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

Short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) catalyzes the penultimate reaction in the mitochondrial fatty acid oxidation spiral, the NAD+dependent conversion of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA. The cDNA and genomic sequences for human SCHAD have been elucidated (1, 2). Northern blot analysis of SCHAD mRNA revealed a single transcript; expression was highest in skeletal and cardiac muscle but also present in liver, kidney, and pancreas (1). Earlier work had shown that the islets of Langerhans contain high SCHAD activity (3, 4). This suggests that the enzyme and the regulation of fat oxidation may have an important function in the β cell. Deficiency of a mitochondrial fatty acid oxidation enzyme typically produces hypoketotic hypoglycemia; some defects also produce hepatomegaly and skeletal and cardiac myopathy (5). Tein et al. reported reduced SCHAD activity in muscle but not fibroblasts of a patient with recurrent myoglobinuria, hypoketotic hypoglycemia, and cardiomyopathy (6). Bennett et al. described reduced SCHAD activity in the fibroblasts of two children with recurrent ketosis and ketotic hypoglycemia (7) and reduced activity in the liver but not the muscle of three sudden infant death victims (8).To date none of these patients with reduced SCHAD activity has been shown to have mutations in the Schad gene (9). One patient presenting with fulminant hepatic failure at 3 years was found to have G118A and C171A mutations in the Schad gene (10). The SCHAD knockout mouse dies if fasted for 10 hours, whereas wild-type mice survive 24 hours (11). Apart from fatty acid oxidation defects (FAODs), the main cause of hypoketotic hypoglycemia in infancy is hyperinsulinism (HI). Unlike patients with FAOD, at the time of hypoglycemia, infants with HI have a raised plasma insulin and C-peptide, a low plasma concentration of nonesterified fatty acids (NEFAs), and a normal NEFA/D3-hydroxybutyrate ratio. The patient described below had clear evidence of elevated plasma insulin and C-peptide when she was hypoglycemic. However, on another occasion, the NEFA/D-3-hydroxybutyrate ratio was at the