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Overexpression of Alpha2A-Adrenergic Receptors Contributes to Type 2 Diabetes.

Author:
  • Anders Rosengren
  • Ramunas Jokubka
  • Damon Tojjar
  • Charlotte Granhall
  • Ola Hansson
  • Dai-Qing Li
  • Vini Nagaraj
  • Thomas Reinbothe
  • Jonatan Tuncel
  • Lena Eliasson
  • Leif Groop
  • Patrik Rorsman
  • S Albert Salehi
  • Valeriya Lyssenko
  • Holger Luthman
  • Erik Renström
Publishing year: 2010
Language: English
Pages: 217-220
Publication/Series: Science (New York, N.Y.)
Volume: 327
Document type: Journal article
Publisher: The American Association for the Advancement of Science

Abstract english

Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Here, using congenic strains from the diabetic GK-rat, we identified a 1.4-Mb genomic locus that was linked to impaired insulin granule docking at the plasma membrane and reduced beta cell exocytosis. In this locus, Adra2a, encoding the alpha2A-adrenergic receptor [alpha(2A)AR], was significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of insulin secretion. Pharmacological receptor antagonism, silencing of receptor expression, or blockade of downstream effectors rescued insulin secretion in congenic islets. Furthermore, we identified a single nucleotide polymorphism in the human ADRA2A gene for which risk allele carriers exhibited overexpression of alpha(2A)AR, reduced insulin secretion, and increased type 2 diabetes risk. Human pancreatic islets from risk allele carriers exhibited reduced granule docking and secreted less insulin in response to glucose; both effects were counteracted by pharmacological alpha(2A)AR antagonists.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Islet patophysiology
  • Medical Genetics Unit
  • Diabetes and Endocrinology
  • Immunology
  • Islet cell exocytosis
  • Islet cell physiology
  • ISSN: 1095-9203
Erik Renström
E-mail: erik [dot] renstrom [at] med [dot] lu [dot] se

Deputy head of department

Department of Clinical Sciences, Malmö

+46 40 39 11 57

+46 40 39 11 57

Principal investigator

Islet patophysiology

+46 40 39 11 57

+46 40 39 11 57

20-3-308

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Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00