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

Martin-Del-Rio, Rafael
Skytt, Dorte M
Waagepetersen, Helle S
Tamarit-Rodriguez, Jorge
Published in Molecular biology of the cell. 2012, vol. 23, no. 19, p. 3851-62
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.
Keywords Alanine Transaminase/metabolismAnimalsAspartate Aminotransferases/metabolismAspartic Acid/biosynthesisCalcium SignalingCells, CulturedFemaleGlucose/physiologyGlutamate Dehydrogenase/deficiency/genetics/physiologyGlutamic Acid/biosynthesis/metabolism/physiologyGlutamine/physiologyInsulin/secretionInsulin-Secreting Cells/enzymology/secretionLeucine/physiologyMaleMiceMice, 129 StrainMice, Inbred C57BLMice, Knockout
PMID: 22875990
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Article (Published version) (1.4 MB) - public document Free access
Research group Mitochondries et métabolisme énergétique (671)
Swiss National Science Foundation: 310030B_135704
(ISO format)
VETTERLI, Laurene Marine et al. 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, 2012, vol. 23, n° 19, p. 3851-62. doi: 10.1091/mbc.E11-08-0676 https://archive-ouverte.unige.ch/unige:28016

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Deposited on : 2013-05-28

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