The patterns of disposition of intravenously injected doses of 131 I proinsulin and I31 I insulin were compared in the rat with respect to plasma clearance, uptake, and degradation in selected organs and tissues, and rates of accumulation of degraded products in plasma and urine. Small doses of 131 I insulin (4 mptg. per 100 gm. rat body weight) were cleared from plasma approximately twice as rapidly as large doses (4 fig. per 100 gm. rat body weight) and three times as rapidly as equi molar small doses (6 m/u,g. per 100 gm. rat body weight) or large doses (6/xg.per 100 gm. rat body weight) of l31 I proinsulin. Conversely, the relative rate of accumulation of l 3 l Ilabeled degradation products in plasma after injection of low doses of l 3 l I insulin was about twice as rapid as the rate of accumulation after large doses and about three times as rapid as the rate of accumulation after either small or large doses of l3 'I proinsulin. Peak uptake and degradation in the liver at one minute was greatest after injection of low doses of l 3 l I insulin (28.8 ±'2.5 per cent of injected radioactivity), less after injection of large doses (15.1 ± 1 . 5 per cent), and least after injection of low doses (5.5 ± 0.9 per cent) or high doses (4.6 ± 0 . 6 per cent) of I31 I proinsulin. In contrast, peak uptake and degradation in the kidneys at seven to eleven minutes was greatest after injection of low doses (24.7 ± 2 . 7 per cent) or high doses (27.5 ± 1 . 2 per cent of l 3 l I proinsulin), least after injection of low doses (9.6 ± 0 . 6 per cent) of l 3 l I insulin, and intermediate after injection of high doses (17.5 ± 2 . 6 per cent). No large differences were noted in patterns of uptake of radioactivity in muscle, fat, or skin compartments. Excretion of degraded products in urine was more delayed after l 3 l I proinsulin injections. An inverse relationship was noted between initial concentration of hormone in plasma and uptake by the liver. Compared to | 3 | I insulin, the hypoglycemic effect of l 3 l I proinsulin was weaker (58 per cent) and more delayed in onset. No evidence of conversion of l 3 l I proinsulin to l 3 l I insulin was noted.The studies indicate that the differences in dose dependency in plasma clearance and degradation of 13I I insulin and | 3 | I proinsulin can be attributed to differences in relative uptakes and degradation by the liver and kidneys. The liver appeared to be the major organ involved in the removal and degradation of insulin, whereas the kidney appeared to be the major organ involved in the case of proinsulin. The hepatic process was rapid but relatively saturable, whereas the kidney process was slower but relatively unsaturable. The inverse relationship between initial concentration of hormone in plasma and uptake by liver suggests that the ratio may provide a sensitive index of the role of the liver in plasma hormone clearance. DIABETES 27:400-10, April, 1978.In 1967 Steiner and his co-workers first demonstrated the existence of a precursor in the biosynthesis of insulin in the pancreatic...

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