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Investigating tissue specificity of glutamate pathway and mitochondrial function in the control of metabolic homeostasis

English title Investigating tissue specificity of glutamate pathway and mitochondrial function in the control of metabolic homeostasis
Applicant Maechler Pierre
Number 135704
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 01.04.2011 - 31.03.2013
Approved amount 358'000.00
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All Disciplines (2)

Discipline
Endocrinology
Biochemistry

Keywords (4)

energy metabolism; glutamate; insulin secretion; pancreatic islet

Lay Summary (French)

Lead
Lay summary

Fonctions mitochondriales et voies du glutamate dans le contrôle métabolique.

Le contrôle métabolique de l’organisme tend vers le maintien d’un équilibre très délicat, continuellement perturbé par les dépenses et les apports énergétiques. Ces perturbations sont corrigées par des signaux hormonaux et cellulaires. Entre autres équilibres, le maintien de la glycémie dans des valeurs physiologiques est essentiellement assuré par l’action de l’insuline sur ses tissus cibles. Toutefois, l’équilibre glycémique résulte avant tout d’un relâchement adéquat d’insuline dans la circulation sanguine par le pancréas endocrine. Cette sécrétion dépend totalement de la bonne fonctionnalité des cellules bêta-pancréatiques qui se situent dans les îlots de Langerhans. La cellule bêta est donc un gluco-senseur couplé à un fournisseur d’insuline, analysant en temps réel toutes modifications du taux de glucose dans le sang et traduisant immédiatement ces changements en ajustant la sécrétion d’insuline. A l’intérieur des cellules bêta, des vésicules gorgées d’insuline n’attendent qu’un signal pour libérer leur contenu dans la circulation sanguine. Cependant, ce n’est pas le glucose lui-même qui sert de signal. Il faut donc transformer un message de nutriment – le glucose – en un message de libération d’insuline. Ce processus est appelé couplage métabolisme-sécrétion car il implique une cascade d’événements qui utilise en grande partie les voies classiques du métabolisme cellulaire. Cette cascade rejoint finalement une voie de signalisation commune à de nombreuses cellules sécrétrice, par exemple du système nerveux. Ces cellules ont en commun d’utiliser le calcium comme  signal cellulaire majeur stimulant le relâchement d’une hormone ou d’un neurotransmetteur. Il y a cependant des spécificités dans les signaux de la cellule bêta. En effet, le calcium seul, s’il est nécessaire, est insuffisant à expliquer la sécrétion soutenue d’insuline observée lors d’une élévation du glucose. 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. Les travaux en cours tentent de mieux comprendre le rôle du glutamate dans différents tissus et comment cette molécule participe à l’homéostasie énergétique de l’organisme dans son entier.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Changes in mitochondrial carriers exhibit stress-specific signatures in INS-1E ß-cells exposed to glucose versus fatty acids
Brun Thierry (2013), Changes in mitochondrial carriers exhibit stress-specific signatures in INS-1E ß-cells exposed to glucose versus fatty acids, in PLoS One, 8, e82364.
Hepatic glucose sensing is required to preserve beta cell glucose competence
Seyer Pascal, Vallois David, Poitry-Yamate Carole, Schuetz Frederic, Metref Salima, Tarussio David, Maechler Pierre, Staels Bart, Lanz Bernard, Grueter Rolf, Decaris Julie, Turner Scott, da Costa Anabela, Preitner Frederic, Minehira Kaori, Foretz Marc, Thorens Bernard (2013), Hepatic glucose sensing is required to preserve beta cell glucose competence, in JOURNAL OF CLINICAL INVESTIGATION, 123(4), 1662-1676.
Loss of prohibitin induces mitochondrial damages altering ß-cell function and survival and responsible for gradual diabetes development
Supale Sachin (2013), Loss of prohibitin induces mitochondrial damages altering ß-cell function and survival and responsible for gradual diabetes development, in Diabetes, 62, 3488-3499.
Mitochondrial function and insulin secretion
Maechler Pierre (2013), Mitochondrial function and insulin secretion, in Mol. Cell Endocrinol., 379, 12-18.
Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic p-cell survival and function via CREB
Zhang Yanling, Zhen Wei, Maechler Pierre, Liu Dongmin (2013), Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic p-cell survival and function via CREB, in JOURNAL OF NUTRITIONAL BIOCHEMISTRY, 24(4), 638-646.
Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission
Frigerio F, Karaca M, De Roo M, Mlynárik V, Skytt DM, Carobbio S, Pajȩcka K, Waagepetersen HS, Gruetter R, Muller D, Maechler P (2012), Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission, in Journal of Neurochemistry, 123(3), 342-348.
Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase
Vetterli L, Carobbio S, Pournourmohammadi S, Martin-del-Rio R, Skytt DM, Waagepetersen HS, Tamarit-Rodriguez J, Maechler P (2012), Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase, in Molecular Biology of the Cell, 23(19), 3851-3862.
Mitochondrial dysfunction in pancreatic β cells.
Supale Sachin, Li Ning, Brun Thierry, Maechler Pierre (2012), Mitochondrial dysfunction in pancreatic β cells., in Trends in endocrinology and metabolism: TEM, 23(9), 477-87.
Mitochondrial Hormesis in Pancreatic beta Cells: Does Uncoupling Protein 2 Play a Role?
Li Ning, Stojanovski Suzana, Maechler Pierre (2012), Mitochondrial Hormesis in Pancreatic beta Cells: Does Uncoupling Protein 2 Play a Role?, in OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 740849.
NADPH Oxidase NOX2 Defines a New Antagonistic Role for Reactive Oxygen Species and cAMP/PKA in the Regulation of Insulin Secretion
Li Ning, Li Bin, Brun Thierry, Deffert-Delbouille Christine, Mahiout Zahia, Daali Youssef, Ma Xiao-Juan, Krause Karl-Heinz, Maechler Pierre (2012), NADPH Oxidase NOX2 Defines a New Antagonistic Role for Reactive Oxygen Species and cAMP/PKA in the Regulation of Insulin Secretion, in DIABETES, 61(11), 2842-2850.
Tissue specificity of glutamate dehydrogenase as illustrated in pancreatic beta-cells and the central nervous system
Carobbio S, Vetterli L, Frigerio F, Karaca M, Maechler P (2012), Tissue specificity of glutamate dehydrogenase as illustrated in pancreatic beta-cells and the central nervous system, in Frontiers in Diabetes, 21, 125-136.
ChREBP mediates glucose repression of peroxisome proliferator-activated receptor alpha expression in pancreatic beta-cells.
Boergesen Michael, Poulsen Lars la Cour, Schmidt Søren Fisker, Frigerio Francesca, Maechler Pierre, Mandrup Susanne (2011), ChREBP mediates glucose repression of peroxisome proliferator-activated receptor alpha expression in pancreatic beta-cells., in The Journal of biological chemistry, 286(15), 13214-25.
From pancreatic islets to central nervous system, the importance of glutamate dehydrogenase for the control of energy homeostasis.
Karaca Melis, Frigerio Francesca, Maechler Pierre (2011), From pancreatic islets to central nervous system, the importance of glutamate dehydrogenase for the control of energy homeostasis., in Neurochemistry international, 59(4), 510-7.
Non-invasive imaging of ferucarbotran labeled INS-1E cells and rodent islets in vitro and in transplanted diabetic rats.
Auer Veronika J, Bucher Julian, Schremmer-Danninger Elisabeth, Paulmurugan Ramasamy, Maechler Pierre, Reiser Maximilian F, Stangl Manfred J, Berger Frank (2011), Non-invasive imaging of ferucarbotran labeled INS-1E cells and rodent islets in vitro and in transplanted diabetic rats., in Current pharmaceutical biotechnology, 12(4), 488-96.
Novel hexahydropyridoindole derivative as prospective agent against oxidative damage in pancreatic β cells.
Račková Lucia, Cumaoğlu Ahmet, Bağrıacık E Umit, Štefek Milan, Maechler Pierre, Karasu Çimen (2011), Novel hexahydropyridoindole derivative as prospective agent against oxidative damage in pancreatic β cells., in Medicinal chemistry (Shāriqah (United Arab Emirates)), 7(6), 711-7.
Resveratrol-activated SIRT1 in liver and pancreatic β-cells: a Janus head looking to the same direction of metabolic homeostasis.
Vetterli Laurène, Maechler Pierre (2011), Resveratrol-activated SIRT1 in liver and pancreatic β-cells: a Janus head looking to the same direction of metabolic homeostasis., in Aging, 3(4), 444-9.
Procyanidins modify insulinemia by affecting insulin production and degradation.
Castell-Auví Anna, Cedó Lídia, Pallarès Victor, Blay M Teresa, Pinent Montserrat, Motilva M José, Garcia-Vallvé Santiago, Pujadas Gerard, Maechler Pierre, Ardévol Anna, Procyanidins modify insulinemia by affecting insulin production and degradation., in The Journal of nutritional biochemistry.
Transglutaminase 2 transamidation activity during first-phase insulin secretion: natural substrates in INS-1E.
Russo Lucia, Marsella Claudia, Nardo Giovanni, Massignan Tania, Alessio Massimo, Piermarini Emanuela, La Rosa Stefano, Finzi Giovanna, Bonetto Valentina, Bertuzzi Federico, Maechler Pierre, Massa Ornella, Transglutaminase 2 transamidation activity during first-phase insulin secretion: natural substrates in INS-1E., in Acta diabetologica.

Collaboration

Group / person Country
Types of collaboration
Mandrup S. Odense University Denmark (Europe)
- Publication
- Research Infrastructure
- Exchange of personnel

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
annual meeting of the European Association for the Study of Diabetes Poster 12.09.2013 Barcelona, Spain Maechler Pierre;
annual meeting of the American Diabetes Association Poster 12.06.2013 Chicago, United States of America Maechler Pierre; Karaca Melis;
Swiss Endocrine & Diabetes Society Talk 23.11.2012 Bern, Switzerland Maechler Pierre; Li Ning;
48th annual meeting of the European Association for the Study of Diabetes Poster 03.10.2012 Berlin, Germany Maechler Pierre;
48th annual meeting of the European Association for the Study of Diabetes Poster 03.10.2012 Berlin, Germany Maechler Pierre; Li Ning;
Scandinavian Physiological Society's Annual Meeting Talk 20.08.2012 Helsinki, Finland Maechler Pierre;
Biochemical Society symposium “keeping the engine clean: role of mitophagy in physiology and pathology” Talk 13.12.2011 London, Great Britain and Northern Ireland Supale Sachin;
annual meeting of the Swiss Endocrine & Diabetes Society Talk 02.12.2011 Bern, Switzerland Supale Sachin; Maechler Pierre;
annual meeting of the Swiss Endocrine & Diabetes Society Talk 02.12.2011 Bern, Switzerland Karaca Melis; Maechler Pierre;
annual meeting of the Swiss Endocrine & Diabetes Society Talk 02.12.2011 Bern, Switzerland Maechler Pierre;
annual meeting of the Swiss Endocrine & Diabetes Society Poster 02.12.2011 Bern, Switzerland Li Ning; Maechler Pierre;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television RTS Western Switzerland 2013

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)
120584 Mitochondrial function and glutamate pathways in the control of metabolic homeostasis 01.04.2008 Project funding (Div. I-III)
166625 Glutamate pathways and metabolic stresses in energy homeostasis 01.09.2016 Project funding (Div. I-III)
166625 Glutamate pathways and metabolic stresses in energy homeostasis 01.09.2016 Project funding (Div. I-III)

Abstract

Glutamate is implicated in metabolic and signaling functions that vary according to specific tissues. Glutamate metabolism is controlled by activities of enzymes and carriers, glutamate dehydrogenase (GDH) playing a pivotal role in this process. Although glutamate-specific enzymes share similar properties in most tissues, their regulation varies greatly according to particular organs in order to achieve tissue specific functions. We recently generated transgenic mice based on Cre-lox technology for tissue specific deletion of GDH. This offers a new model for investigating the role of glutamate in selected tissues. We first deleted GDH in pancreatic beta-cells where glutamate plays a role in the control insulin secretion, as we originally demonstrated (Nature 1999, 402:685-9). We reported that mice with beta-cell-specific GDH deletion (BetGlud1-/-) exhibit reduced insulin secretion (JBC 2009, 284:921-9). Preliminary data showed that when fed a high-calorie diet, BetGlud1-/- animals do not develop diet-induced obesity. Our results indicate that GDH is essential for the amplification of the secretory response in beta-cells. Remarkably, such limited beta-cell function, established prior to initiation of high-calorie feeding, protects against overweight gain. Several questions remain open and this transgenic model offers opportunity to address important points. For instance, the study conducted so far was not designed to investigate in details the amplifying pathway in this beta-cell model lacking GDH, but rather investigated the consequences of genetically limited beta-cell function on metabolic homeostasis. Moreover, we will use Tamoxifen inducible GDH knockout in beta-cells, enabling time-specific abrogation of the enzyme. This will be achieved in the present project proposal.In the brain, energy is mostly derived from glucose breakdown. However, there is also an undetermined contribution of oxidative catabolism of the neurotransmitter glutamate. We generated transgenic mice with brain-specific deletion of GDH, named CnsGlud1-/-. The lack of GDH impairs glutamate oxidation and ATP generation in knockout brains, resulting in an elevated intra-cerebral glutamate pool. This leads to increased brain glucose consumption in the brain, as alternative energy substrate used centrally to compensate the lack of glutamate catabolism. Preliminary data show that impairment of glutamate usage in the brain induces mobilization of energy substrates from the periphery. Changes in brain glutamate metabolism are associated with diseases such as schizophrenia. We aim at drawing a comprehensive integrated model of glutamate pathways, taking into account tissue specificities. The project will focus on the role of glutamate as a source of energy to the brain.Finally, a third project will be conducted to extend our previous observations regarding beta-cell dysfunction related to mitochondrial injuries. This in vitro project, independent of transgenic mice, aims at identifying putative common molecular targets during mitochondrial damages triggered by different stressors (fatty acids, high glucose, and oxidative stress). To this end, we will use a mitochondrial expression array (Mito-array) coupled with new bioinformatics tools (Cytoscape).Overall, the present proposal aims at extending our knowledge on mitochondrial function and glutamate pathways in the control of energy homeostasis.
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