Abstract: Proinsulin:insulin ratios in serum are higher than in pancreatic islets.This ratio is highest in the fasting state and at late times after stimuli to insulin secretion.Differences in peripheral metabolism of endogenous insulin (ti = 4.8 min) and proinsulin (ti = 17.2 min) are partly responsible for these findings.To investigate whether differential pancreatic secretion or variable hepatic clearance of the polypeptides may also contribute, we have calculated posthepatic deliver rates (PHDR) of insulin and proinsulin after oral glucose.Specimens were obtained at 15-to 30-min intervals during 5-h oral GTT's in four healthy subjects.Proinsulin and insulin were separated by gel filtration and measured by radioimmunoassay against human proinsulin and insulin standards.Using a disappearance constant derived for endogenous proinsulin and insulin, PHDR were calculated assuming constant delivery during each time interval.The highest insulin level occurred at 30 min (2.63±0.80ng/ml), while proinsulin peaked at 105 min (1.04±0.45ng/ml).Basal insulin PHDR was 2844 pg/ml per min, and increased to 408±124 pg/ml per min at 15-30 min.Thereafter a gradual decline to 20±4 pg/ml per min occurred by 5 h.Proinsulin PHDR rose from 7±1 pg/ml per min in the basal state to plateau between 36 and 46 pg/ml per min at 15-105 min and returned to vasal values by 5 h.The fasting ratio of insulin PHDR:proinsulin PHDR was 4.5± 0.8, rose to 12.042.4 in the 0-15 min interval, and returned to basal levels by 3 hr.These observations can be explained either by preferential beta cell release of insulin in the early poststimulatory period or relatively decreased hepatic insulin extraction when insulin secretion is maximal.The significant correlation observed between the PHDR ratio of the two polypeptides and insulin PHDR supports the latter interpretation.