Kininogen and prekallikrein increases in the blood of streptozotocin-diabetic rats are normalized by insulin in vivo and in vitro

Twelve days following treatment with 50 mg/kg streptozotocin (STZ), male ra ts were diabetic, with a threefold increase in blood glucose (P<0.001) and increased plasma bradykinin (BK) kininogen reserves of [high(HK)- and low- (LK)-molecular-weight kininogens,+162%, P<0.01 and +63%, P=0.05, respective ly], as determined by bioassay of BK released by trypsin from these precurs ors under standardized conditions. Administration of a single dose (10 U/kg i.v.) of regular insulin decreased plasma HK and LK to near non-diabetic v alues. Within 24 h these values had returned to levels characteristic of un corrected diabetes. Prekallikrein (PK), the precursor of plasma kallikrein, an enzyme which releases BK from HK, was increased by 63.4% (P<0.05) in ST Z-diabetes, but dropped to near normal levels following insulin treatment. Incubation of whole blood of normal or diabetic rats with 0.02-0.2 mU/ml re gular insulin for 10 min at 37 degrees C, decreased HK (P<0.01) and PK (P<0 .05) and led to the appearance (P<0.05) of Arg-Pro-Pro-Gly-Phe, a partially stable product of BK metabolism, detected in the incubation media by an en zyme-linked immunosorbent assay (ELISA). Incubation of cell-free plasma ins ulin had no effect on these parameters, suggesting that blood cells, possib ly neutrophils, are required by insulin for the activation of plasma PK to kallikrein leading to BK release. Insulin may be a factor modulating BK for mation; its reduction in diabetes may explain increases of plasma kininogen and PK observed in this condition.