Mutations in UCP2 in Congenital Hyperinsulinism Reveal a Role for Regulation of Insulin Secretion

作者：Gonzalez Barroso M Mar^*; Giurgea Irina; Bouillaud Frederic; Anedda Andrea; Bellanne Chantelot Christine; Hubert Laurence; de Keyzer Yves; de Lonlay Pascale; Ricquier Daniel

来源：PLos One, 2008, 3(12): e3850.

DOI：10.1371/journal.pone.0003850

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 involment 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.

• 出版日期2008-12-9