Oscillation and Synchronization of Pancreatic Islet Activity

Florida State University, Tallahassee FL

Investigators

Abstract

The long-term goal of this research is to understand the mechanism of insulin secretion from beta-cells, which are clustered into islets of Langerhans within the pancreas. Beta-cells secrete insulin in a pulsatile fashion, with pulse period of approximately five minutes. Disruption of this oscillatory pattern is observed in diabetics and their near relatives. The two primary aims of this project are (1) to better understand the mechanism for pulsatile insulin secretion, and (2) to investigate potential mechanisms for the synchronization of the population of islet oscillators. We focus on oscillations in glycolysis, coupled to the electrical activity of the cell, as a mechanism for pulsatile insulin secretion. This is based on data in the literature and from a collaborating lab showing oscillations in mitochondrial variables. From a mathematical viewpoint, the model consists of two mutually coupled oscillators, which we call a dual-oscillator model. Glycolysis is the slowest of the two oscillators, while electrical bursting in the cell is the faster oscillator. Much of our analysis focuses on the dynamics of this dual-oscillator system. The pancreas contains a large number of islets, and their activity must be synchronized for the insulin release from the islet population to be oscillatory. In this project, two mechanisms for synchronization are investigated. One is the entrainment of islets by peripheral nerves in intrapancreatic ganglia. This will be investigated by applying periodic pulses to the dual-oscillator model and identifying conditions for entrainment and entrainment windows. The other synchronization mechanism is the feedback of insulin onto insulin receptors on the beta-cells. This provides a relatively weak coupling effect on the model islets, but it may be sufficiently strong to achieve synchronization. Failure of beta-cells to secrete the proper amount of insulin in response to changes in the glucose level in the blood is a major factor for type II diabetes. For this reason, it is important to understand the biological mechanism for insulin secretion, and the coordination of the insulin-secreting cells. The beta-cells are very complex, and our approach to understanding their behavior is to combine mathematical modeling and computer simulations with experimental studies, performed at a collaborating lab. Both undergraduate and graduate students are involved in the mathematical modeling and computer simulations, and will meet with experimental collaborators to discuss data and future experiments motivated by the modeling. Our goal is to understand how proper insulin secretion is achieved at the cellular level, and then extend this to understand how beta-cell disfunctions can lead to type II diabetes.