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Mitochondrial function and tissue specificity of glutamate pathways in metabolic homeostasis and disease

English title Mitochondrial function and tissue specificity of glutamate pathways in metabolic homeostasis and disease
Applicant Maechler Pierre
Number 146984
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 01.04.2013 - 31.08.2016
Approved amount 638'880.00
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All Disciplines (2)

Discipline
Endocrinology
Biochemistry

Keywords (5)

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

Lay Summary (French)

Lead
Etudes sur la fonction mitochondriale et sur les spécificités des voies du glutamate dans le contrôle énergétique et certaines maladies métaboliques affectant le pancréas endocrine, le foie, et le système nerveux central.
Lay summary

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. La cellule bêta est donc 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: 09.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
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.
Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?
Pournourmohammadi S Grimaldi M Stridh MH Lavallard V Waagepetersen HS Wollheim CB Maechler P. (2017), Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?, in Int J Biochem Cell Biol., 88, 220.
Glutamate pathways of the beta-cell and the control of insulin secretion.
Maechler P (2017), Glutamate pathways of the beta-cell and the control of insulin secretion., in Diabetes Res Clin Pract., 131, 149.
Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia.
Grimaldi M Karaca M Latini L Brioudes E Schalch T Maechler P. (2017), Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia., in Hum Mol Genet, 26, 3453.
Upregulation of UCP2 in beta-cells confers partial protection against both oxidative stress and glucotoxicity.
Li N Karaca M Maechler P. (2017), Upregulation of UCP2 in beta-cells confers partial protection against both oxidative stress and glucotoxicity., in Redox Biol., 13, 541.
Beta-cell mitochondrial carriers and the diabetogenic stress response.
Brun Thierry (2016), Beta-cell mitochondrial carriers and the diabetogenic stress response., in Biochim. Biophys. Acta., 1863, 2540-2549.
Integrative Genomics Outlines a Biphasic Glucose Response and a ChREBP-RORγ Axis Regulating Proliferation in β Cells.
Schmidt SF Madsen JG Frafjord KØ Poulsen Ll Salö S Boergesen M Loft A Larsen BD Madsen MS H (2016), Integrative Genomics Outlines a Biphasic Glucose Response and a ChREBP-RORγ Axis Regulating Proliferation in β Cells., in Cell Reports, 16, 2359.
The amplifying pathway of the ß-cell contributes to diet-induced obesity
Vetterli Laurene (2016), The amplifying pathway of the ß-cell contributes to diet-induced obesity, in J. Biol. Chem. , 291, 13063.
Beta cell glutamate receptor antagonists: novel oral antidiabetic drugs?
Wollheim Claes B, Maechler Pierre (2015), Beta cell glutamate receptor antagonists: novel oral antidiabetic drugs?, nature publishing group, New York USA.
Diabetogenic milieus induce specific changes in mitochondrial transcriptome and differentiation of human pancreatic islets.
Brun Thierry, Li Ning, Jourdain Alexis A, Gaudet Pascale, Duhamel Dominique, Meyer Jérémy, Bosco Domenico, Maechler Pierre (2015), Diabetogenic milieus induce specific changes in mitochondrial transcriptome and differentiation of human pancreatic islets., in Human molecular genetics, 24(18), 5270-84.
GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution
Karaca Melis, Maechler Pierre (2015), GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution, in Cell Reports, 13(2), 365-375.
Integrated analysis of mRNA and miRNA expression in response to interleukin-6 in hepatocytes.
Lukowski Samuel W, Fish Richard J, Martin-Levilain Juliette, Gonelle-Gispert Carmen, Bühler Leo H, Maechler Pierre, Dermitzakis Emmanouil T, Neerman-Arbez Marguerite (2015), Integrated analysis of mRNA and miRNA expression in response to interleukin-6 in hepatocytes., in Genomics, 106(2), 107-15.
Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells.
Aragón F, Karaca M, Novials A, Maldonado R, Maechler P, Rubí B (2015), Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells., in Biochimica et biophysica acta, 1850(2), 343-51.
Development of mice with brain-specific deletion of floxed glud1 (glutamate dehydrogenase 1) using cre recombinase driven by the nestin promoter.
Karaca Melis, Maechler Pierre (2014), Development of mice with brain-specific deletion of floxed glud1 (glutamate dehydrogenase 1) using cre recombinase driven by the nestin promoter., in Neurochemical research, 39(3), 456-9.
Changes in mitochondrial carriers exhibit stress-specific signatures in INS-1Eβ-cells exposed to glucose versus fatty acids.
Brun Thierry, Scarcia Pasquale, Li Ning, Gaudet Pascale, Duhamel Dominique, Palmieri Ferdinando, Maechler Pierre (2013), Changes in mitochondrial carriers exhibit stress-specific signatures in INS-1Eβ-cells exposed to glucose versus fatty acids., in PloS one, 8(12), 82364-82364.
Loss of prohibitin induces mitochondrial damages altering β-cell function and survival and is responsible for gradual diabetes development.
Supale Sachin, Thorel Fabrizio, Merkwirth Carsten, Gjinovci Asllan, Herrera Pedro L, Scorrano Luca, Meda Paolo, Langer Thomas, Maechler Pierre (2013), Loss of prohibitin induces mitochondrial damages altering β-cell function and survival and is responsible for gradual diabetes development., in Diabetes, 62(10), 3488-99.
Mitochondrial function and insulin secretion.
Maechler Pierre (2013), Mitochondrial function and insulin secretion., in Molecular and cellular endocrinology, 379(1-2), 12-8.

Collaboration

Group / person Country
Types of collaboration
J. Tamarit-Rodriguez (University of Madrid) Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Helle Waagepetersen, University of Copenhagen Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
R. Gruetter (EPFL) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
S. Mandrup (University of Southern Danemark) Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Stephen Rayport, Columbia University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
annual meeting of the Swiss Endocrine & Diabetes Society Talk given at a conference Identification of the molecular dysfunction induced by GDH S445L mutation associated with Hyperinsulinism/Hyperammonemia syndrome 20.11.2015 Bern, Switzerland Karaca Melis; Grimaldi Mariagrazia; Maechler Pierre;
annual meeting of the Swiss Endocrine & Diabetes Society Talk given at a conference Role of FFAR1/GPR40 in the response of INS-1E ß-cells to glucolipotoxicity 20.11.2015 Bern, Switzerland Maechler Pierre;
annual meeting of the European Association for the Study of Diabetes Poster Liver glutamate dehydrogenase knockout mice display impaired gluconeogenesis and altered feeding behavior 15.09.2015 Stockholm, Sweden Grimaldi Mariagrazia; Karaca Melis; Maechler Pierre;
annual meeting of the European Association for the Study of Diabetes Poster Chronic exposure to fructose exaggerates glucose-stimulated insulin secretion in INS-1E beta cells and human islets 15.09.2015 Stockholm, Sweden Maechler Pierre;
SGED Talk given at a conference Human islets exposed to distinct diabetogenic conditions exhibit stress-specific changes in mitochondrion-associated genes 28.11.2014 Bern, Switzerland Maechler Pierre;
SGED Talk given at a conference Absence of brain glutamate dehydrogenase increases central glucose utilization and peripheral energy substrate mobilization 28.11.2014 Bern, Switzerland Karaca Melis; Maechler Pierre;
EASD Poster Brain glutamate dehydrogenase (GDH) knockout mice display modified central glucose metabolism reshaping peripheral energy distribution 16.09.2014 Vienna, Austria Maechler Pierre; Karaca Melis;
EASD Talk given at a conference Mitochondria and metabolic signalling in ß-cells 15.09.2014 Vienna, Austria Maechler Pierre;
Swiss Mito Poster Mitochondrial GDH mutation and the Hyperinsulinism/Hyperammonemia syndrome 03.09.2014 Kandersteg, Switzerland Maechler Pierre; Grimaldi Mariagrazia; Karaca Melis;
Swiss Mito Talk given at a conference From cell metabolism to physiology through mitochondria”. At the first SwissMito meeting 03.09.2014 Kandersteg , Switzerland Maechler Pierre;
MeetOchondrie Poster Changes in mitochondrion-associated genes exhibit stress-specific signatures in human islets exposed to high glucose or fatty acids 04.05.2014 Evian, France Maechler Pierre;
Biochemical Society / British Neuroscience Association Poster Brain glutamate dehydrogenase (GDH) knockout mice compensate for the lack of glutamate oxidation by increasing glucose utilization 28.04.2014 London, Great Britain and Northern Ireland Maechler Pierre; Karaca Melis;
Drug Research Academy Lecture Series in pharmaceutical sciences Individual talk Tissue specificity of glutamate dehydrogenase and its role in metabolic homeostasis 10.10.2013 Copenhagen , Denmark Maechler Pierre;
EASD Poster Identification of mitochondrial targets in human islets exposed to high glucose or fatty acids 21.09.2013 Barcelona, Spain Maechler Pierre;
International Conference for Microcirculation and Chinese Association of Integrative Medicine Talk given at a conference Mitochondria as sensors and generators of metabolic signals for the control of metabolic homeostasis 09.09.2013 Beijing , China Maechler Pierre;
ADA Poster Brain glutamate dehydrogenase (GDH) knockout mice display modified central energy metabolism and reshaped peripheral energy distribution. 10.06.2013 Chicago, United States of America Maechler Pierre; Karaca Melis;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
TecDay Talk 28.04.2015 Carouge, Switzerland Maechler Pierre;


Associated projects

Number Title Start Funding scheme
135704 Investigating tissue specificity of glutamate pathway and mitochondrial function in the control of metabolic homeostasis 01.04.2011 Project funding (Div. I-III)
166625 Glutamate pathways and metabolic stresses in energy homeostasis 01.09.2016 Project funding (Div. I-III)
164095 NMR 600MHz for metabolomics and biomarker identification for life sciences, chemical biology and medical projects at the University of Geneva 01.01.2016 R'EQUIP

Abstract

The mitochondrial enzyme glutamate dehydrogenase (GDH) catalyzes the same reaction in every tissue but it fulfills dedicated and highly specialized functions in different organs. 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 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.Using ß-cell specific GDH knockout ßGlud1-/-, we have shown that GDH is necessary for the full development of glucose-stimulated insulin secretion. We will extend these studies by testing if a primary failure in ß-cells, prior to high calorie intake and insulin resistance would favor diabetes occurrence in mice developing obesity. We also generated CNS specific GDH null mice (Cns-Glud1-/-) and observed that the lack of GDH impairs glutamate oxidation and ATP generation in knockout brains. This leads to increased brain glucose consumption and mobilization of energy substrates from the periphery. We will investigate metabolic adaptation in peripheral organs and crosstalk with CNS. In particular, adaptation of the liver and requirement for hepatic GDH in neoglucogenesis will be studied with help of inducible liver specific GDH knockout (Hep-Glud1-/-). Changes in brain glutamate metabolism are associated with neurological disorders, which will be the subject of specific collaborations. Finally, we will study one of the most frequent GDH mutation associated with hyperinsulinemia/hyperammonia and epilepsy by tissue-selective introduction of the mutation. The last project will be conducted to extend our previous observations regarding ß-cell dysfunction related to mitochondrial injuries. This in vitro project, independent of transgenic mice, aims at identifying putative common molecular targets in human islets subjected to metabolic stressors. Overall, the proposed projects aim at extending our knowledge on mitochondrial function and glutamate pathways in the control of energy homeostasis.
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