Diva D De Leon Crutchlow

faculty photo
Associate Professor of Pediatrics at the Children's Hospital of Philadelphia
Attending Physician, The Children's Hospital of Philadelphia
Director, Congenital Hyperinsulinism Center, The Children’s Hospital of Philadelphia
Chief, Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia
Department: Pediatrics

Contact information
Division of Endocrinology/Diabetes
The Children's Hospital of Philadelphia
3615 Civic Center Blvd
Abramson Research Center, Room 802A
Philadelphia, PA 19104
Office: 267-426-5529
Fax: 215-590-1605
Lab: 267-426-0385
University of Panama, 1992.
M.S.C.E (Clinical Epidemiology)
Perelman School of Medicine at the University of Pennsylvania, 2012.
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Description of Research Expertise

Diva D. De León, M.D. is an Associate 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.

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.

Selected Publications

Stanescu DE, Hughes N, Patel P, De León DD: A novel mutation in GATA6 causes pancreatic agenesis. Pediatr Diabetes 16(1): 67-70, Feb 2015.

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 20(6): 872-86, Feb 2014.

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 98(11): E1786-9, Nov 2013.

Calabria AC, Li C, Gallagher PR, Stanley CA, De León DD: GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism due to inactivating mutations in the ATP-sensitive K+ channel. Diabetes 61(10): 2585-91, Oct 2012.

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 97(10): E2026-30, Oct 2012.

Lin YW, Akrouh A, Hsu YC, Hughes N, Nichols CG, De León DD: Compound heterozygous mutations int eh SUR1 (ABCC 8) subunit of pancreatic K(ATP) channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits. Channels (Austin) 6(2): 133-8, March-April 2012.

Calabria AC, Gallagher PR, Simmons R, Blinman T, De León DD: Postoperative surveillance and detection of postprandial hypoglycemia after fundoplasty in children. J Pediatr 159(4): 597-601, Oct 2011.

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 96(7): 1960-5, Jul 2011.

Masia R, De León DD, MacMullen C, McKnight H, Stanley CA, Nichols CG: A mutations in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM) Diabetes 56(5): 1357-62, May 2007.

De León DD, Stanley CA: Permanent Neonatal Diabetes Mellitus GeneReviews® [Internet] Pagon RA, Adam MP, Ardinger HH, et al., editors (eds.). Seattle (WA): University of Washington, Seattle; 1993-2016. Feb 2008 [Updated 2016 Jul 29] Notes: Available from: http://www.ncbi.nlm.nih.gov/books/NBK1447/

De León DD, Stanley CA, Sperling MA: Hypoglycemia in Neonates and Infants. Pediatric Endocrinology Sperling, MA (eds.). Saunders, 3rd edition, 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 283(38): 25786-93, Sep 2008.

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 94(1): 39-44, Jan 2009.

De León DD: Role of Incretin Hormones in Hyperinsulinemic Hypoglycemia Frontiers in Diabetes: Monogenic Hyperinsulinemic Hypoglycemia Disorders. Stanley CA and De León DD (eds.). Karger, Basel, Switzerland, 21, Feb 2012.

De León DD, Stanley CA: Pathophysiology of Diffuse ATP-Sensitive Potassium Channel Hyperinsulinism. Frontiers in Diabetes: Monogenic Hyperinsulinemic Hypoglycemia Disorders. Stanley CA and De León DD (eds.). Karger, Basel, Switzerland, 21, Feb 2012.

Lord K, De León DD: Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management. Int J Pediatr Endocrinol 1: 3, Feb 2013.

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Last updated: 11/09/2018
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