Fig. 3

Mechanisms of insulin dysregulation in SCHAD deficiency. In SCHAD-deficient islets, loss of the inhibitory protein–protein interaction of SCHAD on GDH results in increased sensitivity of GDH to allosteric activation of leucine. Glutamine plus leucine has the strongest stimulatory effect on islets in vitro assays. On top of glutamine plus leucine stimulation, increasing alanine secondary to more insulin release, as the TCA cycle can produce more ATP. GDH glutamate dehydrogenase, SCHAD short-chain 3-hydroxyacyl-CoA dehydrogenase, α-KG α-ketoglutarate, OAA oxaloacetate, and TCA tricarboxylic acid