This proposal will provide the PI formal and informal training in translational research through mentors, coursework, seminars, and the pursuit of a patient-oriented research project examining the role of glucagon-like peptide-1 (GLP-1) in disorders of carbohydrate metabolism. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to nutrients. The mechanisms involved in GLP-1 secretion are complex, but similarities between the pancreatic a-cells and the L-cells point to a role of KATP channels in GLP-1 secretion. The beneficial physiologic and pharmacologic effects of GLP-1 are well established, less is known about the potential hypoglycemic effects of this peptide in pathologic conditions. The studies proposed here will examine the role of GLP-1 in two hypoglycemic disorders affecting children. These disorders are characterized by dysregulated insulin secretion resulting in severe hypoglycemia and neurodevelopmental sequelae if untreated. Our overall hypothesis is that abnormal GLP-1 secretion resulting from dysfunctional nutrient sensing in L-cells plays a role in these disorders.
In Aim 1 we will examine GLP-1 secretion in children with congenital hyperinsulinism due to mutations in the KATP channel and determine whether inactivation of the GLP-1 receptor by a null mutation or by infusion of an antagonist, Ex9-39, significantly raises blood glucose in mice with an inactivating mutation of the KATP channel.
In Aim 2 we will examine the role of GLP-1 in post-prandial hypoglycemia after Nissen fundoplication. Relevance: The proposed studies are key to the understanding of the pathogenesis of these disorders and will establish the basis for the potential therapeutic use of GLP-1 receptor antagonists for their treatment. Given the lack of effective medical therapies for these conditions, the potential use of GLP-1 receptor antagonist to control the hypoglycemia could have a significant effect on morbidity and long term outcome in this patient population. The PI, whose primary career goal is to become a translational researcher in the area of carbohydrate metabolism, will use this study as a mechanism for career development: 1) to solidify her skills as a clinical and laboratory investigator by working with experts in this area of research, 2) to participate in formal education in clinical and translational research at The University of Pennsylvania,and 3) to continue education in diabetes and endocrinology through local and national seminars.
| Pinney, Sara E; Oliver-Krasinski, Jennifer; Ernst, Linda et al. (2011) Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin-3 gene coding sequence. J Clin Endocrinol Metab 96:1960-5 |
| Palladino, Andrew A; Sayed, Samir; Levitt Katz, Lorraine E et al. (2009) Increased glucagon-like peptide-1 secretion and postprandial hypoglycemia in children after Nissen fundoplication. J Clin Endocrinol Metab 94:39-44 |
| De Leon, Diva D; Li, Changhong; Delson, Madeleine I et al. (2008) Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic beta-cells and inhibiting insulin secretion. J Biol Chem 283:25786-93 |
