The overall objective of this study is to define the ultrastructural and functional changes that occur in the beta cell of the pancreas during aging. Insulin secretion will be studied in the rat under both in vivo and in vitro conditions and the kind and amount of insulin released in response to glucose will be determined. Special emphasis will be placed on age-related environmental factors such as obesity and lack of exercise and information will be obtained on how these factors modulate both the in vivo and in vitro beta cell response. The following measurement of insulin secretion will be made on animals or tissues from animals who vary in age, caloric intake and physical activity. 1) In vivo proinsulin and insulin responses to a glucose challenge in which the magnitude of the response will be assessed in terms of total pancreatic beta cell mass, 2) the proinsulin and insulin secretory response of isolated islets to varying glucose concentrations and the relationship of these responses to either the number of islets used, the number of beta cells per average islet or to the function of an average beta cell, 3) the rates of synthesis, proinsulin/insulin conversion, intracellular transport and release of insulin as calculated per islet or per average beta cell, and 4) the quantitation of alterations in beta cell intracellular structures and their relationship to functional alterations in the synthesis, packaging, transport, intracellular hydrolysis or release of insulin from the cell. It is anticipated that this multidiscipline approach will provide fresh insights into the functioning of the beta cell during the aging process and identify whether, or to what degree, the beta cell may be responsible for glucose intolerance in the aging individual.