Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from the diabetic Goto-Kakizaki rat, we identified a 1.4-megabase 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.

Original publication

DOI

10.1126/science.1176827

Type

Journal article

Journal

Science

Publication Date

08/01/2010

Volume

327

Pages

217 - 220

Keywords

Adolescent, Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-2 Receptor Antagonists, Adrenergic alpha-Agonists, Adrenergic alpha-Antagonists, Adult, Aged, Animals, Animals, Congenic, Blood Glucose, Cell Membrane, Cyclic AMP, Diabetes Mellitus, Type 2, Exocytosis, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Insulin, Insulin-Secreting Cells, Middle Aged, Polymorphism, Single Nucleotide, RNA Interference, Rats, Rats, Inbred Strains, Receptors, Adrenergic, alpha-2, Risk Factors, Secretory Vesicles, Up-Regulation, Young Adult