Albumin binding of acylated insulin (NN304) does not deter action to stimulate glucose uptake.
NN304 [Lys(B29)-tetradecanoyl des(B30) human insulin] is a potentially therapeutic insulin analog designed to exhibit protracted glucose-lowering action. In dogs with infusion rates similar to insulin itself, NN304 exhibits similar glucose uptake (R(d)) stimulation with delayed onset of action. This compartmental modeling study was to determine if NN304 action could be accounted for by the approximately 2% unbound NN304 concentration. NN304 (or human insulin) (n = 6 each) was infused at 10.2 pmol center dot min(-1) center dot kg(-1) under euglycemic clamp conditions in anesthetized dogs. NN304 appearance in lymph, representing interstitial fluid (ISF), was slow compared with insulin (t(1/2) = 70 +/- 7 vs. 14 +/- 1 min, P < 0.001). R(d) was highly correlated with the ISF concentration for insulin and NN304 (r = 0.86 and 0.93, respectively), suggesting that slow transendothelial transport (TET) is responsible for sluggish NN304 action. Insulin and NN304 concentration data were fit to a two-compartment (plasma and ISF) model. NN304 plasma elimination and TET were reduced to 10 and 7% of insulin, respectively. Thus, there was reduction of NN304 transport, but not to the degree expected. In ISF, there was no reduction in NN304 elimination. Thus, this acylated insulin analog demonstrates blunted kinetics in plasma, and full efficacy in the compartment of action, ISF.
Dea
Melvin K
MK
Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California 90033, USA.
Hamilton-Wessler
Marianthe
M
Ader
Marilyn
M
Moore
Donna
D
Schäffer
Lauge
L
Loftager
Mette
M
Vølund
Aage
A
Bergman
Richard N
RN
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002352:Carrier Proteins / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D004285:Dogs; D005947:Glucose / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology*; D000069057:Insulin Detemir; D049528:Insulin, Long-Acting; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D010953:Plasma Volume; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*
D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D049528:Insulin, Long-Acting; D012709:Serum Albumin; D000069057:Insulin Detemir; D005947:Glucose