The research deals with the pathophysiologic mechanisms that lead to maturity-type diabetes mellitus. It has been shown by detailed analysis, including simulations, that even in the mildest forms of diabetes the acute insulin response of the islet is reduced. However, even in the absence of obesity, also the efficiency of insulin to reduce blood glucose is diminished. It is assumed that the basic defect in diabetes is an islet deficiency, but that insulin resistance creates the negative balance which initiates diabetes. Studies are performed in order to assess, in quantitative terms, the respective importance of insulin output and insulin efficiency for the control of glucose tolerance in subjects with widely varying tolerances to glucose and to insulin. The complex dynamic control of insulin release by glucose is further evaluated with experiments in man, in vitro with the perfused pancreas of the rat, and with islets isolated from rats and animals with various forms of spontaneous diabetes and/or obesity. It is aimed at clarifying whether conditions known to alter the acute insulin response of the islets also modify the "memory" of the islet to glucose.