Disposition of ¹³¹I proinsulin in the rat. Comparisons with ¹³¹I insulin

The patterns of disposition of intravenously injected doses of ¹³¹I proinsulin and ¹³¹I 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 ¹³¹I insulin (4 mμg. per 100 gm. rat body weight) were cleared from plasma approximately twice as rapidly as large doses (4 μg. per 100 gm. rat body weight) and three times as rapidly as equimolar small doses (6 mμg. per 100 gm. rat body weight) or large doses (6 μg. per 100 gm. rat body weight) of ¹³¹I proinsulin. Conversely, the relative rate of accumulation of ¹³¹I-labeled degradation products in plasma after injection of low doses of ¹³¹I insulin was about twice as rapid as the rate of accumulation after large doses and about three times as rapid as the rate of ¹³¹I proinsulin. Peak uptake and degradation in the liver at one minute was greatest after injection of low doses of ¹³¹I insulin (28.8 ± 2.5% of injected radioactivity), less after injection of large doses (15.1 ± 1.5%), and least after injection of low doses (5.5 ± 0.9%) or high doses (4.6 ± 0.6%) of ¹³¹I 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%) or high doses (27.5 ± 1.2% of ¹³¹I proinsulin), least after injection of low doses (9.6 ± 0.6%) of ¹³¹I insulin, and intermediate after injection of high doses (17.5 ± 2.6%). 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 ¹³¹I proinsulin injections. An inverse relationship was noted between initial concentration of hormone in plasma and uptake by the liver. Compared to ¹³¹I insulin, the hypoglycemic effect of ¹³¹I proinsulin was weaker (58%) and more delayed in onset. No evidence of conversion of ¹³¹I proinsulin to ¹³¹I insulin was noted. The studies indicate that the differences in dose dependency in plasma clearance and degradation of ¹³¹I insulin and ¹³¹I 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.