Glucagon, a hormone released from pancreatic α cells, plays a key role in maintaining proper glucose homeostasis and has been implicated in the pathophysiology of diabetes. In vitro studies suggest that intraislet glucagon can modulate the function of pancreatic β cells. However, because of the lack of suitable experimental tools, the in vivo physiological role of this intraislet cross-talk has remained elusive. To address this issue, we generated a mouse model that selectively expressed an inhibitory designer GPCR (Gi DREADD) in α cells only. Drug-induced activation of this inhibitory designer receptor almost completely shut off glucagon secretion in vivo, resulting in markedly impaired insulin secretion, hyperglycemia, and glucose intolerance. Additional studies with mouse and human islets indicated that intraislet glucagon stimulates insulin release primarily by activating β cell GLP-1 receptors. These findings strongly suggest that intraislet glucagon signaling is essential for maintaining proper glucose homeostasis in vivo. Our work may pave the way toward the development of novel classes of antidiabetic drugs that act by modulating intraislet cross-talk between α and β cells.
Lu Zhu, Diptadip Dattaroy, Jonathan Pham, Lingdi Wang, Luiz F. Barella, Yinghong Cui, Kenneth J. Wilkins, Bryan L. Roth, Ute Hochgeschwender, Franz M. Matschinsky, Klaus H. Kaestner, Nicolai M. Doliba, Jürgen Wess
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