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Damon Tojjar

Research student

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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

Summary, in 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.

Department/s

  • Diabetes - Islet Patophysiology
  • Genetics
  • Genomics, Diabetes and Endocrinology
  • Immunology
  • Diabetes - Islet Cell Exocytosis
  • Islet cell physiology
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2010

Language

English

Pages

217-220

Publication/Series

Science (New York, N.Y.)

Volume

327

Document type

Journal article

Publisher

American Association for the Advancement of Science

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Islet Patophysiology
  • Genetics
  • Genomics, Diabetes and Endocrinology
  • Immunology
  • Diabetes - Islet Cell Exocytosis
  • Islet cell physiology

ISBN/ISSN/Other

  • ISSN: 1095-9203