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Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion.

ABSTRACT: Although the most common mechanism underlying congenital hyperinsulinism is dysfunction of the pancreatic ATP-sensitive potassium channel, the pathogenesis and genetic origins of this disease remains largely unexplained in more than half of all patients. UCP2 knockout mice exhibit an hyperinsulinemic hypoglycemia, suggesting an involvement of UCP2 in insulin secretion. However, a possible pathogenic role for UCP2 protein in the development of human congenital hyperinsulinism or of any human disease has not yet been investigated. We studied ten children exhibiting congenital hyperinsulinism, without detectable mutations in the known congenital hyperinsulinism-causing genes. Parental-inherited heterozygous UCP2 variants encoding amino-acid changes were found in two unrelated children with congenital hyperinsulinism. Functional assays in yeast and in insulin-secreting cells revealed an impaired activity of UCP2 mutants. Therefore, we report the finding of UCP2 coding variants in human congenital hyperinsulinism, which reveals a role for this gene in the regulation of insulin secretion and glucose metabolism in humans. Our results show for the first time a direct association between UCP2 amino acid alteration and human disease and highlight a role for mitochondria in hormone secretion.

SUBMITTER: Gonzalez-Barroso MM

PROVIDER: S-EPMC2588657 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion.

González-Barroso M Mar MM Giurgea Irina I Bouillaud Fredéric F Anedda Andrea A Bellanné-Chantelot Christine C Hubert Laurence L de Keyzer Yves Y de Lonlay Pascale P Ricquier Daniel D

PloS one 20081209 12

Although the most common mechanism underlying congenital hyperinsulinism is dysfunction of the pancreatic ATP-sensitive potassium channel, the pathogenesis and genetic origins of this disease remains largely unexplained in more than half of all patients. UCP2 knockout mice exhibit an hyperinsulinemic hypoglycemia, suggesting an involvement of UCP2 in insulin secretion. However, a possible pathogenic role for UCP2 protein in the development of human congenital hyperinsulinism or of any human dise ...[more]

PMID: 19065272

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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.

Project description:IntroductionCongenital hyperinsulinism is a rare inherited disease caused by mutations in genes responsible for β-cell's function in glucose hemostasis leading to profound and recurrent hypoglycemia. The incidence of the disease is about 1 in 50000 newborns. Mutations in at least 8 genes have been reported to cause congenital hyperinsulinism. Mutations in ABCC8 gene are the most common cause of the disease that account for approximately 40% of cases. Less frequently KCNJ11 gene mutations are responsible for the disease. Mutations in other genes such as HADH account for smaller fractions of cases. In nearly half of the cases the cause remains unknown.Case presentationDuring the period between 2005 and 2010, a total of six patients with persistent hyperinsulinism were investigated at Mofid Children's Hospital. In this study all of the patients had early onset hyperinsulinemia. Five patients had consanguineous parents. After failure of medical treatment in three patients, They were undergone pancreatectomy. Two diffuse types and one focal type had been recognized in pathological analysis of intra-operative frozen specimens of pancreas in these patients. Genetic analysis was performed using polymerase chain reaction followed by Sanger sequencing for ABCC8, KCNJ11and HADH genes. In five patients homozygous mutations in these genes were identified that indicated an autosomal recessive pattern of inheritance. In one patient a heterozygous mutation in ABCC8 was identified, indicating possible autosomal dominant inheritance of the disease.ConclusionsCongenital hyperinsulinism can have different inheritance pattern. Autosomal recessive inheritance is more common but less frequently autosomal dominant inheritance can be seen. It appears that mutations in ABCC8 gene can show both autosomal recessive and autosomal dominant inheritance of the disease. PCR followed by Sanger sequencing proved to be an efficient method for mutation detection in three investigated genes. Despite early diagnosis, psychomotor retardation was seen in two patients.

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Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion.

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Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion.

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