Gq signaling in α cells is critical for maintaining euglycemia

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 G q family. The use of a chemogenetic strategy allowed us to selectively activate G q signaling in mouse α cells in vitro and in vivo. Acute stimulation of α cell G q 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 G q -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 G q -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 G q signaling represents an important regulator of glucagon secretion, resulting in multiple beneficial metabolic effects. Thus, drugs that target α cell–enriched G q -coupled receptors may prove useful to restore euglycemia in various pathophysiological conditions.

Intra-islet α-cell Gs signaling promotes glucagon release

“… 27 , followed by the monitoring of changes in plasma glucagon, plasma insulin, and blood glucose levels. Similar to previous observations 13 , 35 , i.p. injection of control and α-GsD mice with saline or of control mice with DCZ resulted in reduced plasma glucagon levels 15 and 30 min after injection ( p < 0.0001; one-way repeated measures ANOVA, followed by post-hoc Bonferroni adjustment) (Fig.…”

Tmem117 in AVP neurons regulates the counterregulatory response to hypoglycemia

“…Our physiological studies indicated that AVP neurons are activated by insulin-induced hypoglycemia, leading to CPP secretion, a response that was augmented by Tmem117 inactivation and was accompanied by increased GCG secretion. These observations are in agreement with previous studies showing increased secretion of AVP in response to hypoglycemia (Baylis & Robertson, 1980;Baylis et al, 1981;Chiodera et al, 1992) and that AVP stimulates GCG secretion through its binding to the AVP V1b receptor of pancreatic a cells (Dunning et al, 1984;Spruce et al, 1985;Gao et al, 1992;Yibchok-anun et al, 2004;Kim et al, 2021;Liu et al, 2021). On the other hand, these results are also in line with our genetic screen that showed a negative correlation between Tmem117 expression and insulin-induced GCG secretion.…”

Paracrine signaling by pancreatic δ cells determines the glycemic set point in mice

“…Conversely, under post-prandial conditions when glycemia is low, α cells secrete glucagon to stimulate hepatic glucose production. There is increasing evidence that paracrine glucagon signaling also amplifies glucose-stimulated insulin secretion (GSIS) by direct stimulation of β cells (Chambers et al 2017;Svendsen et al 2018;Capozzi et al 2019a, b;Zhu et al 2019;Tellez et al 2020;Liu et al 2021). This suggests that glucagon acts locally to stimulate GSIS as a paracrine factor during the prandial state, while systemic glucagon action in the absence of insulin release is responsible for its counterregulatory function during the post-prandial state (Huising 2020).…”