FIGURE 7.

Mechanism of insulin dysregulation in SCHAD deficiency. In SCHAD-deficient islets, the loss of an inhibitory protein-protein interaction of SCHAD on GDH leads to an increase in the sensitivity of the GDH reaction to allosteric activation by leucine. Stimulation of islets by glutamine plus leucine in vitro produces a submaximal insulin response compared with stimulation with a complete physiological mixture of amino acids, because glutamate trans-deamination to aspartate uses only part of the TCA cycle to generate ATP as a trigger for insulin release. Addition of alanine to stimulation by glutamine plus leucine produces a greater release of insulin, equal to that of a mixture of amino acids, because the TCA cycle can be completed to generate a greater ATP response (18 versus 9 mol of ATP per mol of glutamate oxidized). GDH, glutamate dehydrogenase; SCHAD, short-chain 3-hydroxyacyl-CoA dehydrogenase; α-KG, α-ketoglutarate; OAA, oxaloacetate; and TCA, tricarboxylic acid.