Intra-islet α-cell Gs signaling promotes glucagon release
Liu Liu, Kimberley EI, Diptadip Dattaroy, Luiz F. Barella, Yinghong Cui, Sarah M. Gray, Carla Guedikian, Min Chen, Lee S. Weinstein, Emily R. Knuth, Erli Jin, Matthew J. Merrins, Jeffrey Roman, Klaus H. Kaestner, Nicolai M. Doliba, Jonathan E. Campbell, Jürgen Wess
Abstract
Abstract 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.