The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice
Antonia Sassmann, Belinda Gier, Hermann-Josef Gröne, Gisela Drews, Stefan Offermanns, Nina Wettschureck
Antonia Sassmann, Belinda Gier, Hermann-Josef Gröne, Gisela Drews, Stefan Offermanns, Nina Wettschureck
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Research Article Metabolism

The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice

Abstract

A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that β cell–specific inactivation of the genes encoding the G protein α-subunits Gαq and Gα11 resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Gαq/Gα11-deficient β cells were not restricted to loss of muscarinic or metabolic potentiation of insulin release; the response to glucose per se was also diminished. Electrophysiological recordings revealed that glucose-induced depolarization of isolated β cells was impaired in the absence of Gαq/Gα11, and closure of KATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of β cell–autonomous potentiation of insulin secretion through factors cosecreted with insulin. We identified as autocrine mediators involved in this process extracellular nucleotides such as uridine diphosphate acting through the Gq/G11-coupled P2Y6 receptor and extracellular calcium acting through the calcium-sensing receptor. Thus, the Gq/G11-mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators.

Authors

Antonia Sassmann, Belinda Gier, Hermann-Josef Gröne, Gisela Drews, Stefan Offermanns, Nina Wettschureck

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Figure 3

Loss of Gαq/Gα11 impairs not only agonist-induced potentiation but also glucose-induced insulin secretion per se.

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Loss of Gαq/Gα11 impairs not only agonist-induced potentiation but also ...
(A) Potentiation of glucose-induced insulin secretion from perifused control islets and islets from β-Gαq/Gα11 DKOs by OxoM (50 μM), palmitic acid (PA), cholecystokinin-8 (CCK), endothelin-1 (ET), GLP-1 (100 μM each), or PACAP (10 nM) (n = 3–5 independent experiments). Data are expressed as x-fold above insulin secretion induced by 16.7 mM glucose alone. (B) Example of insulin secretion from perifused islets of control mice and β-Gαq/Gα11 DKOs in response to 16.7 mM glucose (G16.7). (C) Quantification of the maximal stimulatory effect of 16.7 mM glucose or 40 mM KCl on insulin secretion from perifused control and mutant islets (n = 5–6 independent experiments). Data are expressed as x-fold above insulin secretion at 2.8 mM glucose. *P ≤ 0.05.