Theinsulin-likegrowthfactor(IGF)systemistheprimaryregulatorofnormalbodygrowthandregeneration,affectingcellproliferation,differentiationandapoptosis.Inaddition,theIGF-systemappearstomodifyinsulinsensitivityandlong-termglucosemetabolism.Finally,numerousepidemiological,experimentalandclinicaldataindicatethattheIGF-systemisalsoinvolvedinthedevelopmentofseveralcommoncancersaswellasfrequentdiseasessuchasatherosclerosisandtype2diabetesmellitus.TheIGF-systemconsistsofafamilyofcloselyrelatedpeptides,whichincludesthetwoprimarygrowthpromotingpeptides,IGF-IandIGF-II,6specifichigh-affinityIGF-bindingproteins(IGFBP-1to-6),andalargenon-IGF-bindingglycoprotein,the“acidlABIlesubunit”(ALS).IGFBP-3isthemostabundantIGF-bindingprotein,accountingforasmuchas75%ormoreofthecirculatingIGF-bindingcapacityinhealthysubjects.IGFBP-3sharesfunctionalpropertieswithIGFBP-5inthatbothpeptidesareabletoformhighmolecularweightternarycomplexesof~150kiloDaltonwithALSandeitherIGF-Ior–II.However,IGFBP-5circulatesinmuchlowerconcentrationsthanIGFBP-3,andinhealthysubjectstheternarycomplexescarryasmuchas90%ofIGFBP-3butonlyabout50%ofIGFBP-5.Originally,theIGFBPswerethoughttoserveasIGF-carrierproteins,stabilizingplasmaIGFlevelsandcontrollingtheegressofIGFfromthecirculationtotheextra-vascularcompartment.FurThermore,itwasassumedthatIGFBP-complexedIGFwasBIOLOGicallymoreorlessinactive,beingdepriveditsabilitytointeractwiththeIGF-Ireceptor.However,itsoonbecameapparentthatinsomeexperimentalsettingstheIGFBPsstimulatedratherthaninhibitedIGF-Imediatedactions,andaccordingly,theIGFBPsarenowoftenreferredtoasmodulatorsofIGF-Ibioactivity.Inaddition,themajorityoftheIGFBPs,andinparticularIGFBP-3,exertsIGF-IandIGF-Ireceptorindependenteffects,possIBLeinvolvinginteractionswithspecificreceptorslocatedatthecellsurfaceandintracellular.Forexample,IGFBP-3isnowadaysconsideredtoserveasananti-cancermolecule,apparentlyprotectingagainstseveralcommoncancers,andeffectsofIGFBP-3oninsulinsignalinginculturedADIpocyteshavealsobeensuggested.Theturnoveroftheternarycomplexesisveryslow,andtheplasmaconcentrationofIGFBP-3remainsstablethroughouttheday,beingunaffectedbyshort-termnutritionalchanges.Thus,thelevelofIGFBP-3maybedeterminedbyonesinglemeasurement.GHistheprimaryregulatorofIGFBP-3aswellasofIGF-IandALSandtherefore,allthreepeptidesincreaseduringthepubertalgrowthspurt,whereafterlevelsgraduallydeclinewithincreasingage.Inchildren,IGFBP-3hasbeenshowntocorrelatewiththe24-hintegratedGHsecretionandinparticularinchildrenIGFBP-3maybehelpfulinthediagnosisofGHdeficiency.