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

Rosengren, Anders LU ; Jokubka, Ramunas LU ; Tojjar, Damon LU ; Granhall, Charlotte LU ; Hansson, Ola LU orcid ; Li, Dai-Qing LU ; Nagaraj, Vini LU ; Reinbothe, Thomas LU ; Tuncel, Jonatan LU and Eliasson, Lena LU orcid , et al. (2010) In Science (New York, N.Y.) 327. p.217-220
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science (New York, N.Y.)
volume
327
pages
217 - 220
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • wos:000273394000039
  • pmid:19965390
  • scopus:74249123937
  • pmid:19965390
ISSN
1095-9203
DOI
10.1126/science.1176827
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Islet patophysiology (013212132), Medical Genetics Unit (013241550), Diabetes and Endocrinology (013241530), Islet cell physiology (013212142), Islet cell exocytosis (013212135), Medical Inflammation Research (013212019)
id
4bcb97f4-2cca-4656-a5d6-42d5ea36b9f3 (old id 1523890)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19965390?dopt=Abstract
date added to LUP
2016-04-04 09:30:59
date last changed
2025-04-04 14:49:08
@article{4bcb97f4-2cca-4656-a5d6-42d5ea36b9f3,
  abstract     = {{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.}},
  author       = {{Rosengren, Anders and Jokubka, Ramunas and Tojjar, Damon and Granhall, Charlotte and Hansson, Ola and Li, Dai-Qing and Nagaraj, Vini and Reinbothe, Thomas and Tuncel, Jonatan and Eliasson, Lena and Groop, Leif and Rorsman, Patrik and Salehi, S Albert and Lyssenko, Valeriya and Luthman, Holger and Renström, Erik}},
  issn         = {{1095-9203}},
  language     = {{eng}},
  pages        = {{217--220}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science (New York, N.Y.)}},
  title        = {{Overexpression of Alpha2A-Adrenergic Receptors Contributes to Type 2 Diabetes.}},
  url          = {{http://dx.doi.org/10.1126/science.1176827}},
  doi          = {{10.1126/science.1176827}},
  volume       = {{327}},
  year         = {{2010}},
}