Probing the mechanism of reduced in vivo potency of insulin detemir

BackgroundInsulin detemir (IDet) is an insulin analog used to treat diabetes. IDet shows full efficacy but reduced potency compared to human insulin (HI) in both man and rat. In contrast, in pigs and dogs, IDet appears to have full in vivo potency. Non-receptor mediated degradation (NRMD) has previously been suggested as an explanation for the low potency of IDet, but this hypothesis has not been investigated further until now. Bacitracin is a nonspecific protease inhibitor which we hypothesized could inhibit NRMD of IDet in rats.Research design and methodsHealthy male rats instrumented with permanent catheters underwent euglycemic clamp during constant infusion of either HI or IDet at effect-matched doses with co-infusion of vehicle or bacitracin.ResultsPlasma concentrations of IDet increased significantly (p < 0.005) during bacitracin compared to vehicle co-infusion and the concomitant increase in glucose infusion rate (GIR, p < 0.001) required to maintain euglycemic clamp indicates that the IDet rescued from NRMD indeed was active. No significant differences were detected with co-infusions of HI with either bacitracin or vehicle.ConclusionsA large proportion of NRMD of IDet which can be inhibited by bacitracin may partly explain the reduced potency of IDet observed in rats and likely also in man.