Linda Steinkrauss

Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2 (UCP2).

Context The rarest genetic form of congenital hyperinsulinism (HI) has been associated with dominant inactivating mutations in uncoupling protein 2 (UCP2), a mitochondrial inner membrane carrier that modulates oxidation of glucose vs amino acids. Objective To evaluate the frequency of UCP2 mutations in children with HI and phenotypic features of this form of HI. Design We examined 211 children with diazoxide-responsive HI seen at The Childrens Hospital of Philadelphia (CHOP) between 1997 and October 2016. Setting CHOP Clinical and Translational Research Center. Results Of 211 cases of diazoxide-responsive HI, we identified 5 unrelated children with UCP2 mutations (5 of 211; 2.4%). All 5 were diagnosed with HI before 6 months of age; diazoxide treatment was only partly effective in 3 of the 5. Among the 5 cases, 4 unique mutations (3 missense and 1 splicing) were identified. Three mutations were novel; 1 was previously reported. In vitro functional assays showed 30% to 75% decrease in UCP2 activity. Two of the children, when not taking diazoxide, developed hypoketotic-hypoglycemia after fasting 15 to 20 hours; a similar trend toward hypoglycemia after fasting 24 hours occurred in 4 adult carriers. In contrast, both children and 2 of the 4 carriers developed symptomatic hypoglycemia 4 hours following oral glucose. Unusual oscillating glucose and insulin responses to oral glucose were seen in both cases and carriers. Conclusions These data indicate that dominant UCP2 mutations are a more important cause of HI than has been recognized and that affected individuals are markedly hypersensitive to glucose-induced hypoglycemia.

Hypoglycemia: Symptom or Diagnosis?

Although hypoglycemia is a medical diagnosis, it is generally a sign of an underlying disorder of fasting adaptation. In the normal process of fasting, the body has several mechanisms for keeping blood glucose from dropping too low. First, there is a breakdown of glycogen stores (glycogenolysis) in the liver to release glucose. This process occurs about 2 to 3 hours after eating. When the glycogen stores are used up, fatty acid oxidation and ketogenesis, which produce free fatty acids and ketones, occur. The timing for this process varies from 8 to 12 hours after eating. Anyone who fasts long enough will eventually develop hypoglycemia. Glucose fuels brain metabolism, and free fatty acids and ketones fuel muscle. Ketones can also be used as an alternative fuel for the brain during prolonged fasting. Unrecognized, prolonged, or repeated episodes of hypoglycemia, particularly in infants and children, can lead to seizures, permanent brain damage, developmental delay, and death (De Leon, Stanley, & Sperling, 2008).