| First Author | Vetterli L | Year | 2012 |
| Journal | Mol Biol Cell | Volume | 23 |
| Issue | 19 | Pages | 3851-62 |
| PubMed ID | 22875990 | Mgi Jnum | J:199757 |
| Mgi Id | MGI:5504580 | Doi | 10.1091/mbc.E11-08-0676 |
| Citation | Vetterli L, et al. (2012) Delineation of glutamate pathways and secretory responses in pancreatic islets with beta-cell-specific abrogation of the glutamate dehydrogenase. Mol Biol Cell 23(19):3851-62 |
| abstractText | In pancreatic beta-cells, glutamate dehydrogenase (GDH) modulates insulin secretion, although its function regarding specific secretagogues is unclear. This study investigated the role of GDH using a beta-cell-specific GDH knockout mouse model, called betaGlud1(-/-). The absence of GDH in islets isolated from betaGlud1(-/-) 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 betaGlud1(-/-) islets fully restored the secretory response. Regarding glucose stimulation, insulin secretion in islets isolated from betaGlud1(-/-) 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 betaGlud1(-/-) islets. On glucose stimulation, net synthesis of glutamate from alpha-ketoglutarate was impaired in GDH-deficient islets. Accordingly, glucose-induced elevation of glutamate levels observed in control islets was absent in betaGlud1(-/-) 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 betaGlud1(-/-) 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. |
