Editors' ChoiceBiomedicine

Too Much of a Good Thing

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Science Translational Medicine  25 Nov 2009:
Vol. 1, Issue 8, pp. 8ec28
DOI: 10.1126/scitranslmed.3000637

We know that common variations in several genes predispose for type 2 diabetes (T2D), yet the cellular mechanisms that underlie the etiology of the disease remain elusive. Using inbred rat strains, Rosengren et al. honed in on a locus on chromosome 1 and found that this region is linked to features central to T2D: insulin resistance and impaired pancreatic β-cell function. Five protein-coding genes are found at this locus, and the researchers determined that one of them, the gene encoding the alpha2A-adrenergic receptor [alpha(2A)AR], was overexpressed by 59% at the mRNA level in pancreatic islet cells and upregulated by 90% at the protein level in both islets and brain. Because alpha(2A)AR functions in adrenaline-mediated suppression of insulin secretion, the authors characterized the effect of alpha(2A)AR activity using pharmacological agonists and antagonists in vivo, as well as siRNA and blockade of a downstream effector—-calcineurin—in vitro, and showed unambiguously that overexpression of Adra2a impairs pancreatic cell function in both islets and single β cells. Furthermore, the researchers identified and validated a common variant, rs553668, in the human Adra2a gene, carriers of which have pancreatic islets that overexpressed alpha(2A)AR and exhibit a 30% decrease in insulin secretion. Moreover, carriers had a reduced number of docked insulin granules, a phenotype that could be corrected with alpha(2A)AR pharmacological antagonists. These observations suggest that impaired insulin signaling in people carrying the rs553668 SNP is likely to be the result of hyperactive alpha(2A)AR signaling.

A. H. Rodengren et al., Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 17 November 2009 (10.1126/science.1176827) [Full Text]

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