title: Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase.
abstract: In pancreatic β-cells, glutamate dehydrogenase (GDH) modulates insulin secretion, although its function regarding specific secretagogues is unclear. This study investigated the role of GDH using a β-cell-specific GDH knockout mouse model, called βGlud1(-/-). The absence of GDH in islets isolated from βGlud1(-/-) mice resulted in abrogation of insulin release evoked by glutamine combined with 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or l-leucine. Reintroduction of GDH in βGlud1(-/-) islets fully restored the secretory response. Regarding glucose stimulation, insulin secretion in islets isolated from βGlud1(-/-) mice exhibited half of the response measured in control islets. The amplifying pathway, tested at stimulatory glucose concentrations in the presence of KCl and diazoxide, was markedly inhibited in βGlud1(-/-) islets. On glucose stimulation, net synthesis of glutamate from α-ketoglutarate was impaired in GDH-deficient islets. Accordingly, glucose-induced elevation of glutamate levels observed in control islets was absent in βGlud1(-/-) islets. Parallel biochemical pathways, namely alanine and aspartate aminotransferases, could not compensate for the lack of GDH. However, the secretory response to glucose was fully restored by the provision of cellular glutamate when βGlud1(-/-) islets were exposed to dimethyl glutamate. This shows that permissive levels of glutamate are required for the full development of glucose-stimulated insulin secretion and that GDH plays an indispensable role in this process.
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland.
authors.forename: Laurène
authors.initials: L
authors.lastname: Vetterli
authors.forename: Stefania
authors.initials: S
authors.lastname: Carobbio
authors.forename: Shirin
authors.initials: S
authors.lastname: Pournourmohammadi
authors.forename: Rafael
authors.initials: R
authors.lastname: Martin-Del-Rio
authors.forename: Dorte M
authors.initials: DM
authors.lastname: Skytt
authors.forename: Helle S
authors.initials: HS
authors.lastname: Waagepetersen
authors.forename: Jorge
authors.initials: J
authors.lastname: Tamarit-Rodriguez
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001224:Aspartic Acid / Q000096:biosynthesis; D020013:Calcium Signaling; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000502:physiology; D005969:Glutamate Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018698:Glutamic Acid / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D005973:Glutamine / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism*; D007930:Leucine / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D007328:Insulin; D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007930:Leucine; D005947:Glucose