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Mechanism of Action in Dogs of Slow-Acting Insulin Analog O346

Department of Physiology and Biophysics (M.E., M.H.-W., S.P.K., M.K.D., E.K., A.P., J.M., R.N.B.), Keck School of Medicine, University of Southern California, Los Angeles, California 90033; and Novo Research Institute (J.M.), Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark

Address all correspondence and requests for reprints to: Richard N. Bergman, Ph.D., Department of Physiology and Biophysics, University of Southern California School of Medicine, 1333 San Pablo Street, MMR 626, Los Angeles, California 90033. E-mail: rbergman{at}usc.edu.

We compared metabolic effects as well as plasma and interstital fluid kinetics of fatty acid-acylated insulin, Lys^B29(N--carboxynonadecanoyl)-des(B30) human insulin (O346), with previously determined kinetics of native insulin and insulin detemir. Euglycemic clamps with iv injection of O346 (90 pmol/kg) or saline control were performed in 10 male mongrel dogs under inhalent anesthesia. The t_1/2 for the clearance of O346 from plasma was 375.7 ± 26.7 min; the t_1/2 for the appearance of O346 in interstital fluid was 137 ± 20 min (mean ± SEM). Glucose disposal with O346 injection was increased 4-fold (t = 480 min, 8.3 ± 1.42 mg/min/kg) compared with preinjection (t = 0 min, 2.1 ± 0.13 mg/min/kg; P < 0.05) or saline control (t = 480 min, 2.09 ± 0.22 mg/min/kg; P < 0.05). O346 plasma elimination and transendothelial transport were 0.3% and 3.5% of regular insulin and 3% and 50% of insulin detemir, respectively. Combination of in vivo results and compartmental modeling suggests that the duration of action of O346 after iv injection is about 25-fold and 10-fold longer compared with regular human insulin and insulin detemir, respectively. This study demonstrates that O346 stimulates glucose disposal very slowly, but when injected iv, its effect may be maintained for as long as 48 h as estimated from simulation analysis. The data suggest that O346 bound to albumin in plasma acts as a storage compartment for O346 from which the analog is slowly released to insulin-sensitive tissues. Reduced liver clearance of O346 is suggested to be the major mechanism for the protracted action.

This work was supported by grants from Novo Nordisk A/S and the National Institutes of Health (DK-27619 and DK-29867). S.P.K. was supported by a predoctoral training grant from the National Institute of Aging (T32-AG-00093).

Abbreviations: EGP, Endogenous glucose production; FABF, femoral artery blood flow; GINF, glucose infusion; MAP, mean arterial pressure; NEFA, nonesterified fatty acid.