How does the blood glucose level control the rate of insulin release by pancreatic islet cells? This project will address the first step in this process by determining how the islets sense the blood glucose level. The working hypothesis is that blood glucose level controls the glycolytic rate at the step of phosphorylation by glucokinase, and that this rate is further transformed into an ultimate insulin-release signal. This project will combine laboratory experiments on pancreatic islets and islet-derived insulinomas with computer analysis involving data base construction and information retrieval, experimental design, optimization, simulation, and sensitivity analysis. The computer-based techniques are necessary because of the limited amount of experimental material available and the complexity of even this limited area of metabolism. This project will determine the properties and amounts of the glycolytic enzymes present in islets, especially which isozyme is present, and what the mechanisms and controls are if this information is not known. The enzymes phosphofructokinase and pyruvate kinase will be emphasized. This project will determine the levels of glycolytic metabolites and coenzymes in islets or insulinomas when the glycolytic rate is varied in response to varying levels of glucose with additional insulin secretagogues or substitute sugars. The information from these experiments will be incorporated initially into computer models of individual enzymes and then into models of the glycolytic pathway as a whole, using computer programs and techniques built up over a long time. These models will then be analyzed to determine whether the glycolytic rate is primarily controlled by glucose phosphorylation under physiological conditions, what modifies this control, and whether this is compatible with the known relationship between blood glucose and insulin release. A currently interesting question included in this process is how the known anomeric specificity of the islet for insulin release (they prefer the Alpha-anomer of glucose) relate to the anomeric specificities of the hexose-phosphate handling enzymes. It is expected that the information obtained from this study would be useful to such workers as those trying to explain the body's glucose-insulin system and its derangement in diabetes.
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