Description of Research Expertise

Diva D. De León is a Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. She is Chief of the Division of Endocrinology and Diabetes and the Director of the Congenital Hyperinsulinism Center at the Children’s Hospital of Philadelphia, the largest center in the world dedicated to the management of children with hypoglycemia disorders. Dr. De León specializes in pediatric hypoglycemia disorders, particularly, congenital hyperinsulinism. An emphasis of Dr. De León’s clinical practice is the establishment of evidence-based guidelines for the diagnosis and treatment of hypoglycemia disorders in children with the goal of improving long-term outcomes. Dr. De León directs an active translational research program funded by the National Institute of Health focused on examining the pathophysiology of monogenic disorders of insulin regulation resulting in hyper and hypoglycemia in children, the role of the entero-insular axis in the pathogenesis of these disorders, and how the understanding of these mechanisms can be applied towards developing novel therapies for these conditions.

Description of Itmat Expertise

Dr. De León’s translational research program focuses on examining the role of the insulinotropic hormone glucagon-like peptide-1 in the pathophysiology of congenital and acquired forms of hyperinsulinemic hypoglycemia. Hyperinsulinemic hypoglycemia is the most common cause of hypoglycemia in children and adults. Most commonly in children, hyperinsulinemic hypoglycemia is the result of genetic defects affecting regulation of insulin secretion, particularly KATP channel mutations, also known as KATP hyperinsulinism (KATPHI). Surgical procedures affecting nutrient delivery to the gastrointestinal tract, particularly Nissen fundoplication and gastric bypass surgery, can also result in hyperinsulinemic hypoglycemia. We have estimated that approximately 24% of children undergoing a Nissen fundoplication develop hypoglycemia, which is frequently unrecognized.

Using an animal model of KATP hyperinsulinsm (SUR1-/- mouse) we have shown that antagonism of the GLP-1 receptor suppresses the dysregulated insulin secretion and corrects fasting hypoglycemia. These findings suggest that GLP-1 and its receptor may play a role in the pathophysiology of KATPHI and that the GLP-1 receptor may be a viable therapeutic target for this disease.

In children with hyperinsulinemic hypoglycemia (late dumping syndrome) after Nissen fundoplication, we have shown that endogenous secretion of GLP-1 in response to a meal is significantly increased compared to normal children. We postulate that this increased secretion of GLP-1 is responsible for the exaggerated insulin response and subsequent hypoglycemia observed.

Currently, we are conducting proof-of-concept studies to examine the effects of the GLP-1 receptor antagonist, exendin-(9-39), on glucose metabolism and pancreatic islet function in children with hyperinsulinemic hypoglycemia. In addition, we are conducting studies in mouse and human islets to understand the mechanisms by which exendin-(9-39) inhibits KATP-independent insulin secretion. Please visit www.clinicaltrials.gov for a complete list of our clinical trials.

The aim of Dr. De León research program is to improve our understanding of mechanisms responsible for hyperinsulinemic hypoglycemia with the goal of developing effective and innovative therapies for this condition and to further our understanding of the pathophysiologic interactions between the gut and the pancreatic islet.