Oladapo O. Yeku

2nd Year Graduate Student

Department: Pharmacological Sciences

Graduate Program: Molecular & Cellular Pharmacology

Advisor: Michael Frohman

Abstract:

Title: The Role PLD2 in Glucose-Stimulated Insulin Release

Preceptor: Dr. Michael Frohman, Dept. of Pharmacological Sciences, Stony Brook University

Diabetes is a chronic disease that affects millions of people worldwide. The disease is characterized by elevated serum glucose caused by pancreatic beta cell failure, peripheral insulin resistance or both. Efforts to treat the disease have focused on understanding the signaling events leading to glucose-stimulated insulin release in pancreatic beta cells. Our efforts involve the elucidation of the role of phospholipase D (PLD) in Glucose-Stimulated Insulin Release (GSIR). The PLD family of enzymes consists of PLD1 and PLD2. Both isoforms of PLD have been shown to be important in mediating different aspects of regulated exocytosis. PLD generates the membrane lipid Phosphatidic acid (PA) from Phosphatidylcholine (PC). PA is an important lipid mediator that is responsible for several effector activities of PLD.

We have evidence that supports an inhibitory role for PLD2 in GSIR. Attenuation of PLD2 activity by RNAi or genetic knockout (KO) in mice leads to an increase in GSIR. PLD2 KO animals have decreased random and fasting serum glucose and demonstrate more efficient glucose tolerance (GTT) than wile type (WT) counterparts. Pancreatic islets isolated from PLD2 KO mice show increased insulin secretion upon glucose stimulation in agreement with the results observed from the whole animal. NIT-1 insulinoma cell-lines transfected with PLD2 RNAi also show increased insulin secretion under basal and stimulating glucose conditions. We are currently engaged in investigating the role of PLD1 in GSIR.