Mitochondria-derived glutamate at the interplay between branched-chain amino acid and glucose-induced insulin secretion.
In pancreatic beta-cells, glutamate has been proposed to mediate insulin secretion as a glucose-derived factor, although it is also considered for its sole catabolic function. Hence, changes in cellular glutamate levels are a matter of debate. Here, we investigated the effects of glucose and the glutamate precursor glutamine on kinetics of glutamate levels together with insulin secretion in INS-1E beta-cells. Preincubation at low (1 mM) glucose resulted in reduced cellular glutamate levels, which were doubled by exposure to glutamine. In glutamine-deprived cells, 5 mM glucose restored glutamate concentrations. Incubation at 15 mM glucose increased cellular glutamate, along with stimulation of insulin secretion, following both glutamine-free and glutamine-rich preincubations. Nuclear magnetic resonance (NMR) spectroscopy of INS-1E cells exposed to 15 mM D-[1-(13)C]glucose revealed glutamate as the major glucose metabolic product. Branched-chain amino acids, such as leucine, reduced cellular glutamate levels at low and intermediate glucose. This study demonstrates that glucose stimulates glutamate generation, whereas branched-chain amino acids promote competitive glutamate expenditure.
Broca
Christophe
C
DBC-9100, Department of Internal Medicine, University Medical Centre, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland.
Brennan
Lorraine
L
Petit
Pierre
P
Newsholme
Philip
P
Maechler
Pierre
P
D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002999:Clone Cells; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured
D000597:Amino Acids, Branched-Chain; D007328:Insulin; D018698:Glutamic Acid; D005969:Glutamate Dehydrogenase; D005947:Glucose