Abstract
Protein-sensitive hypoglycemia in children with congenital hyperinsulinism (HI) highlights the important role of amino acids in regulation of insulin secretion. The studies of insulin secretion in three HI mouse models suggested that glutamine (Q)-glutamate (E)-alpha-ketoglutarate (αKG) axis played a key role in amino acid-stimulated insulin secretion. The mechanism of dysregulated insulin secretion in HI with a glutamate dehydrogenase (GDH) gain of function mutation is due to increased amino acid oxidation via this key axis. Loss of function mutation of Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) also cause HI, the study of SCHAD knockout mice indicated that SCHAD inhibits GDH via protein-protein interaction; HI due to SCHAD deficiency shares a similar mechanism with GDH gain of function. In contrast, loss of function mutations of ATP-dependent potassium channels are sensitive to glutamine but not to leucine-stimulated insulin secretion. 13C tracing studies in islets suggested that generation of glutamine via the reverse flux of Q-E-αKG axis during glucose oxidation is important to maintain insulin secretion stimulated by glucose. The key enzymes in the Q-E-αKG axis, including glutaminase, GDH and glutamine synthetase, serve as intracellular energy sensors to determine the sensitivity of amino acid stimulation of insulin secretion.
Published Version
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