The long term goal of this project is to establish the normal physiologic role of the cyclic secretory pattern by the islets of Langerhans. These studies will provide the foundation for assessment of its potential pathophysiologic significance in Diabetes Mellitus, obesity, and other disorders of metabolic regulation. The impact of oscillating hormonal signals upon target tissues will be compared to provision of the same signal in a constant mode. Using perifused isolated rat hepatocytes as an in vitro model and normal and streptozotocin diabetic non-human primates as in vivo models, the effect of pulsatile administration of insulin and glucagon upon regulation of hepatic metabolic pathways will be examined, the pathways entrained, the determinants of the kinetics for onset and decay of responses, the time dependencies and dose dependencies of responses, the duration of desensitization and the impact of pulses upon receptor regulation will be studied. Overall dose response characteristics of pathways to the same time averaged concentration of hormone administered as pulses or continuously will be determined. Similar studies for insulin stimulation of peripheral tissues will be done in vivo and in perifused isolated rat adipocytes. A mathematical model has been developed that relates the kinetics of single responses to the integrated response to a series of hormone pulses. The model will be used to design experiments to test the effect of frequency and phase changes in the secretion of insulin and glucagon upon metabolic regulation.
