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.

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

“…The importance of this statement is stressed by the observation that ADRA2A rs10885122 was not associated with HOMA-B at genome-wide significance in the MAGIC paper and did not replicate strongly (p=0.03) in ∼60,000 individuals [18]; yet the current data provide strong evidence of a postprandial insulin release defect. The functional and genetic impact of ADRA2A on dynamic insulin secretion was also described in a recent paper showing reduced in vitro insulin secretion and impaired docking of insulin granule in carriers of variants in ADRA2A [30]. Despite the application of OGTT-based estimates of beta cell function, we cannot rule out the possibility that the lack of consistent association with beta cell function for variants at ADCY5, MADD, FADS1, CRY2 and SLC2A2 in the present study is due to lack of statistical power.…”

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

“…Our results also suggest that the loss of sympathetic ligands working through their cognate Gi-GPCRs on β cells could explain the increased perinatal β-cell replication in mice lacking neurons in the pancreas (34) and may explain how activating variants in ADRA2A and stress contribute to diabetes risk in humans (5,6,35). Although important, sympathetic ligands alone likely do not explain all the PTX-sensitive inhibition of β-cell proliferation, and other Gi-GPCRs, such as Cnr1, along with non-cell-autonomous effects of Gα i/o signaling, surely contribute as well (24,(36)(37)(38).…”

“…Gi-GPCR gene variants associated with human diseases are thought to influence disease risk by modifying acute cellular behaviors such as insulin release (3)(4)(5)(6)(7)(8)(9). However, diabetes also is associated with decreased pancreatic β-cell mass (10)(11)(12)(13), and little is known about the role Gi-GPCR signaling plays in organ development or size or whether Gi-GPCR variants could impact disease risk by altering organ size.…”

“…Examples include the gut incretins GIP and GLP1, which stimulate insulin secretion in a glucose-dependent manner through their cognate Gα s -linked GPC receptors, GIPR and GLP1R; acetylcholine, which stimulates insulin secretion in a glucose-independent manner through the Gα q -linked cholinergic receptor, muscarinic 3 (CHRM3); and catecholamines and somatostatin, which inhibit insulin secretion through the Gi-GPCRs α2A adrenergic receptor (ADRA2A) and SSTR3, respectively (3,14). Variants in the genes encoding GIPR and ADRA2A alter the risk of type 2 diabetes (5,6,15).…”

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

“…Insulinrelease measurements were conducted as previously described [32]. Culture of INS-1 832/13 cells and tests for glucose-induced insulin secretion (GSIS) were performed as previously described [20].…”