The Hypoglycemic Phenotype Is Islet Cell–Autonomous in Short-Chain Hydroxyacyl-CoA Dehydrogenase–Deficient Mice

Congenital hyperinsulinism of infancy (CHI) can be caused by inactivating mutations in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a ubiquitously expressed enzyme involved in fatty acid oxidation. The hypersecretion of insulin may be explained by a loss of interaction between SCHAD and glutamate dehydrogenase in the pancreatic beta-cells. However, in affected individuals there is also a general accumulation of metabolites specific for the enzymatic defect. It remains to be explored whether hypoglycemia in SCHAD-CHI can be uncoupled from the systemic effect on fatty acid oxidation. We therefore transplanted islets from global SCHAD knock-out (SCHADKO) mice into mice with streptozotocin-induced diabetes. Following transplantation, SCHADKO islet recipients exhibited significantly lower random and fasting blood glucose compared with mice transplanted with normal islets or non-diabetic, non-transplanted controls. Furthermore, intraperitoneal glucose tolerance was improved in animals receiving SCHADKO islets compared with those receiving normal islets. Graft beta-cell proliferation and apoptosis rates were similar in the two transplantation groups. We conclude that hypoglycemia in SCHAD-CHI is islet cell-autonomous.