Mechanism of protracted metabolic effects of fatty acid acylated insulin, NN304, in dogs: retention of NN304 by albumin.
OBJECTIVE
The provision of stable, reproducible basal insulin is crucial to diabetes management. This study in dogs examined the metabolic effects and interstitial fluid (ISF) profiles of fatty acid acylated insulin, Lys(B29)-tetradecanoyl, des-(B30) human insulin (NN304).


METHODS
Euglycaemic clamps were carried out under inhalant anaesthesia during equimolar intravenous infusions (3.6 pmol. min(-1) x kg(-1) for 480 min) of human insulin or NN304 (n = 8 per group).


RESULTS
Steady-state total NN304 (albumin-bound and unbound) was considerably higher in plasma compared with human insulin (1895 +/- 127 vs 181 +/- 10 pmol/l, p < 0.001) and increased in interstitial fluid (163 +/- 14 vs 106 +/- 9 pmol/l, p < 0.01). The halftime for appearance of NN304 in interstitial fluid was slower than human insulin (92 vs 29 min, p < 0.001). Yet, equivalency of action was shown for glucose turnover; steady-state glucose uptake (Rd) of 7.28 +/- 0.55 and 6.76 +/- 0.24 mg. min(-1). kg(-1) and endogenous glucose production of 0.11 +/- 0.12 and 0.22 +/- 0.03 mg x min(-1) x kg(-1) (p > 0.40; NN304 and human insulin, respectively). Similar to interstitial fluid, half times for Rd and endogenous glucose production were delayed during NN304 infusion (162 vs 46 min and 80 vs 31 min, respectively; p < 0.01 vs human insulin).


CONCLUSIONS
Firstly equivalency of steady-state action is found at equimolar physiologic infusions of human insulin and NN304. Secondly NN304 binding to plasma albumin results in slower NN304 appearance in the interstitial compartment compared with human insulin. Thirdly the delay in appearance of NN304 in interstitial fluid may not in itself be a source of the protracted action of this insulin analogue. The protracted effect is due primarily to albumin binding of the insulin analogue NN304. [Diabetologia (1999) 42: 1254-1263]
Hamilton-Wessler
M
M
Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California 90033, USA.
Ader
M
M
Dea
M
M
Moore
D
D
Jorgensen
P N
PN
Markussen
J
J
Bergman
R N
RN
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs; D005110:Extracellular Space / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000069057:Insulin Detemir; D049528:Insulin, Long-Acting; D008297:Male; D012039:Regional Blood Flow / Q000187:drug effects; D012709:Serum Albumin / Q000378:metabolism*
D001786:Blood Glucose; D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D049528:Insulin, Long-Acting; D012709:Serum Albumin; D000069057:Insulin Detemir