Thebestofbothworlds:adesignermoleculetocombattype2diabetes
AteamofscientistsfromKielandMelbournehavedevelopedanewproteinfromtwonaturallyoccurringproteins,whichhasprovenveryeffectiveagainsttype2diabetesinlaboratoryexperiments.
ScientistsledbyProfessorStefanRose-John,abiochemistatKielUniversity(CAU)andmemberoftheClusterofExcellence"PrecisionMedicineinChronicInflammation",havedevelopedandproducedamoleculewhichimprovesinsulinsensitivityintype2diabetesinlaboratoryexperiments.Themoleculeismadeupofpartsoftwonaturallyoccurringsignalingmolecules,IL-6andCNTF.Throughthenewcomposition,thesyntheticproteincombinesthepositivepropertiesofbothoriginalproteins,butwithouttheirunwantedside-effects.Inthefuture,itcouldbeusedasanewtypeofmedicationfortreatingtype2diabetes.TheteamledbyRose-John,togetherwithscientistsfromMelbourneinAustralia,publishedtheirresultsonWednesdayinthescientificjournalNature.
Anestimated370millionpeopleworldwidesufferfromtype2diabetes,butaccordingtopredictions,thisnumbercouldevendoubleby2030.Themainriskfactorsfortype2diabetesareobesityandlackofexercise.Withtype2diabetes,thebodycellsrespondprogressivelyworsetothehormoneinsulin,i.e.theybecomemoreandmoreinsulinresistant.Asaresult,muscleandfatcellscannolongertakeupglucose(i.e.sugar),sincethisprocessiscontrolledbyinsulin.Inaddition,sinceitnolongerrespondstoinsulin,theliverstartsuninhibitedlyproducingglucoseandreleasingitintotheblood.Thus,theentirebloodsugarbalancebreaksdown,andthebloodsugarlevelrisesmoreandmore.
Twopromisingmoleculeswithunwantedside-effects
PreviousstudieshaveshownthatthesignalingmoleculeIL-6hasapositiveeffectonthemetabolicreactiondisturbedbytype2diabetes:inbothmiceandinhumans,itwasabletoreduceobesityaswellasinsulinresistance.Assuch,thiscouldactuallybeagoodactiveingredientagainsttype2diabetes.However,thesignalingmoleculeactsonthebodyinmanydifferentways-amongotherthings,itisalsopro-inflammatory,andthereforecannotbeconsideredasamedicationforthetreatmentoftype2diabetes.
Instudies,themoleculeCNTFhasalsoimprovedinsulinsensitivityandreducedobesity.However,clinicalstudieshavealsoshownthattwo-thirdsofpatientsformantibodiesagainstCNTF,renderingthemoleculeineffective.Theirimmunesystemidentifiesthemoleculeasaforeignsubstance,andtriestofightit.Therefore,bothCNTFaswellasIL-6areunsuitableasmedicationfortype2diabetes.
Thesolution:acombinationofthetwo
"Inourlaboratory,wealreadydesignedamoleculesometimeago,whichconsistsmainlyofcomponentsofIL-6,andinwhichaparthasbeenreplacedbyasectionofCNTF,"reportedRose-John,fromtheInstituteofBiochemistryattheCAU."InexchangewithmyAustraliancolleagueMarkFebbraiofromMonashUniversityinMelbourne,wecameupwiththeideathatthisconstructedmoleculecouldfunctionsimilarlytoCNTFandIL-6fortype2diabetes,butwithoutthewell-knownunwantedside-effects."
TheresearchersledbyRose-Johnoriginallyproducedthemoleculetofindoutmoreaboutthestructureandfunctioningoftheso-calledreceptorcomplexesofIL-6andCNTF.Thesearetwopartstructuresinbodycells,towhichspecificsignalingmoleculesfromoutsidethecellbindthemselves-inthiscaseIL-6orCNTF-therebymergingbothpartsandtriggeringaspecificreactionintherespectivecell.Initsreceptorcomplex,thenewmoleculeincorporatesanelementfromtheIL-6receptorcomplexandanotherfromtheCNTFreceptorcomplex-acombinationthatdoesnotoccurnaturallyintheorganism.Thisisadecisiveadvantage:asthenewmoleculeactivatesareceptorcomplex,whichisnotactivatedbyanyothermolecule,theresearchersassumedthatitwouldalsonotproduceaninflammatoryresponselikeIL-6.Inaddition,theyhopedthatthenewmoleculewouldalsonottriggeranautoimmuneresponselikeCNTF,sinceitlargelyconsistsofIL-6blocks,whichthebody'simmunesystemrecognizesasself.
Promisingeffect
Rose-JohnandFebbraiothereforedecidedtotestthismoleculeinmoredetail.InRose-JohnslabinKiel,theyfirstadapteditsothatitisbettersuitedforuseintheexperiments.TheAustralianresearchersthentesteditsmetaboliceffectindetailinthelaboratory,andinexperimentsonanimals.
Andinfact,themoleculenamedIC7Fcdeliveredonitspromise:itloweredthesugarcontentinthebloodofobesemice,andrestoredinsulinsensitivity.Inaddition,micethatweretreatedwiththemoleculelostweight.Atthesametime,IC7Fccausednounwantedimmunesystemorinflammatoryreactions.Theresearchershavealsodemonstratedthisinhumancells.IC7FcisthusapparentlymuchmoretolerablethanpureCNTF."Iamdelightedwithhowwellitworks.Next,wewanttotestourmoleculeinclinicaltrials.Ifourobservationsareconfirmed,IC7Fccouldbecomeanewdrugfortreatingtype2diabetes,"saidRose-John.
Contact:
Prof.StefanRose-John
ExecutiveDirectoroftheInstituteofBiochemistry,KielUniversity(CAU)
FacultyofMedicine
+49431/880-3336
rosejohn@biochem.uni-kiel.de
TheartificialmoleculeIC7(andalsotheensuingmoleculeIC7Fc)largelyconsistsofblocksofInterleukin-6(IL-6,gray)andasectionfromablockofCNTF(gold).
ProfessorStefanRose-John,memberoftheClusterofExcellence"PrecisionMedicineinChronicInflammation",formerExecutiveDirectoroftheInstituteofBiochemistryatKielUniversity(CAU),andheadoftheCollaborativeResearchCentre(CRC)877"ProteolysisasaRegulatoryEventinPathophysiology".
Originalpublication:
MariaFindeisen,TamaraLAllen,(),StefanRose-JohnandMarkAFebbraio,Treatmentoftype2diabeteswiththedesignercytokineIC7Fc,Nature(2019).
www.nature.com/articles/s41586-019-1601-9
AbouttheClusterofExcellencePMI
TheClusterofExcellence"PrecisionMedicineinChronicInflammation"(PMI)isbeingfundedfrom2019to2025throughtheGermanExcellenceStrategy(ExStra).Itsucceedsthe"InflammationatInterfacesCluster,whichwasalreadyfundedintwoperiodsoftheExcellenceInitiative(2007-2018).Around300membersfromeightinstitutionsatfourlocationsareinvolved:Kiel(KielUniversity,UniversityMedicalCenterSchleswig-Holstein(UKSH),MuthesiusUniversityofFineArtsandDesign,KielInstitutefortheWorldEconomy(IfW),LeibnizInstituteforScienceandMathematicsEducation(IPN)),Lbeck(UniversityofLbeck,UniversityMedicalCenterSchleswig-Holstein(UKSH)),Pln(MaxPlanckInstituteforEvolutionaryBiology)andBorstel(ResearchCenterBorstel-LeibnizLungCenter).
Thegoalistotranslateinterdisciplinaryresearchfindingsonchronicinflammatorydiseasesofbarrierorganstohealthcaremoreintensively,aswellastofulfilpreviouslyunsatisfiedneedsofthepatients.Threepointsareimportantinthecontextofsuccessfultreatment,andarethereforeattheheartofPMIresearch:theearlydetectionofchronicinflammatorydiseases,thepredictionofdiseaseprogressionandcomplications,andthepredictionofindividualresponsestotreatment.
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