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Glutamate pathways and metabolic stresses in energy homeostasis

English title Glutamate pathways and metabolic stresses in energy homeostasis
Applicant Maechler Pierre
Number 166625
Funding scheme Project funding (Div. I-III)
Research institution Département de physiologie cellulaire et métabolisme Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Endocrinology
Start/End 01.09.2016 - 30.09.2019
Approved amount 678'000.00
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All Disciplines (4)

Discipline
Endocrinology
Neurophysiology and Brain Research
Physiology : other topics
Biochemistry

Keywords (5)

insulin; beta-cell; glutamate dehydrogenase; mitochondria; metabolism

Lay Summary (French)

Lead
Le maintien de la concentration de sucre dans le sang (glycémie) dans des valeurs physiologiques est essentiellement assuré par l’action de l’hormone insuline sur ses principaux tissus cibles que sont le foie, les muscles squelettiques et le tissu adipeux. Toutefois, l’équilibre glycémique résulte avant tout d’un relâchement adéquat d’insuline dans le sang. Cette sécrétion dépend totalement du bon fonctionnement des cellules bêta qui se situent dans la partie endocrine du pancréas.
Lay summary

La cellule bêta est un gluco-senseur couplé à un fournisseur d’insuline, analysant en temps réel toute modification du taux de glucose dans le sang et traduisant immédiatement ces changements en ajustant la sécrétion d’insuline. Ce processus est appelé couplage métabolisme-sécrétion, impliquant une cascade d’étapes cellulaires rejoignant une voie de signalisation commune à de nombreuses cellules sécrétrice, soit le signal calcium. Cependant, le calcium seul est insuffisant à expliquer la sécrétion soutenue d’insuline. Il existe donc d’autres signaux cellulaires, dérivés du glucose, participant avec le calcium à la libération de l’insuline. Notre laboratoire a identifié le glutamate, molécule produite dans les mitochondries, comme signal intracellulaire participant à la stimulation de la sécrétion d’insuline. Dans les mitochondries, le glutamate est produit grâce à l’enzyme glutamate déshydrogénase (GDH) dont le gène GLUD1 peut contenir des mutations altérant le bon fonctionnement des tissus métaboliquement actifs. En particulier, il semble que la cellule bêta-pancréatique, le foie, ou encore le système nerveux central soient particulièrement sensibles à ces mutations. Les travaux en cours tentent de mieux comprendre le rôle du glutamate dans différents tissus, comment cette molécule participe à l’homéostasie énergétique de l’organisme dans son entier, et quelles sont les conséquences relatives de mutations du gène GLUD1 sur les différents organes régulant le métabolisme.

Direct link to Lay Summary Last update: 28.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Chronic fructose renders pancreatic β-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling
Bartley Clarissa, Brun Thierry, Oberhauser Lucie, Grimaldi Mariagrazia, Molica Filippo, Kwak Brenda R., Bosco Domenico, Chanson Marc, Maechler Pierre (2019), Chronic fructose renders pancreatic β-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling, in American Journal of Physiology-Endocrinology and Metabolism, 317(1), E25-E41.
Resveratrol long-term treatment differentiates INS-1E beta-cell towards improved glucose response and insulin secretion
Casimir Marina, Chaffard Gaelle, Maechler Pierre (2019), Resveratrol long-term treatment differentiates INS-1E beta-cell towards improved glucose response and insulin secretion, in Pflügers Archiv - European Journal of Physiology, 471(2), 337-345.
Liver Glutamate Dehydrogenase Controls Whole-Body Energy Partitioning Through Amino Acid–Derived Gluconeogenesis and Ammonia Homeostasis
Karaca Melis, Martin-Levilain Juliette, Grimaldi Mariagrazia, Li Lingzi, Dizin Eva, Emre Yalin, Maechler Pierre (2018), Liver Glutamate Dehydrogenase Controls Whole-Body Energy Partitioning Through Amino Acid–Derived Gluconeogenesis and Ammonia Homeostasis, in Diabetes, 67(10), 1949-1961.
Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia
Grimaldi Mariagrazia, Karaca Melis, Latini Livia, Brioudes Estelle, Schalch Thomas, Maechler Pierre (2017), Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia, in Human Molecular Genetics, 26(18), 3453-3465.
Glutamate pathways of the beta-cell and the control of insulin secretion
Maechler Pierre (2017), Glutamate pathways of the beta-cell and the control of insulin secretion, in Diabetes Research and Clinical Practice, 131, 149-153.

Collaboration

Group / person Country
Types of collaboration
J-C. Martinou (University of Geneva) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
S. Mandrup (University of Southern Danemark) Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Helle Waagepetersen, University of Copenhagen Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Thomas Schalch (University of Geneva) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Stephen Rayport, Columbia University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
N. Zamboni (ETHZ) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
R. Gruetter (EPFL) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Roberto Coppari, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions journée portes ouvertes Diabète & Obésité Western Switzerland 2016

Associated projects

Number Title Start Funding scheme
146984 Mitochondrial function and tissue specificity of glutamate pathways in metabolic homeostasis and disease 01.04.2013 Project funding (Div. I-III)
170794 3D cryo-electron microscopy for analysis of macromolecular assemblies at atomic resolution 01.09.2017 R'EQUIP
135704 Investigating tissue specificity of glutamate pathway and mitochondrial function in the control of metabolic homeostasis 01.04.2011 Project funding (Div. I-III)
135704 Investigating tissue specificity of glutamate pathway and mitochondrial function in the control of metabolic homeostasis 01.04.2011 Project funding (Div. I-III)

Abstract

Glutamate pathways are crucial for several organs but are associated with different and very specific functions. Key to glutamate homeostasis is the mitochondrial enzyme glutamate dehydrogenase (GDH) that catalyzes the same biochemical reaction in every tissue but fulfills dedicated and highly specialized roles according to its organ. In the brain, GDH plays a major role in the recycling of the neurotransmitter glutamate. In pancreatic ß-cells, GDH participates to the regulation of insulin secretion. Hepatic GDH controls metabolism of most amino acids and plays a key role in gluconeogenesis. Over the last years, we generated transgenic mice based on Cre-lox technology for tissue specific deletion of GDH in ß-cells, brain, and liver. These models are not yet fully characterized and are instrumental in the delineation of GDH-specificity in terms of tissues and activity. Using ß-cell specific GDH knockout ßGlud1-/-, we have shown that GDH is necessary for the full development of glucose-stimulated insulin secretion. Using brain-specific GDH null mice (Cns-Glud1-/-), we uncovered the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole body energy homeostasis. This suggests that GDH might serve as central sensor for amino acid availability, a point that will be investigated in the present project. Changes in brain glutamate metabolism are associated with neurological disorders, which will be the subject of specific collaborations. We will also study liver GDH and its requirement for hepatic gluconeogenesis with help of inducible liver specific GDH knockout mice (Hep-Glud1-/-) recently generated. An important part of the proposal focuses on one of the most frequent GDH mutation associated with hyperinsulinemia/hyperammonia and epilepsy. We will analyze the effects of this mutation upon tissue-selective adenovirus-mediated introduction of this S445L-GDH mutant. Biochemical properties of the S445L-GDH mutant will complement the study.The last part of the project will be conducted to extend our previous observations regarding ß-cell dysfunction related to glucolipotoxicity. This in vitro project, independent of transgenic mice, will revisit GPR40 function in ß-cells through the potential implication of these fatty acid receptors in the glucolipotoxicity response.Overall, the proposed projects aim at extending our knowledge on glutamate pathways and metabolic stresses in the control of energy homeostasis.
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