Kinetics of Insulin Secretion in Pancreatic Beta Cells

Diabetes, Digestive, Kidney Diseases

Investigators

Abstract

Modeling insulin secretion with a localized-calcium model: Insulin secretion from islets of Langerhans in pancreas is important in regulating glucose homeostasis in humans and animals. One research goal of our laboratory is to develop a ?virtual? pancreatic beta cell or islets so that insulin secretion in response to glucose (or other stimulants) can be calculated quantitatively with mathematical formulas. In general, the glucose-stimulated insulin secretion process can be divided into two parts: the ?stimulation? and the ?secretion?. The pathway for stimulation contains a number of steps, such as transport of glucose into the cell, glucose metabolism, K-ATP channel closure, membrane depolarization, activation of Ca2+ channels, and the coupled electrical activity and Ca2+ influx; while that for secretion may include insulin synthesis, insulin-granule packaging, granule transport, granule docking, and fusion and exocytosis of docked granules induced by Ca2+ influx. Dr. Sherman and his colleagues at our Laboratory are working on modeling the ?stimulation? process and we are working on the ?secretion? process. In this project, we developed a ?molecular? kinetic model for fusion and exocytosis of docked granules in a beta cell that can be used to simulate quantitatively the rate of insulin secretion from an islet when it is electrically stimulated. The model is developed based on two assumptions. (1) It is assumed that a ?primed? granule can be fused only when it is situated at the ?micro-domain? near a calcium channel. This assumption implies that granule fusion and the ?electrical activity? of the cell membrane are completely coupled. This also implies that there are two Ca++ pools inside a beta cell: the one in the micro-domain (in tens of micro-molar) that serves as the ?triggering? signal for granule fusion in the ?readily releasable pool? (RRP) and the one in the bulk phase (in sub micro-molar) that serves as the ?amplifying? signal and the triggering signal for fusion in the ?slow releasable pool? (SRP). (2) It is also assumed that there are two slow exocytosis steps after the granule fusion step. These slow exocytosis steps are responsible for the slow insulin secretion rate measured from isolated islets. Effects of various amplifying signals, such as the cytosal calcium concentration, the ATP concentration, etc., on the rate of granule fusion and insulin secretion were studied.