Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase

Research output: Contribution to journalJournal articleResearchpeer-review

Laurène Vetterli, Stefania Carobbio, Shirin Pournourmohammadi, Rafael Martin-Del-Rio, Dorte M Skytt, Helle S. Waagepetersen, Jorge Tamarit-Rodriguez, Pierre Maechler

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.

Original languageEnglish
JournalMolecular Biology of the Cell
Volume23
Issue number19
Pages (from-to)3851-62
Number of pages12
ISSN1059-1524
DOIs
Publication statusPublished - Oct 2012

    Research areas

  • Alanine Transaminase, Animals, Aspartate Aminotransferases, Aspartic Acid, Calcium Signaling, Cells, Cultured, Female, Glucose, Glutamate Dehydrogenase, Glutamic Acid, Glutamine, Insulin, Insulin-Secreting Cells, Leucine, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout

ID: 120585546