energy metabolism; glutamate; insulin secretion; pancreatic islet
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.
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.
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.
Maechler Pierre (2013), Mitochondrial function and insulin secretion, in Mol. Cell Endocrinol.
, 379, 12-18.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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
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
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.