Albumin Binding of Acylated Insulin (NN304) Does Not Deter Action to Stimulate Glucose Uptake
- Melvin K. Dea1,
- Marianthe Hamilton-Wessler1,
- Marilyn Ader1,
- Donna Moore1,
- Lauge Schäffer2,
- Mette Loftager2,
- Aage Vølund2 and
- Richard N. Bergman1
- 1Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California
- 2Novo Research Institute, Novo Nordisk A/S, Bagsvaerd, Denmark
NN304 [LysB29-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 (Rd) stimulation with delayed onset of action. This compartmental modeling study was to determine if NN304 action could be accounted for by the ∼2% unbound NN304 concentration. NN304 (or human insulin) (n = 6 each) was infused at 10.2 pmol · min−1 · kg−1 under euglycemic clamp conditions in anesthetized dogs. NN304 appearance in lymph, representing interstitial fluid (ISF), was slow compared with insulin (t1/2 = 70 ± 7 vs. 14 ± 1 min, P < 0.001). Rd 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.
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Received for publication 25 August 2001 and accepted in revised form 27 November 2001.
ELISA, enzyme-linked immunoabsorbent assay; FFA, free fatty acid; ISF, interstitial fluid; TET, transendothelial transport.