The long-term objective of this project is to understand the molecular mechanisms that control secretion of insulin from the pancreatic B-cell. These mechanisms are complex, and quantitative theoretical methods, including the kinetic-molecular theory of nonequilibrium thermodynamics, will be used to formulate the appropriate mathematical description. Our approach is based on experimental schemes of molecular processes involved in insulin granule formation, Ca2+ handling, phosphorylation, and insulin granule exocytosis. Translating these schemes into elementary processes, and thence into rate equations, we will explore the effect of the following mechanisms on rate of insulin release: 1) Complex electrical activity of the plasma membrane related to Ca2+ and pH; 2) electrical coupling between B-cells in islets; 3) Ca2+ handling mechanisms; 4) phospholipid-based biochemical mechanisms involved in the control of insulin secretion. These mechanisms will be explored using mathematical analysis and computer simulations of the corresponding ordinary differential equations. Sufficient experimental information regarding the rates of the processes is available to justify these calculations, which will be interfaced closely with ongoing experimental work. The work will provide insight into the cellular-molecular mechanisms involved in type II (noninsulin dependent) diabetes. More generally, this work will help provide a basis for a theoretical cell biology and cell physiology. The complexity of the cell requires a good analytical foundation to complement experimental studies in order to develop a good theoretical basis for understanding the mechanism of cellular function.
