Publication Date:
2009-12-08
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rosengren, Anders H -- Jokubka, Ramunas -- Tojjar, Damon -- Granhall, Charlotte -- Hansson, Ola -- Li, Dai-Qing -- Nagaraj, Vini -- Reinbothe, Thomas M -- Tuncel, Jonatan -- Eliasson, Lena -- Groop, Leif -- Rorsman, Patrik -- Salehi, Albert -- Lyssenko, Valeriya -- Luthman, Holger -- Renstrom, Erik -- New York, N.Y. -- Science. 2010 Jan 8;327(5962):217-20. doi: 10.1126/science.1176827. Epub 2009 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lund University Diabetes Centre, Malmo, SE-20502 Malmo, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19965390" target="_blank"〉PubMed〈/a〉
Keywords:
Adolescent
;
Adrenergic alpha-2 Receptor Agonists
;
Adrenergic alpha-2 Receptor Antagonists
;
Adrenergic alpha-Agonists/pharmacology
;
Adrenergic alpha-Antagonists/pharmacology
;
Adult
;
Aged
;
Animals
;
Animals, Congenic
;
Blood Glucose/metabolism
;
Cell Membrane/metabolism
;
Cyclic AMP/metabolism
;
Diabetes Mellitus, Type 2/*genetics/metabolism
;
Exocytosis
;
Genetic Association Studies
;
Genetic Predisposition to Disease
;
Humans
;
Insulin/blood/*secretion
;
Insulin-Secreting Cells/*secretion
;
Middle Aged
;
Polymorphism, Single Nucleotide
;
RNA Interference
;
Rats
;
Rats, Inbred Strains
;
Receptors, Adrenergic, alpha-2/*genetics/*metabolism
;
Risk Factors
;
Secretory Vesicles/metabolism
;
Up-Regulation
;
Young Adult
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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