Defining novel genetic mechanisms of congenital hyperinsulinism

Congenital hyperinsulinism is a condition that causes the pancreas to make too much insulin. High insulin levels cause severe hypoglycaemia (low blood glucose).
Hypoglycaemia is a major cause of brain damage, mental retardation and cerebral palsy during the newborn, infancy and childhood periods. The mechanisms that lead to too much insulin production from the pancreas are only understood in a small number of patients. We have collected a very large number of patients with congenital hyperinsulinism from all over the world. We will do further genetic studies on these patients to try and understand why they have congenital
hyperinsulinism. Our research will help to understand how the pancreas controls insulin secretion. This information is very important for understanding more common conditions such as diabetes mellitus and will provide new knowledge about the function of the pancreas

Congenital hyperinsulinism (CHI) is a cause of severe hypoglycaemia in the childhood period and a major cause of hypoglycaemic brain injury. The genetic basis of CHI involves defects in key genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, SLC16A1, and HADH) involved in regulating insulin secretion from pancreatic beta-cells. CHI is an extremely heterogeneous condition where the genetic aetiology is known in only about 40% of patients suggesting other novel genetic mechanisms. Our research focuses on understanding the genetic mechanisms of CHI that lead to dysregulated insulin secretion. We have established the largest (800) cohort of patients with CHI in the world that have been systemically phenotyped and genotyped and will form the backbone of our proposed research. We have generated significant preliminary data illustrating novel mechanisms of insulin secretion. Understanding the mechanisms that regulate insulin secretion will have important implications for beta-cell physiology and other common conditions such as diabetes mellitus. Even more importantly unrevealing these mechanisms will help in patient management and allow appropriate genetic counseling