Overexpression of Alpha2A-Adrenergic Receptors Contributes to Type 2 Diabetes

TLDR

Type 2 diabetes is linked to common genetic variations, yet the precise mechanisms remain poorly understood, and alpha(2A)-adrenergic receptors mediate adrenergic suppression of insulin secretion. In congenic Goto‑Kakizaki rat strains, a 1.4‑Mb locus linked to impaired insulin granule docking and reduced beta‑cell exocytosis was identified, and pharmacological antagonism, gene silencing, or downstream effector blockade restored insulin secretion. Adra2a overexpression in the identified locus, a risk‑allele SNP in human ADRA2A, and reduced granule docking in risk‑allele carriers all correlate with impaired insulin secretion, but pharmacological alpha(2A)-adrenergic receptor antagonists restore secretion.

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.