The effects of human proinsulin on glucose turnover and intermediary metabolism

Abstract

We compared the effects of human proinsulin and human insulin on glucose disposal, suppression of hepatic glucose production (HGP), and intermediary carbohydrate and lipid metabolism. Six young, lean, subjects underwent eight separate euglycemic clamps with low-dose intravenous (IV) infusions of insulin and proinsulin (four each). The insulin infusions gave steady-state levels of 0.08 ± 0.004 (I 1), 0.12 ± 0.003 (I 2), 0.18 ± 0.07 (I 3), and 0.25 ± 0.06 nmol/L (I 4). The proinsulin infusions were chosen to give steady-state levels approximately 20-fold higher on a molar basis than insulin, based on previous findings that proinsulin has only 5% to 10% the biological potency of insulin. Steady-state proinsulin levels were 1.2 ± 0.04 (P 1), 2.8 ± 0.07 (P 2), 4.5 ± 0.3 (P 3), and 6.9 ± 0.3 nmol/L (P 4). HGP was suppressed equally by proinsulin and insulin at the four dose levels. Percentage elevation of glucose disposal was significantly increased during each of the insulin infusions compared with proinsulin: I 1 107% ± 4%, P 1 87% ± 4% ( P = .03); I 2 143% ± 7%, P 2 125% ± 12% ( P = .01); I 3 238% ± 38%, P 3 173% ± 22% ( P = .03); I 4 283% ± 17%, P 4 178% ± 11% ( P = .002). Dose-response curve analysis demonstrated that proinsulin stimulated glucose disposal approximately 3.3% compared with insulin. The effectiveness of proinsulin in suppressing HGP was approximately 5% compared with insulin. Plasma nonesterified fatty acids, blood glycerol, and 3-hydroxybutyrate were suppressed by similar amounts during each of the four insulin and proinsulin doses. Blood alanine concentrations were similar during the proinsulin and insulin infusions. Proinsulin caused a significant net decrease in blood lactate ( P = .001) and pyruvate levels ( P < .05) compared with an increase during the insulin infusions. We conclude that (1) proinsulin has a preferential effect on the liver compared with muscle in terms of glucose handling; (2) proinsulin has similar effects to those of insulin on lipid metabolism; and (30 proinsulin may have a different action on lactate and pyruvate metabolism compared with insulin in normal man.