The Complex Mechanism of Glutamate Dehydrogenase in Insulin Secretion
Leucine is the only physiologic amino acid that can stimulate insulin release by itself, and a great deal of evidence suggests that leucine does this by allosterically activating glutamate dehydrogenase (GDH). GDH catalyzes the oxidative deamination of endogenous glutamate, which is present at a high concentration in the pancreatic β-cell. Studies that support this role of leucine include the fact that leucine and 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), a nonmetabolizable leucine analog, are activators of GDH and promote insulin release from pancreatic islets (1–4). Although the addition to pancreatic islets of glutamine alone—which by its conversion to glutamate enormously increases the intracellular concentration of glutamate—does not stimulate insulin release, adding glutamine in the presence of leucine or BCH causes a robust stimulation of insulin release. Patients with mutations in the region of the GDH gene that encodes the part of the GDH protein where the allosteric inhibitor guanosine triphosphate (GTP) binds to the enzyme suffer from hyperinsulinism and hypoglycemia (5), and this indicates that GDH is involved in insulin secretion in humans. In addition, recent studies showed that short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency causes hyperinsulinism secondary to a loss of inhibition of GDH by SCHAD (6). Antischizophrenic drugs can produce hyperglycemia in patients (7,8) perhaps due to their ability to inhibit GDH. Both insulin release and GDH activity are decreased by SIRT4 (9), a mitochondrial ADP-ribosyl transferase, and deletion of GDH in β-cells partially abolishes the insulin secretory response (10).
THE GDH REACTION
GDH catalyzes the reaction NAD(P) + Glutamate ⇆ NAD(P)H + α-ketoglutarate + NH4+ (Fig. 1). The catalytically active form of the enzyme is six identical 5.7 × 104 molecular weight monomers configured as a hexamer (11–13). When the concentration of the hexamer is high, it polymerizes (12,13). In addition to …