Gq signaling in α cells is critical for maintaining euglycemia.

Liu Liu,Klaus H Kaestner,Yinghong Cui,Katherine F Simpson,Nicolai M Doliba,Jürgen Wess,Diptadip Dattaroy,Jian Jin,Evi Kostenis,Gabriele M König,Yan Xiong,Jefferey C Roman,Luiz F Barella

doi:10.1172/jci.insight.152852

Abstract

Glucagon, a hormone released from pancreatic α cells, plays a key role in maintaining euglycemia. New insights into the signaling pathways that control glucagon secretion may stimulate the development of novel therapeutic agents. In this study, we investigated the potential regulation of α cell function by G proteins of the Gq family. The use of a chemogenetic strategy allowed us to selectively activate Gq signaling in mouse α cells in vitro and in vivo. Acute stimulation of α cell Gq signaling led to elevated plasma glucagon levels, accompanied by increased insulin release and improved glucose tolerance. Moreover, chronic activation of this pathway greatly improved glucose tolerance in obese mice. We also identified an endogenous Gq-coupled receptor (vasopressin 1b receptor; V1bR) that was enriched in mouse and human α cells. Agonist-induced activation of the V1bR strongly stimulated glucagon release in a Gq-dependent fashion. In vivo studies indicated that V1bR-mediated glucagon release played a key role in the counterregulatory hyperglucagonemia under hypoglycemic and glucopenic conditions. These data indicate that α cell Gq signaling represents an important regulator of glucagon secretion, resulting in multiple beneficial metabolic effects. Thus, drugs that target α cell–enriched Gq-coupled receptors may prove useful to restore euglycemia in various pathophysiological conditions.

Highlights

Glucagon is a metabolically important polypeptide hormone that is secreted from α cells of the pancreatic islets of Langerhans [1,2,3,4,5]
Recent advances in the glucagon/α cell field have led to renewed interest in the role of glucagon as a key regulator of glucose homeostasis
Several recent in vitro and in vivo studies demonstrated that glucagon release from α cells can act in a paracrine fashion to promote insulin release from β cells and that this activity is required for maintaining euglycemia in animal models [7,8,9,10,11]

Summary

Introduction

Glucagon is a metabolically important polypeptide hormone that is secreted from α cells of the pancreatic islets of Langerhans [1,2,3,4,5]. Additional work suggested that this paracrine glucagon effect is mediated primarily by glucagon activation of β cell glucagon-like peptide 1 (GLP-1) receptors [7, 8]. A more recent study clearly demonstrated that glucagon acts as an insulinotropic hormone in the fed state, enhancing rather than opposing the ability of insulin to maintain euglycemia [11]. In line with these recent findings, agents that can simultaneously activate GLP-1 and glucagon receptors (so-called dual agonists) are currently undergoing clinical trials as potential novel drugs for the treatment of T2D and related metabolic disorders [12, 13]

Methods

Results

Conclusion