GLUD1 encodes a mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate to alpha-ketoglutarate (α-KG), a crucial intermediate in the tricarboxylic acid cycle and glutamine anaplerosis 1234. The enzyme plays a critical role in insulin homeostasis by regulating glucose-stimulated insulin secretion from pancreatic β-cells 56. Under low glucose conditions, GLUD1 phosphorylation at serine 384 enables interaction with NF-κB signaling components, allowing α-KG to directly activate IKKβ and NF-κB, promoting compensatory glucose uptake 7. GLUD1 mutations cause familial hyperinsulinemic hypoglycemia type 6 (FHHI6), a rare neonatal disorder characterized by inappropriate insulin secretion despite hypoglycemia 8910. GLUD1-related hyperinsulinism typically presents as diazoxide-responsive and is frequently accompanied by hyperammonemia, distinguishing it from other genetic forms of congenital hyperinsulinism 118. Beyond glucose regulation, GLUD1 supports glutaminolysis in cancer cells, where its product α-KG fuels metabolic reprogramming in pancreatic and brain tumors 127.