 30 Nr 6-7 DIABETOLOGNYTT Medlemstidning För Svensk Förening För Diabetologi
    År 2017 Årgång 30 Nr 6-7 DIABETOLOGNYTT Medlemstidning för Svensk Förening för Diabetologi År 2017 Årgång 30 Nr 6-7 Höstnumret Ordföranden har ordet 150 Redaktören har ordet 152 NDR-Nytt 153 Diabetesproil Claes-Göran Östensson 154 Sett & Hört 160 Ny ADA-standard för diabetesutbildning 162 Managing diabetes in pre-school ISPAD Guidelines 170 Better quick screening för monogenic diabetes 192 Sveriges första TV-Gala till förmån för diabetes 14/11 199 TLV kan lära av Frankrike kring implementering av Libre 202 Exercise Management in T1DM Consensus 215 ADA rapporter från amerikanska diabetesmötet 229 LCHF till T1DM barn är en livsfara 257 Recension böcker 265 Endo-diabetesmötet i Göteborg 7-9/3 2018 267 Res med SFD till ATTD, ADA, EASD, ISPAD 272 Kongress- och möteskalender 276 Redaktör Adress till redaktionen Internet Doc Stig Attvall Doc Stig Attvall www.diabetolognytt.com [email protected] Diabetescentrum, Blå Stråket 5 www.dagensdiabetes.se SU/Sahlgrenska med dagliga uppdateringar av Ansvarig utgivare 413 45 Göteborg diabetesnyheter David Nathanson VO internmedicin, Medlemsavgift Nästa nummer av DiabetologNytt Södersjukhuset 200:– per år Planerad utgivning 180215 Sjukhusbacken 10, Deadline för bidrag 180115 118 83 Stockholm Bankgiro 5662-5577 Tryck & layout Annonsansvarig Swishkonto Litorapid Media AB [email protected] 123 084 9125 Miljömärkt Trycksak 3041 0834 www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 149 Ordföranden har ordet Övergången från sommar till höst Lund SUS är ny vetenskaplig se- För att bli ännu bättre på att brukar kännas lättare när de ar- kreterare i SFD. kommunicera viktiga händelser betsuppgifter som ligger framför Styrelsen hade en öppen dis- i svensk diabetesvård och forsk- oss är spännande och utvecklan- kussion om SFDs strategiska mål ning, så vill SFD satsa mer på de.
    [Show full text]
  • Gs/Gq Signaling Switch in Β Cells Defines Incretin Effectiveness in Diabetes
    Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes Okechi S. Oduori, … , Patrik Rorsman, Susumu Seino J Clin Invest. 2020. https://doi.org/10.1172/JCI140046. Research Article Endocrinology Metabolism Graphical abstract Find the latest version: https://jci.me/140046/pdf The Journal of Clinical Investigation RESEARCH ARTICLE Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes Okechi S. Oduori,1 Naoya Murao,1 Kenju Shimomura,2 Harumi Takahashi,1 Quan Zhang,3 Haiqiang Dou,4 Shihomi Sakai,1 Kohtaro Minami,1 Belen Chanclon,4 Claudia Guida,3 Lakshmi Kothegala,4 Johan Tolö,4 Yuko Maejima,2 Norihide Yokoi,1,5 Yasuhiro Minami,6 Takashi Miki,1 Patrik Rorsman,3,4 and Susumu Seino1 1Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan. 2Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan. 3Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom. 4Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden. 5Laboratory of Animal Breeding and Genetics, Division of Applied Biosciences, Kyoto University Graduate School of Agriculture, Kyoto, Japan. 6Division of Cell Physiology, Kobe University Graduate School of Medicine, Kobe, Japan. By restoring glucose-regulated insulin secretion, glucagon-like peptide-1–based (GLP-1–based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic β cells. However, the reason why only GLP-1–based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved.
    [Show full text]
  • Oscillations, Intercellular Coupling, and Insulin Secretion in Pancreatic Β Cells Patrick E
    Primer Oscillations, Intercellular Coupling, and Insulin Secretion in Pancreatic β Cells Patrick E. MacDonald, Patrik Rorsman* t’s easy to say we are what we eat, but this simple state and resulted in diabetes. Therefore, TGF-β is important statement belies the complexity of metabolic signalling for maintaining the functional characteristics of β cells. Ithat goes into balancing food intake with energy In type 1 diabetes, the less common but more severe expenditure. One hormone in particular—insulin—is form of the disease, pancreatic β cells are destroyed by a critically important regulator of whole body energy an autoimmune reaction. Type 2 diabetes accounts for metabolism. It is secreted from the pancreas when blood greater than 85% of the cases of diabetes. In this form of glucose levels are high, and it acts to maintain glucose the disease, the β cells persist, but for reasons that remain homeostasis by promoting glucose uptake and storage in to be established they fail to secrete insulin in suffi cient muscle, fat, and liver. When insulin secretion is absent or quantities to maintain blood glucose within the normal reduced, or when peripheral tissues fail to respond to insulin, range. Disrupted insulin secretion is observed prior to the result is hyperglycaemia leading ultimately to diabetes. onset of type 2 diabetes [4], and when combined with the Diabetes affects more than 170 million people worldwide and development of insulin resistance in peripheral tissues, results is associated with several long-term complications including in chronic hyperglycaemia. Further deterioration of β cell nerve damage, kidney failure, microcirculatory impairment, function contributes to the progression of type 2 diabetes and a greater risk for heart disease and stroke.
    [Show full text]
  • Lectures and Seminars, Michaelmas Term 2010
    Thursday 6 ocTober 2010 • suPPLeMeNT (1) To No. 4928 • VoL 141 Gazette Supplement Lectures and Seminars, Michaelmas Term 2010 Principal Lectures Inaugural lecture: Professor in the analysis of Partial differential equations 67 sydney ball Lecture 67 cyril Foster Lecture 67 harmsworth Lecture 67 hensley henson Lectures 67 John G. Winant Visiting Professor of american Government lecture 67 brasenose humanitas Visiting Professor of architecture 67 hudson Lecture 67 changing character of War annual lecture 67 dorothy rowe Memorial Lecture 67 The annual ronald syme Lecture 67 european research council (erc) funding schemes presentation 67 Divisions, Departments and Faculties english Language and Literature 67 history/centre for Political Ideologies, department of Politics 68 history of art 68 Law 68 Linguistics, Philology and Phonetics 68 Mathematical, Physical and Life sciences 69 Medical sciences 70 Medieval and Modern Languages 71 Music 71 oriental studies 72 Faculty of Philosophy/oxford Martin school 72 social sciences 72 Theology 75 Institutes, Centres and Museums oxford Institute of ageing 75 oxford centre for Late antiquity 75 ashmolean Museum 75 bodleian Library: centre for the study of the book 75 university botanic Garden 75 65 66 University of Oxford Gazette • supplement (1) to No. 4928 • 6 october 2010 oxford university computing services 76 smith school of enterprise and the environment 76 smith school of enterprise and the environment/environmental change Institute 76 The europaeum 76 Wellcome unit for the history of Medicine
    [Show full text]
  • Acknowledgment of Reviewers, 2009
    Proceedings of the National Academy ofPNAS Sciences of the United States of America www.pnas.org Acknowledgment of Reviewers, 2009 The PNAS editors would like to thank all the individuals who dedicated their considerable time and expertise to the journal by serving as reviewers in 2009. Their generous contribution is deeply appreciated. A R. Alison Adcock Schahram Akbarian Paul Allen Lauren Ancel Meyers Duur Aanen Lia Addadi Brian Akerley Phillip Allen Robin Anders Lucien Aarden John Adelman Joshua Akey Fred Allendorf Jens Andersen Ruben Abagayan Zach Adelman Anna Akhmanova Robert Aller Olaf Andersen Alejandro Aballay Sarah Ades Eduard Akhunov Thorsten Allers Richard Andersen Cory Abate-Shen Stuart B. Adler Huda Akil Stefano Allesina Robert Andersen Abul Abbas Ralph Adolphs Shizuo Akira Richard Alley Adam Anderson Jonathan Abbatt Markus Aebi Gustav Akk Mark Alliegro Daniel Anderson Patrick Abbot Ueli Aebi Mikael Akke David Allison David Anderson Geoffrey Abbott Peter Aerts Armen Akopian Jeremy Allison Deborah Anderson L. Abbott Markus Affolter David Alais John Allman Gary Anderson Larry Abbott Pavel Afonine Eric Alani Laura Almasy James Anderson Akio Abe Jeffrey Agar Balbino Alarcon Osborne Almeida John Anderson Stephen Abedon Bharat Aggarwal McEwan Alastair Grac¸a Almeida-Porada Kathryn Anderson Steffen Abel John Aggleton Mikko Alava Genevieve Almouzni Mark Anderson Eugene Agichtein Christopher Albanese Emad Alnemri Richard Anderson Ted Abel Xabier Agirrezabala Birgit Alber Costica Aloman Robert P. Anderson Asa Abeliovich Ariel Agmon Tom Alber Jose´ Alonso Timothy Anderson Birgit Abler Noe¨l Agne`s Mark Albers Carlos Alonso-Alvarez Inger Andersson Robert Abraham Vladimir Agranovich Matthew Albert Suzanne Alonzo Tommy Andersson Wickliffe Abraham Anurag Agrawal Kurt Albertine Carlos Alos-Ferrer Masami Ando Charles Abrams Arun Agrawal Susan Alberts Seth Alper Tadashi Andoh Peter Abrams Rajendra Agrawal Adriana Albini Margaret Altemus Jose Andrade, Jr.
    [Show full text]
  • And Β-Cells Reflect Cell-Specific Scn3a and Scn9a Expression
    This is a repository copy of Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/165326/ Version: Published Version Article: Zhang, Q., Chibalina, M.V., Bengtsson, M. et al. (12 more authors) (2014) Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression. The Journal of Physiology, 592 (21). pp. 4677-4696. ISSN 0022-3751 https://doi.org/10.1113/jphysiol.2014.274209 Reuse This article is distributed under the terms of the Creative Commons Attribution (CC BY) licence. This licence allows you to distribute, remix, tweak, and build upon the work, even commercially, as long as you credit the authors for the original work. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ J Physiol 592.21 (2014) pp 4677–4696 4677 Na+ current properties in islet α-andβ-cells reflect cell-specific Scn3a and Scn9a expression Quan Zhang1, Margarita V. Chibalina1, Martin Bengtsson1, Lukas N. Groschner1, Reshma Ramracheya1, Nils J. G. Rorsman1,VeronikaLeiss2,3, Mohammed A. Nassar4,5,AndreaWelling2, Fiona M. Gribble6, Frank Reimann6, Franz Hofmann2,7, John N. Wood4, Frances M. Ashcroft8 and Patrik Rorsman1,9 1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK 2Institut fur¨ Pharmakologie und Toxikologie, TU Munchen,¨ Biedersteiner Str.
    [Show full text]