POPULATION-BASED MODELING TO DEMONSTRATE EXTRAPANCREATIC EFFECTS OF TOLBUTAMIDE

Tolbutamide is used increasingly as an investigative tool in in vivo s tudies of the physiology of glucose tolerance. Its hypoglycemic effect in nondiabetic subjects is widely variable, reflecting possible varia bility in its pharmacokinetics, an insulinergic response, an extrapanc reatic effect of the drug, or the hypoglycemic effect of insulin itsel f. Using population-based modeling, we have investigated the kinetics and dynamics of tolbutamide and assessed covariates in two groups of h ealthy subjects. The results indicate a high variability in insulinerg ic effect, measured by the area under of the curve of insulin (0-60 mi n), in response to tolbutamide injection (coefficient of variation = 2 9-96%). However, it appears that impaired insulin sensitivity is compe nsated by higher insulin secretion in response to tolbutamide. Thus th e hypoglycemic effect of high insulin secretion is minimal in insulin- resistant subjects. Application of the model indicated that tolbutamid e has appreciable extrapancreatic effects mediated by prolongation of the residence time of insulin in a remote effect and by enhancement of glucose effectiveness. An effect in increasing the insulin sensitivit y index is also possible but could not be confirmed statistically for all groups of subjects studied. These observations may explain inconsi stencies between the results of tolbutamide and insulin injection in t he frequently sampled intravenous glucose tolerance test and call for further study of insulin-vs. tolbutamide-modified frequently sampled i ntravenous glucose tolerance tests in the assessment of the insulin se nsitivity and glucose effectiveness indexes.