RGD Reference Report - Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. - Rat Genome Database

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Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes.

Authors: Rosengren, AH  Jokubka, R  Tojjar, D  Granhall, C  Hansson, O  Li, DQ  Nagaraj, V  Reinbothe, TM  Tuncel, J  Eliasson, L  Groop, L  Rorsman, P  Salehi, A  Lyssenko, V  Luthman, H  Renstrom, E 
Citation: Rosengren AH, etal., Science. 2010 Jan 8;327(5962):217-20. Epub 2009 Nov 19.
RGD ID: 2316628
Pubmed: PMID:19965390   (View Abstract at PubMed)
DOI: DOI:10.1126/science.1176827   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F344.GK-(D1Swe8-D1Gpam-1)/SweRatglucose intolerance treatmentIAGPclonidine RGD 
ADRA2AHumantype 2 diabetes mellitus susceptibilityIAGP DNA:SNP:3' utr:rs553668 (human)RGD 
Adra2aRattype 2 diabetes mellitus susceptibilityISOADRA2A (Homo sapiens)DNA:SNP:3' utr:rs553668 (human)RGD 
Adra2aMousetype 2 diabetes mellitus susceptibilityISOADRA2A (Homo sapiens)DNA:SNP:3' utr:rs553668 (human)RGD 
Adra2aRattype 2 diabetes mellitus  IEP mRNA and protein:increased expression:pancreatic islet RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F344.GK-(D1Swe8-D1Gpam-1)/SweRatabnormal exocytosis inducedIAGPcalcium ioncompared to F344.GK-D1Got251-D1Gpam-1/SweRGD 
F344.GK-(D1Swe8-D1Gpam-1)/SweRatdecreased circulating insulin level inducedIAGPfastingcompared to F344.GK-D1Got251-D1Gpam-1/SweRGD 
F344.GK-(D1Swe8-D1Gpam-1)/SweRatdecreased insulin secretion inducedIAGPglucosecompared to F344.GK-D1Got251-D1Gpam-1/SweRGD 
F344.GK-(D1Swe8-D1Gpam-1)/SweRatimpaired glucose tolerance inducedIAGPglucose solutioncompared to F344.GK-D1Got251-D1Gpam-1/SweRGD 

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ADRA2AHumanImpaired glucose tolerance  IAGP DNA:SNP: :rs553668(human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Adra2a  (adrenoceptor alpha 2A)
Ppp3ca  (protein phosphatase 3 catalytic subunit alpha)

Genes (Mus musculus)
Adra2a  (adrenergic receptor, alpha 2a)

Genes (Homo sapiens)
ADRA2A  (adrenoceptor alpha 2A)

Objects referenced in this article
Strain F344.GK-(D1Got251-D1Gpam-1)/Swe null Rattus norvegicus
QTL Niddm66 Non-insulin dependent diabetes mellitus QTL 66 Rattus norvegicus

Additional Information