Role of a2A adrenergic receptors and Gbg-SNARE interaction in impaired insulin secretion in T2D

One of the earliest and most important pathophysiological signs of type 2 diabetes (T2D) is impaired insulin release. A number of therapies used in the clinic, such as GLP1- agonists and DPP-4 inhibitors, act to enhance insulin release from the beta cell. Gi/o-coupled G-protein coupled receptors (GPCRs) inhibit insulin release. One mechanism through which these receptors inhibit insulin release is through liberating G protein βγ subunits. We have demonstrated that Gβγ can directly inhibit exocytosis at a point distal to Ca2+ entry by binding to soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. It has been shown that beta cell α2A adrenergic receptors (α2AAR) profoundly inhibit insulin release by this mechanism. This proposal aims to investigate the role of the α2AAR in the inhibition of insulin release in animal models of T2D. We hypothesize that overactive inhibition of insulin secretion by Gi/o coupled GPCRs is a part of the impaired insulin secretion in the pathogenesis of T2D. In Aim 1, we will test whether α2AARmediated inhibition is enhanced in islets isolated from animal models of T2D. In Aim 2, we will test whether small molecule inhibitors of the Gβγ-SNARE interaction are able to overcome the inhibitory effect of α2AAR agonists upon insulin release. Finally, in Aim 3, we will determine whether the inhibitors synergize with α2AAR antagonists or compounds that enhance insulin secretion such as sulfonylureas, agonists of Gs or Gqcoupled receptors (e.g. GLP-1 agonists). These studies should allow us to evaluate both the role of α2A adrenergic receptor-mediated inhibitory signaling and the Gβγ-SNARE interaction in impaired insulin secretion in T2D.