Abarkan, Myriam, GAITAN, Julien, Lebreton, Fanny, Perrier, Romain, Jaffredo, Manon, Mulle, Christophe, Magnan, Christophe, Raoux, Matthieu, Lang, Jochen, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Pôle de recherche pour l'organisation et la diffusion de l'information géographique (PRODIG), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Sorbonne (UP4)-École pratique des hautes études (EPHE)-Institut de Recherche pour le Développement (IRD)-Université Panthéon-Sorbonne (UP1), Indisciplinary Institute for Neuroscience, UMR 5297, Mulle, Christophe, Transistors multimodaux sensibles aux ions à polymères ambivalents pour biocapteurs hybrides - - MULTISPOT2017 - ANR-17-CE09-0015 - AAPG2017 - VALID, Identification de biomarqueurs du stress et de l'inflammation des cellules B pancréatiques en explorant les communications inter-organes dans des modèles précliniques d'obésité et de diabète de type 2 - - betadiamark2015 - ANR-15-CE14-0027 - AAPG2015 - VALID, Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MA and FL hold PhD scholarships from the French Research Agency (ANR-17-CE09-0015 MULTISPOT to JL) or the French Ministry of Education (to JL).We acknowledge institution a lfunding from the CNRS and the University of Bordeaux (JL). C Magnan received funding from the French Research Agency (ANR PRCI-15-CE14-0027-01 Beta Dia-mark) and the French Society for Study of Diabetes (SFD-MSD)., ANR-17-CE09-0015,MULTISPOT,Transistors multimodaux sensibles aux ions à polymères ambivalents pour biocapteurs hybrides(2017), ANR-15-CE14-0027,betadiamark,Identification de biomarqueurs du stress et de l'inflammation des cellules B pancréatiques en explorant les communications inter-organes dans des modèles précliniques d'obésité et de diabète de type 2(2015), and École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)
Objective Islets secrete neurotransmitters including glutamate which participate in fine regulation of islet function. The excitatory ionotropic glutamate receptor GluK2 of the kainate receptor family is widely expressed in brain and also found in islets, mainly in α and γ cells. α cells co-release glucagon and glutamate and the latter increases glucagon release via ionotropic glutamate receptors. However, neither the precise nature of the ionotropic glutamate receptor involved nor its role in glucose homeostasis is known. As isoform specific pharmacology is not available, we investigated this question in constitutive GluK2 knock-out mice (GluK2−/−) using adult and middle-aged animals to also gain insight in a potential role during aging. Methods We compared wild-type GluK2+/+ and knock-out GluK2−/− mice using adult (14–20 weeks) and middle-aged animals (40–52 weeks). Glucose (oral OGTT and intraperitoneal IPGTT) and insulin tolerance as well as pyruvate challenge tests were performed according to standard procedures. Parasympathetic activity, which stimulates hormones secretion, was measured by electrophysiology in vivo. Isolated islets were used in vitro to determine islet β-cell electrical activity on multi-electrode arrays and dynamic secretion of insulin as well as glucagon was determined by ELISA. Results Adult GluK2−/− mice exhibit an improved glucose tolerance (OGTT and IPGTT), and this was also apparent in middle-aged mice, whereas the outcome of pyruvate challenge was slightly improved only in middle-aged GluK2−/− mice. Similarly, insulin sensitivity was markedly enhanced in middle-aged GluK2−/− animals. Basal and glucose-induced insulin secretion in vivo was slightly lower in GluK2−/− mice, whereas fasting glucagonemia was strongly reduced. In vivo recordings of parasympathetic activity showed an increase in basal activity in GluK2−/− mice which represents most likely an adaptive mechanism to counteract hypoglucagonemia rather than altered neuronal mechanism. In vitro recording demonstrated an improvement of glucose-induced electrical activity of β-cells in islets obtained from GluK2−/− mice at both ages. Finally, glucose-induced insulin secretion in vitro was increased in GluK2−/− islets, whereas glucagon secretion at 2 mmol/l of glucose was considerably reduced. Conclusions These observations indicate a general role for kainate receptors in glucose homeostasis and specifically suggest a negative effect of GluK2 on glucose homeostasis and preservation of islet function during aging. Our observations raise the possibility that blockade of GluK2 may provide benefits in glucose homeostasis especially during aging., Highlights • KO of GluK2 improved glucose tolerance and lowered fasting glucagon levels in vivo. • KO of GluK2 reduced in vitro islet glucagon secretion and increased β-cell activity. • GluK2 contributes to the known impact of aging on glucose homeostasis.