The Effects of Biosynthetic Human Proinsulin on Carbohydrate Metabolism R. R. REVERS, R. HENRY, L. SCHMEISER, 0. KOLTERMAN, R. COHEN, R. BERGENSTAL, K. POLONSKY, J. JASPAN, A. RUBENSTEIN, B. FRANK, J. GALLOWAY, AND J. M. OLEFSKY SUMMARY Large quantities of biosynthetic human proinsulin have recently become available through recombinant DNA technology. Since the in vivo effects of human proin- sulin have not been studied in man, we compared the dose-response relationship for stimulation of glucose disposal and suppression of hepatic glucose output by proinsulin and insulin. Ten normal subjects were stud- ied using the euglycemic glucose clamp technique. The human proinsulin and insulin infusion rates were chosen to achieve steady-state proinsulin levels 10- fold higher than insulin levels on a molar basis, based on previous observations that porcine proinsulin has -10% the potency of insulin. Proinsulin infusion rates of 2.75, 7.5, 22.5, and 45 ng/m 2 /min were compared with insulin infusion rates of 0.63, 1.67, 5, and 10 jig/ m 2 /min. Primed, continuous infusions of insulin yielded steady-state levels within 25 min, whereas proinsulin levels did not reach a steady state for 120- 180 min. The metabolic clearance rate of insulin was 11-12 ml/kg/min at the lower infusion rates but fell to 8.4 ml/kg/min at the highest infusion rate. The meta- bolic clearance rate of proinsulin was 3.0-3.5 ml/kg/ min at all infusion rates. Dose-response analysis dem- onstrated that proinsulin-mediated glucose disposal was —8% that of insulin. In contrast, proinsulin-me- diated suppression of hepatic glucose output was -12% that seen with insulin. We conclude that: (1) primed, continuous infusions of proinsulin and insulin have considerably different kinetics; (2) the metabolic clearance rate of proinsulin is only - 2 8 % that of insulin, but the processes re- sponsible for removal of insulin from the circulation are more saturable than those responsible for removal From the Department of Medicine, University of Colorado Health Sciences Center, Division of Endocrinology, and the Denver Veterans Administration Hospital, Denver, Colorado; the Department of Medicine, University of Chi- cago, Chicago, Illinois; and Eli Lilly and Company, Indianapolis, Indiana. Address reprint requests to Jerrold M. Olefsky, M.D., University of California, San Diego, Department of Medicine, M-023E, La Jolla, California 92093. Received for publication 15 August 1983 and in revised form 6 December 1983. of proinsulin; and (3) proinsulin appears to exert a greater effect on hepatic than on peripheral tissues. DIABETES 33:762-770, August 1984. I n recent years, much effort has been devoted to de- veloping highly purified insulin preparations for the treat- ment of diabetic patients. One of the "impurities" re- moved in this process is proinsulin. Although proinsulin constitutes 10-20% of the measurable circulating immuno- reactive insulin in normal man, 1 its physiologic importance has been viewed as minor because of its weak biologic activity. 2 Nevertheless, when one considers the total amount of proinsulin secreted and its prolonged half-life in the cir- culation compared with insulin, 3 it is clear that the 24-h ex- posure of tissues to proinsulin in normal individuals is sub- stantial. From a teleologic point of view, it is interesting to speculate that with this large amount of tissue exposure, proinsulin might produce physiologic effects that are addi- tive to insulin or perhaps even have unique biologic effects not shared by insulin. Until recently, it was not possible to test this hypothesis because of the limited availability of hu- man proinsulin. However, through recombinant DNA tech- nology it has now become possible to prepare large quan- tities of human proinsulin, 4 and this in turn has led to a renewed interest in the possible physiologic importance and clinical usage of this hormone. In the present study, we have performed serial euglycemic glucose clamp studies in normal man using several different infusion rates of human proinsulin. We have previously used this approach to define insulin's dose-response relationship for stimulation of glucose disposal and suppression of he- patic glucose output in normal, obese, and diabetic sub- jects. 56 By constructing dose-response curves for both in- sulin and proinsulin action in the same subjects, these studies have allowed us to delineate proinsulin's relative biol- ogic activity on carbohydrate metabolism and its metabolic clearance rate in normal man. 762 DIABETES, VOL. 33, AUGUST 1984 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/33/8/762/353286/33-8-762.pdf by guest on 04 November 2022