Gq signaling in α cells is critical for maintaining euglycemia
Liu Liu, Diptadip Dattaroy, Katherine F. Simpson, Luiz F. Barella, Yinghong Cui, Yan Xiong, Jian Jin, Gabriele M. König, Evi Kostenis, Jefferey C. Roman, Klaus H. Kaestner, Nicolai M. Doliba, Jürgen Wess
Liu Liu, Diptadip Dattaroy, Katherine F. Simpson, Luiz F. Barella, Yinghong Cui, Yan Xiong, Jian Jin, Gabriele M. König, Evi Kostenis, Jefferey C. Roman, Klaus H. Kaestner, Nicolai M. Doliba, Jürgen Wess
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Research Article Metabolism

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 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.

Authors

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

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Figure 5

Chronic activation of α cell Gq signaling improves glucose homeostasis in obese α-GqD mice.

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Chronic activation of α cell Gq signaling improves glucose homeostasis i...
α-GqD mice and control littermates were maintained on a high-fat diet for at least 6 weeks. Metabolic studies were carried out with mice that had received daily injections of DCZ (10 μg/kg i.p.) for 27 days. (A) Glucose tolerance test carried out with overnight-fasted mice. Glucose was administered (1 g glucose/kg i.p.) 1 hour after the last DCZ injection. (B and C) Plasma glucagon (B) and insulin (C) levels of fasted mice prior to (time 0) and 15 minutes after glucose injection (1 g/kg i.p.). (D) Glucose tolerance test (see A for details) carried out with mice injected with exendin(9-39) (Ex-9, 50 mg/mouse) or vehicle (saline) prior to glucose treatment. The panel to the right shows area under the curve (AUC) for each mouse (arbitrary units). (E) Pyruvate tolerance test (PTT) (1 g/kg i.p.) performed with overnight-fasted mice. (F) Glucagon challenge test (100 μg/kg i.p.) carried out with mice fasted for 6 hours. All experiments were carried out with male littermates that were about 35 weeks old. Data are given as mean ± SEM (α-GqD: n = 8–11; control: n = 5–10). *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 (mixed effects repeated measures ANOVA for after injection differences).