Intra-islet α-cell Gs signaling promotes glucagon release

Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell G_s signaling on modulating α-cell function. Studies with α-cell-specific mouse models showed that activation of α-cell G_s signaling causes a marked increase in glucagon secretion. We also found that intra-islet adenosine plays an unexpected autocrine/paracrine role in promoting glucagon release via activation of α-cell G_s-coupled A_2A adenosine receptors. Studies with α-cell-specific Gα_s knockout mice showed that α-cell G_s also plays an essential role in stimulating the activity of the Gcg gene, thus ensuring proper islet glucagon content. Our data suggest that α-cell enriched G_s-coupled receptors represent potential targets for modulating α-cell function for therapeutic purposes.