Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of β-oxidation in insulin secretion

Abstract

A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the beta cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.

Mechanism of Hyperinsulinism in Short-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency Involves Activation of Glutamate Dehydrogenase

“…A total of five families has been reported with hyperinsulinism associated with SCHAD deficiency, and we are aware of three additional unpublished cases (2)(3)(4)23). All of these cases had recessive mutations identified, and most appear to be associated with the absence of SCHAD protein, as well as enzymatic activity.…”

“…In addition, patients with K ATP channel inactivation are unresponsive to treatment with diazoxide, a K ATP channel agonist, whereas patients with SCHAD deficiency respond well to diazoxide (2,3,6,23). Thus, the hyperinsulinism associated with SCHAD deficiency is not due to abnormalities of the K ATP channel.…”

Hipoglicemia hiperinsulinêmica da infância

“…Nesses casos, a hipoglicemia pode ocorrer tanto após a ingestão de leucina quanto após um período de jejum, em recém-natos, mas também em crianças mais velhas. Tipicamente, essas crianças apresentam convulsões do tipo ausência associadas a alterações eletroencefalográficas de padrão de epilepsia generalizada (22)(23)(24)(25)(26).…”

“…Os portadores desse tipo de defeito sofrem de HH sensível ao diazóxido, na maioria das vezes. Recentemente foi descrito um portador de HH severa e não responsiva ao diazóxido e que apresentava uma mutação "de novo" no gene da glicoquinase (22)(23)(24)(25)(26). A deficiência da SCHD é a causa ainda de mecanismo não totalmente explicado de HH.…”

Does chasing selected ‘Fox’ to the nucleus prevent diabetes?

“…This is associated with reduced expression of the ATP-sensitive K C -channel subunits Kir6.2 and Sur1 and short-chain 3-hydroxyacyl-CoA dehydrogenase (Schad) [11,24]. Human loss-of-function mutations in these three genes are linked to persistent hyperinsulinemic hypoglycemia of infancy [25,26]. Conversely, the gain of function following Foxa2 overexpression in rat insulinoma INS-1 cells suppresses insulin secretion [27].…”