title: Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes.
abstract: 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.
authors: Lund University Diabetes Centre, Malmö, SE-20502 Malmö, Sweden.
authors: Anders H
authors: AH
authors: Rosengren
authors: Ramunas
authors: R
authors: Jokubka
authors: Damon
authors: D
authors: Tojjar
authors: Charlotte
authors: C
authors: Granhall
authors: Ola
authors: O
authors: Hansson
authors: Dai-Qing
authors: DQ
authors: Li
authors: Vini
authors: V
authors: Nagaraj
authors: Thomas M
authors: TM
authors: Reinbothe
authors: Jonatan
authors: J
authors: Tuncel
authors: Lena
authors: L
authors: Eliasson
authors: Leif
authors: L
authors: Groop
authors: Patrik
authors: P
authors: Rorsman
authors: Albert
authors: A
authors: Salehi
authors: Valeriya
authors: V
authors: Lyssenko
authors: Holger
authors: H
authors: Luthman
authors: Erik
authors: E
authors: Renström
mesh_terms: D000293:Adolescent; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000818:Animals; D020296:Animals, Congenic; D001786:Blood Glucose / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005089:Exocytosis; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D051381:Rats; D011919:Rats, Inbred Strains; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics* / Q000378:metabolism*; D012307:Risk Factors; D022142:Secretory Vesicles / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C547768:ADRA2A protein, human; C547770:Adra2a protein, rat; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D007328:Insulin; D018341:Receptors, Adrenergic, alpha-2; D000242:Cyclic AMP