Accelerated fibrinogen disappearance in diabetic patients is reversible with normalization of blood glucose. To define the time course of this reversal, we measured 125I-fibrinogen disappearance in 19 diabetic patients experiencing acute changes in blood glucose, as monitored and controlled by a microprocessor-controlled closed loop insulin infusion system (artificial beta cell). The data were corrected for blood volume dilutional changes and fit to a model describing two sequential exponential functions and a single exponential function. The sequential model provided the best fit for all but one patient. This indicates that there were two distinct rates of fibrinogen disappearance and suggests that the time course of reversal of accelerated fibrinogen disappearance in diabetic patients is very rapid, if not immediate. Rapid fibrinogen turnover during hyperglycemia was temporally associated with vascular volume changes, reflected as dilutional changes of 51Cr-RBC concentrations. These findings were also associated with an increase in pulse pressure during hyperglycemia, suggesting blood volume expansion due to an osmotic mechanism. The results of this study suggest a picture of vascular volume expansion and contraction, perhaps secondary to the osmotic effects of hyperglycemia. Accelerated fibrinogen turnover associated with these events may be related to increased vascular permeability and/or increased fibrin formation. These events, in concert, may contribute to the initiation and/or propagation of diabetic vascular sequelae.