Insulin detemir is a fully efficacious, low affinity agonist at the insulin receptor.
OBJECTIVE
To compare the properties of insulin detemir with human insulin or insulin aspart in various in vitro and in vivo experiments, thereby highlighting the importance of performing dose-response studies when investigating insulin analogues, in this study specifically insulin detemir.


METHODS
Displacement of membrane-associated insulin receptors from human and rat hepatocytes, and from Chinese Hamster Ovary cells over-expressing human insulin receptor (CHO-hIR) at varying albumin concentrations is measured. Lipogenesis in primary rat adipocytes over time and the effects in the simultaneous presence of insulin detemir and human insulin or insulin aspart are assessed. The hyperinsulinaemic euglycaemic clamp technique in rats is used to establish dose-response curves for multiple metabolic endpoints and to investigate the effects of the simultaneous presence of insulin detemir and human insulin.


RESULTS
Both in vitro and in vivo, insulin detemir shows full efficacy and right-shifted parallel dose-response curves compared with human insulin. The potency estimates are different between the in vivo and in vitro conditions and among different in vitro conditions, that is the potency decreases in vitro with increasing albumin concentration. The effects of insulin detemir and human insulin are additive both in vitro and in vivo.


CONCLUSIONS
Insulin detemir is fully efficacious compared with human insulin on all metabolic endpoints measured in vitro and in vivo. The fact that the potency estimates are method-dependent emphasizes the importance of establishing full dose-response relationships when characterizing insulin detemir.
Sørensen
A R
AR
Diabetes Biology & Pharmacology, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. ars@novonordisk.com
Stidsen
C E
CE
Ribel
U
U
Nishimura
E
E
Sturis
J
J
Jonassen
I
I
Bouman
S D
SD
Kurtzhals
P
P
Brand
C L
CL
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006442:Glycated Hemoglobin; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D061267:Insulin Aspart; D000069057:Insulin Detemir; D049528:Insulin, Long-Acting; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism
D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D061267:Insulin Aspart; D000069057:Insulin Detemir; D049528:Insulin, Long-Acting; D008055:Lipids; D011972:Receptor, Insulin