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

ABSTRACT: 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 Children's 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.

SUBMITTER: Ferrara CT

PROVIDER: S-EPMC5460685 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Ferrara Christine T CT Boodhansingh Kara E KE Paradies Eleonora E Fiermonte Giuseppe G Steinkrauss Linda J LJ Topor Lisa Swartz LS Quintos Jose Bernardo JB Ganguly Arupa A De Leon Diva D DD Palmieri Ferdinando F Stanley Charles A CA

The Journal of clinical endocrinology and metabolism 20170301 3

<h4>Context</h4>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.<h4>Objective</h4>To evaluate the frequency of UCP2 mutations in children with HI and phenotypic features of this form of HI.<h4>Design</h4>We examined 211 children with diazoxide-responsive HI seen at The Children's Hospital of Philadelphia (CHO ...[more]

PMID: 27967291

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Project description:The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response.Article highlightsOur evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in β-cells and α-cells to regulate glucose homeostasis.

Dataset Information

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

Publications

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

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