De Leon Crutchlow
M.D., M.S.C.E.
Division of Endocrinology/Diabetes The Children's Hospital of Philadelphia 3615 Civic Center Blvd Abramson Research Center, Room 802A

Dr. De León specializes in the diagnosis and management of monogenic disorders of insulin regulation resulting in diabetes and hypoglycemia, and general endocrinologic problems. Dr. De León predominantly cares for children with congenital and acquired forms of hyperinsulinemic hypoglycemia.

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.

Diva D. De León, M.D. is an Assistant Professor of Pediatrics and a Pediatric Endocrinologist in the Division of Endocrinology and Diabetes at The Children's Hospital of Philadelphia. Dr. De León research interest focuses on congenital and acquired forms of hyperinsulinemic hypoglycemia. She is particularly interested in the role that alterations of the entero-insular axis may play in the pathophysiology of these disorders.

Associate Professor of Pediatrics at the Children's Hospital of Philadelphia (2014– present)
Assistant Professor of Pediatrics at the Children's Hospital of Philadelphia (2003 – 2014)
M.S.C.E, Clinical Epidemiology, Perelman School of Medicine at the University of Pennsylvania (2012)
M.D., University of Panama (1992)
Selected Publications
Stanescu DE, Hughes N, Patel P, De León DD. A novel mutation in GATA6 causes pancreatic agenesis. Pediatric Diabetes. 2013 In Press.
Browning E, Wang H, Hong N, Yu K, Buerk DG, DeBolt K, Gonder D, Sorokina EM, Patel P, De León DD, Feinstein SI, Fisher AB and Chatterjee S. Mechanotransduction drives post ischemic revascularization through KATP channel closure and production of reactive oxygen species. Antioxidants & Redox Signaling. 2013 Epub 2013 July 31.
Lord K, Dzata E, Snider KE, Gallagher PR, De León DD. Clinical presentation and management of children with diffuse and focal hyperinsulinism: a review of 223 cases. J Clin Endocrinol Metab. Vol 98(11) . 2013 Nov:E1786-9.
Calabria AC, Gallagher PR, Stanley CA, De León DD. The GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism due to inactivating mutations in the ATP-sensitive potassium channel. Diabetes. Vol 61(10) . 2012 Oct [Epub 2012 Aug 1]:2585-91.
Stanescu DE, Hughes N, Kaplan B, Stanley CA, De León DD. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab. Vol 97(10) . 2012 Oct [Epub 2012 Ju 16]:E2026-30.
Lin YW, Akrouh A, Hsu YC, Hughes N, Nichols CG, De León DD. Compound heterozygous mutations int eh SUR1 (ABCC 8) subunit of pancreatic KATP channels causes neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits. Channels. Vol 6(2) . 2012 March/April:133-8.
Calabria AC, Gallagher PR, Simmons R, Blinman T, De León DD. Postoperative surveillance and detection of postprandial hypoglycemia after fundoplasty in children. J Pediatr. Vol 159(4) . 2011 October:597-601.
Pinney SE, Oliver-Krasinski J, Ernst L, Hughes N, Patel P, Stoffers DA, Russo P, De León DD. Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin-3 gene coding sequence. J Clin Endocrinol Metab. Vol 96(7) . 2011 July:1960-5.
Masia R, De León DD, MacMullen C, McKnight H, Stanley CA, Nichols CG. A mutations in the TMD0-L0 region of SUR1 (L225P) causes permanent neonatal diabetes mellitus (PNFM).. Diabetes. Vol 56(5) . 2007 May:1357-62.
De León DD, Stanley CA, Sperling MA. Hypoglycemia in Neonates and Infants. Pediatric Endocrinology. Vol 3rd edition. Saunders; 2008.
De León DD, Li C, Delson MI, Matschinsky FM, Stanley CA, Stoffers DA. Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic beta-cells and inhibiting insulin secretion.. J Biol Chem. Vol 283(38) . 2008 Sep [Epub 2008 Jul 17]:25786-93.
Palladino AA, Sayed S, Katz LE, Gallagher PR, De León DD. Increased glucagon-like peptide-1 secretion and post-prandial hypoglycemia in children after Nissen fundoplication. J Clin Endocrinol Metab. Vol 94(1) . 2009 Jan:39-44.
De León DD, Stanley CA. Permanent Neonatal Diabetes Mellitus. in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle, 1997-2010.; 2011 July.
De León DD. Role of Incretin Hormones in Hyperinsulinemic Hypoglycemia. Frontiers in Diabetes: Monogenic Hyperinsulinemic Hypoglycemia Disorders. Vol 21. Karger; 2012 February.
De León DD, Stanley CA. Pathophysiology of Diffuse ATP-Sensitive Potassium Channel Hyperinsulinism. Frontiers in Diabetes: Monogenic Hyperinsulinemic Hypoglycemia Disorders. Vol 21. Karger; 2012 February.
Lord K, De León DD. Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management. Int J Pediatr Endocrinol. Vol 1. 2013 February:3.