This patient-oriented research study of pancreatic beta-cell regulation in infants with congenital hyperinsulinism addresses the most important cause of recurrent hypoglycemia in early childhood. The majority of cases have genetic defects of insulin secretion, including recessive mutations of the KATP channel genes, SUR1 and Kir6.2, and dominant mutations of the glutamate dehydrogenase and glucokinase genes. However, 40 percent of cases have focal pancreatic lesions which express KATP channel mutations that are always paternal in origin. Since molecular diagnosis of these disorders is not possible, our goal is to correlate abnormalities of insulin secretion with individual genotypes and, thus, develop clinical methods for diagnosing specific disorders based on acute insulin response (AIR) tests with secretogogs, including glucose, tolbutamide, calcium, and leucine.
Our first aim i s to determine the abnormalities of beta-cell insulin secretion which are specific for SUR1 mutations, the most important cause of congenital hyperinsulinism.
Our second aim i s to establish the differences in beta-cell regulation between SUR1 mutations and other genetic forms of congenital hyperinsulinism in order to be able to identify these disorders clinically.
Our third aim i s to develop AIR tests for specifically diagnosing hyperinsulinism induced by perinatal stress (birth asphyxia, maternal hypertension, SGA) since this acquired disorder can mimic genetic hyperinsulinism due to SUR1 mutations.
Our fourth aim i s to develop and prospectively evaluate a new clinical protocol based on AIR tests for distinguishing focal and diffuse pancreatic lesions expressing SUR1 mutations. Our hypothesis is that the pattern of calcium and tolbutamide AIR tests will permit preoperative identification of infants who have surgically curable disease. Methods will include exhaustively scanning for mutations in SUR1, Kir6.2, and GK using conformation specific gel electrophoresis (CSGE) and infra-pancreatic arterial calcium infusion to locate focal lesions. The results of this research will enhance the clinical diagnosis and rational treatment of affected children with hyperinsulinism and will also provide unique insights into the normal control of insulin secretion in human beings.
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