Characteristics of signalling properties mediated by long-acting insulin analogue glargine and detemir in target cells of insulin.
Glargine and detemir are long-acting human insulin analogues with a smooth peakless profile of action. Although their binding affinities to the insulin receptor have been studied, little is known about the subsequent signalling properties activated after the binding. We directly compared intracellular signalling properties of them in various cultured cells. Regarding the metabolic signalling, glargine and insulin-induced comparable dose-dependent phosphorylation of insulin receptor, IRS-1, Akt, and GSK3, whereas detemir-induced kinetics were markedly lower in 3T3-L1 adipocytes and L6 myocytes. A similar pattern of phosphorylation induction was observed in primary hepatocytes and vascular smooth muscle cells (VSMCs). Because of the binding of detemir to albumin with high affinity, the phosphorylation kinetics and glucose uptake of detemir, but not glargine, decreased with increasing concentrations of BSA. Concerning the mitogenic properties, glargine and insulin-induced comparable dose-dependent phosphorylation of MAP kinase (MAPK) and 5-bromo-2'-deoxyuridine (BrdU) incorporation. Detemir-induced phosphorylation of MAPK was apparently reduced, whereas it stimulated BrdU incorporation with relatively similar dose-dependent manner in VSMCs. These results indicate that glargine has comparable properties to human insulin in metabolic and mitogenic signalling and action. In contrast, detemir-induced metabolic signaling is less potent in all cell types studied, and is reduced further by increasing concentrations of albumin.
Wada
Tsutomu
T
Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Azegami
Mari
M
Sugiyama
Maine
M
Tsuneki
Hiroshi
H
Sasaoka
Toshiyasu
T
D016475:3T3 Cells; D000818:Animals; D018929:Cell Culture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000069057:Insulin Detemir; D000069036:Insulin Glargine; D000078790:Insulin Secretion; D049528:Insulin, Long-Acting; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D007328:Insulin; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D000069057:Insulin Detemir; D005947:Glucose