Overexpression of Alpha2A-Adrenergic Receptors Contributes to Type 2 Diabetes.
Författare
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.
Avdelning/ar
- Diabetes - öpatofysiologi
- Genetik
- Translationell Muskel Forskning
- Immunology
- Diabetes - öcellsexocytos
- Islet cell physiology
- EXODIAB: Excellence of Diabetes Research in Sweden
Publiceringsår
2010
Språk
Engelska
Sidor
217-220
Publikation/Tidskrift/Serie
Science (New York, N.Y.)
Volym
327
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
American Association for the Advancement of Science (AAAS)
Ämne
- Endocrinology and Diabetes
Status
Published
Forskningsgrupp
- Diabetes - Islet Patophysiology
- Genetics
- Genomics, Diabetes and Endocrinology
- Immunology
- Diabetes - Islet Cell Exocytosis
- Islet cell physiology
ISBN/ISSN/Övrigt
- ISSN: 1095-9203