metabolism; glutamate dehydrogenase; mitochondria; beta-cell; insulin
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.
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.
Maechler P (2017), Glutamate pathways of the beta-cell and the control of insulin secretion., in Diabetes Res Clin Pract.
, 131, 149.
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.
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.
Brun Thierry (2016), Beta-cell mitochondrial carriers and the diabetogenic stress response., in Biochim. Biophys. Acta.
, 1863, 2540-2549.
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.
Vetterli Laurene (2016), The amplifying pathway of the ß-cell contributes to diet-induced obesity, in J. Biol. Chem.
, 291, 13063.
Wollheim Claes B, Maechler Pierre (2015), Beta cell glutamate receptor antagonists: novel oral antidiabetic drugs?
, nature publishing group, New York USA.
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.
Karaca Melis, Maechler Pierre (2015), GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution, in Cell Reports
, 13(2), 365-375.
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.
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.
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.
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.
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.
Maechler Pierre (2013), Mitochondrial function and insulin secretion., in Molecular and cellular endocrinology
, 379(1-2), 12-8.
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.