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The Effects of Proinsulin Pretreatment on the Combined Actions of Insulin and Proinsulin in Normal Man^*

Departments of Medicine, University of California San Diego, La Jalla, California 92093
veterans Admininstration Medical Center, Medical Research Service San Diego, California 92161
Eli Lilly Company Indianapolis, Indiana 46285

With the recent availability of biosynthetic human proinsulin there has beena renewed interest in evaluating its metabolic effects, either alone or in combination with insulin. It has been suggested that pretreatment with proinsulin enhances the hypoglycemic response to subsequently administered insulin. On the other hand, the simultaneous administration of proinsulin and insulin has additive, not synergistic, effects. To clarify this question we used the euglycemic glucose clamp technique in 10 normal subjects to compare the steady state effects on glucose disposal of combined infusions of insulin (0.54 µg/M².min, equivalent to 15 mU/M².min) and proinsulin (2.75 µg/M².min) given both simultaneously and sequentially. The mean ± SEM steady state glucose disposal rates were similar whether the two hormones were given simultaneously (7.2 ± 0.7 mg/min.kg), after proinsulin pretreatment (7.7 ± 0.7 mg/min.kg), or after insulin pretreatment (7.1 ± 0.7 mg/min.kg). The serum proinsulin concentration of 5.39 ± 0.3 pmol/ml during the infusion of proinsulin alone was unchanged by the simultaneous infusion of insulin, suggesting that in the doses used, insulin did not affect proinsulin clearance. We conclude that in normal subjects there is no enhancement of the combined action of insulin and proinsulin to stimulate glucose disposal by pre-treatment with proinsulin or insulin.

^* This work was supported by funds from the Medical Research Service of the V.A., Grants AM-26180, AM-13941, and AM-20595 from the NIH, Grant RR-00827 to the UCSD General Clinical Research Center (NIH Division of Research Resources), and a research grant from Eli Lilly Co.

¹ Address all correspondence and requests for reprints to: J. M Olefsky, M.D., Veterans Administration Medical Center, 3350 La Jolla Village Drive (111G), San Diego, California 92161.

Received September 4, 1985.