insulin; beta-cell; glutamate dehydrogenase; mitochondria; metabolism
Oberhauser Lucie, Granziera Sabrina, Colom Adai, Goujon Antoine, Lavallard Vanessa, Matile Stefan, Roux Aurélien, Brun Thierry, Maechler Pierre (2020), Palmitate and oleate modify membrane fluidity and kinase activities of INS-1E β-cells alongside altered metabolism-secretion coupling, in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
, 1867(2), 118619-118619.
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.
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.
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.
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.
Maechler Pierre (2017), Glutamate pathways of the beta-cell and the control of insulin secretion, in Diabetes Research and Clinical Practice
, 131, 149-153.
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.