Molecular Characterisation of Long-Acting Insulin Analogues in Comparison with Human Insulin, IGF-1 and Insulin X10 英文参考文献.docVIP

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Molecular Characterisation of Long-Acting Insulin Analogues in Comparison with Human Insulin, IGF-1 and Insulin X10 英文参考文献.doc

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Molecular Characterisation of Long-Acting Insulin Analogues in Comparison with Human Insulin, IGF-1 and Insulin X10 英文参考文献

MolecularCharacterisationofLong-ActingInsulin AnaloguesinComparisonwithHumanInsulin,IGF-1and InsulinX10 BoF.Hansen*,TineGlendorf,AnneC.Hegelund,AndersLundby,AnneLu¨tzen,RitaSlaaby,Carsten EnggaardStidsen DiabetesResearchUnit,NovoNordiskA/S,Ma?l?v, Denmark Abstract Aims/Hypothesis:Thereiscontroversywithrespecttomolecularcharacteristicsofinsulinanalogues.Wereportaseriesof experiments forming a comprehensive characterisation of the long acting insulin analogues, glargine and detemir, in comparisonwithhumaninsulin,IGF-1,andthesuper-mitogenicinsulin,X10. Methods: We measured binding of ligands to membrane-bound and solubilised receptors, receptor activation and mitogenicityinanumberofcelltypes. Results:Detemirandglargineeachdisplayedabalancedaffinityforinsulinreceptor(IR)isoformsAandB.Thiswasalsotrue forX10,whereasIGF-1hadahigheraffinityforIR-AthanIR-B.X10andglarginebothexhibitedahigherrelativeIGF-1Rthan IRbindingaffinity,whereasdetemirdisplayedanIGF-1R:IRbindingratioof#1.LigandswithhighrelativeIGF-1Raffinityalso hadhighaffinityforIR/IGF-1Rhybridreceptors.Ingeneral,therelativebindingaffinitiesoftheanalogueswerereflectedin theirabilitytophosphorylatetheIRandIGF-1R.DetailedanalysisrevealedthatX10,incontrasttotheotherligands,seemed toevokeapreferentialphosphorylationofjuxtamembraneandkinasedomainphosphorylationsitesoftheIR.Sustained phosphorylationwasonlyobservedfromtheIRafterstimulationwithX10,andafterstimulationwithIGF-1fromtheIGF-1R. BothX10andglargineshowedanincreasedmitogenicpotencycomparedtohumaninsulinincellsexpressingmanyIGF- 1Rs,whereasonlyX10showedincreasedmitogenicityincellsexpressingmanyIRs. Conclusions: Detailed analysis of receptor binding, activation and in vitro mitogenicity indicated no molecular safety concernwithdetemir. Citation:HansenBF,GlendorfT,HegelundAC,LundbyA,Lu¨tzenA,etal.(2012)MolecularCharacterisationofLong-ActingInsulinAnaloguesinComparisonwith HumanInsulin,IGF-1andInsulinX10.PLoSONE7(5):e34274.doi:10.1371/journal.pone.0034274 Editor:Step