Oladapo O. Yeku

2nd Year Graduate Student

Department: Pharmacological Sciences

Graduate Program: Molecular & Cellular Pharmacology

Advisor: Michael Frohman

Abstract:

Title:  Exaggerated insulin release in the absence of phosphatidylinositol 4-Phosphase 5-Kinase is mediated by cortical actin reorganization

Huang, P., O. Yeku, J. Pessin, and M. Frohman

Phosphatidylinositol (PIP) kinases play an important role in insulin secretion and regulated exocytosis by generating phosphatidylinositol 4-5 bisphosphate (PIP₂). In this study, we show that mice deficient in PI4P5K type α exhibit lower serum glucose and higher basal serum insulin levels. When challenged with a high fat diet, PI4P5Kα KO mice resist the development of type II diabetes. Islets from the KO mice release more insulin upon glucose stimulation and we further demonstrate that reduction in plasma membrane PIP₂ corresponds to disruptions in the actin cytoskeletal membrane providing a potential mechanism for the observed increase in insulin secretion. Islet size, mass, insulin granule number and total insulin content were also examined as possible causes for the increased insulin secretion. Upon exclusion of those factors, we measured cytoplasmic Ca²⁺ influx as a marker for the culmination of all upstream signaling events and found no difference between PI4P5Kα KO islets and their wild type counterparts. In conclusion, our work shows a positive role for PI4P5Kα in the maintenance of membrane PIP₂ levels leading to the regulation of membrane actin cytoskeleton.