Abstract
One of the genetic forms of hyperinsulinism highlights the role of glutamate dehydrogenase (GDH) in pancreatic beta-cells. GDH is a mitochondrial enzyme which plays a pivotal role between carbohydrate and protein metabolisms by controlling production and consumption of the messenger molecule glutamate in neuroendocrine cells. GDH activity is controlled by several regulators that confer energy-sensor properties to this enzyme. Moreover, GDH is allosterically regulated by GTP and ADP. GDH is also regulated by ADP-ribosylation, mediated by a member of the energy-sensor family sirtuins, namely SIRT4. In the brain, GDH ensures the cycling of the neurotransmitter glutamate between neurons and astrocytes. GDH also controls ammonia metabolism and detoxification (mainly in the liver and kidney).In pancreatic beta-cells, the importance of GDH as a key enzyme in the regulation of insulin secretion is now well established. Inhibition of GDH activity decreases insulin release, while activating mutations are associated with a hyperinsulinism syndrome. Although GDH enzyme catalyzes the same reaction in every tissue, its function regarding metabolic homeostasis varies greatly according to specific organs. Newly generated mouse models lacking GDH in specific tissues offer an opportunity to decipher organ specificities of GDH regulation.
Published Version
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