Biosynthetic Human Insulin and Proinsulin Have Additive but Not Synergistic Effects on Total Body Glucose Disposal*

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Abstract
Recent studies from our laboratory have demonstrated that human biosynthetic proinsulin has a much slower MCR than insulin as well as a greater effect on hepatic than on peripheral tissues. Since both of these features make proinsulin potentially useful as an adjunct to insulin, the present study was undertaken to characterize the biological effects of combined infusions of insulin and proinsulin. As an initial study, multiple euglycemic clamp studies were performed in six normal subjects to construct dose-response curves for insulin- and proinsulinmediated glucose disposal. Insulin infusion rates of 0.63,1.67, 5, and 10 μg/M2min were compared to proinsulin infusion rates of 2.75, 7.5, 22.5, and 45 μg/M2-min. Analysis of these doseresponse curves indicated that proinsulin-mediated glucose disposal was approximately 7% that of insulin. Each subject also received a combined infusion of insulin (0.63 μg/M2-min) and proinsulin (2.75 μg/M2min). The mean (±SE) glucose disposal rate obtained during the combination study (319 ± 21 mg/M2min) was similar to that predicted by adding the results from the individual hormone infusions (307 ± 21 mg/M2min). Analysis of the dose-response curves for insulin and proinsulin was also useful in predicting the glucose disposal rate during the combination study (290 ± 19 mg/M2- min). Thus, using either approach to predict the glucose disposal rates, insulin and proinsulin appeared to have additive effects on total body glucose disposal.

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