NOVEL HEPATOSELECTIVE INSULIN ANALOGS - STUDIES WITH COVALENTLY-LINKED THYROXYL-INSULIN COMPLEXES

To explore the possibility that insulin analogues designed to have res tricted access to peripheral tissues may display relative hepatoselect ivity in vivo, N-alpha beta gamma-thyroxyl-insulin (B1-T4-lns) and N-a lpha beta gamma-thyroxyl-aminohexanoyl insulin (B1-T4-AHA-lns) were sy nthesized. These insulin analogues bind thyroid hormone binding protei ns to form high molecular weight complexes. Effects of intravenous inf usions of B1-T4-lns; B1-T4-AHA-lns; combined thyroxine binding globuli n (TBG) and B1-T4-lns and combined TBG and B1-T4-AHA-lns were compared with those of insulin infusion in hyperinsulinaemic euglycaemic clamp protocols in anaesthetized beagles (n = 4 and n = 3 for combined TBC infusions). Glucose turnover rates were measured using D-[3-H-3]glucos e infusion. With all 5 protocols the rate of glucose disappearance (Rd ) was increased and the rate of endogenous glucose production (Ra) dec reased from basal level 13.53+/-0.60 mu mol kg(-1) min(-1) (p < 0.05). insulin-like activity for Ra and Rd was calculated as the area betwee n the basal values of each variable and the subsequent values plotted graphically against time (AUC). For insulin, B1-T4-lns, B1-T4-AHA-lns, combined infusions of TBG + B1-T4-lns, and TBG + B1-T4-AHA-Ins, respe ctively, AUC for Rd values were 6.30 +/- 0.69, 3.35 +/- 0.53, 4.40 +/- 0.64, 2.82 +/- 0.40 and 3.46 +/- 0.95 (mmol kg(-1)), all analogue inf usions being different from insulin (p< 0.05). AUC for Rd was further reduced by addition of TBC to B1-T4-AHA-lns (p < 0.05). In contrast th e effect of all analogues on AUC for Ra was similar to that of insulin . These observations are compatible with the suggestion that insulin a nalogues which bind to thyroid hormone binding proteins retain access to hepatic insulin receptors which primarily control Ra. The reduced p eripheral insulin-like effect (Rd) could be due to reduced transcapill ary access to peripheral insulin receptor sites. (C) 1998 John Wiley & Sons, Ltd.