Fertility and Pregnancy-Associated ？-Cell Proliferation in Mice Deficient in Proglucagon-Derived Peptides 英文参考文献.docVIP

FertilityandPregnancy-Associated?-CellProliferationin MiceDeficientinProglucagon-DerivedPeptides ChisatoSugiyama1,2,MichiyoYamamoto1,TomomiKotani2,FumitakaKikkawa2,YoshiharuMurata1, YoshitakaHayashi1* 1Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan, 2Department of Obstetrics and Gynecology, Nagoya UniversityGraduateSchoolofMedicine,Nagoya,Japan Abstract Proglucagon, which is encoded by the glucagon gene (Gcg), is the precursor of several peptide hormones, including glucagonandglucagon-likepeptide1(GLP-1).Whereasglucagonstimulateshepaticglycogenolysisandgluconeogenesis, GLP-1 stimulates insulin secretion to lower blood glucose and also supports ?-cell proliferation and protection from apoptotic stimuli. Pregnancy is a strong inducer of change in islet function, however the roles of proglucagon-derived peptidesinpregnancyareonlypartiallyunderstood.Inthepresentstudy,weanalyzedfertilityandpregnancy-associated changes in homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcggfp/gfp), which lack all the peptides derivedfromproglucagon.FemaleGcggfp/gfp micecoulddeliverandraiseGcggfp/gfp pupstoweaningandGcggfp/gfp pups fromGcggfp/gfp damswereviableandfertile.Pregnancyinduced?-cellproliferationinGcggfp/gfp miceaswellasincontrol mice.However,seruminsulinlevelsinpregnantGcggfp/gfpfemaleswerelowerthanthoseincontrolpregnantfemalesunder adlibitumfeeding,andbloodglucoselevelsinpregnantGcggfp/gfp femaleswerehigheraftergestationalday12.Gcggfp/gfp femalesshowedadecreasedpregnancyrateandsmallerlittersize.Therateofsuccessfulbreedingwassignificantlylowerin Gcggfp/gfpfemalesandwasnotimprovedbyexperienceofbreeding.Takentogether,proglucagon-derivedpeptidesarenot required for pregnancy-associated ?-cell proliferation, however, are required for regulation of blood glucose levels and normalreproductivecapacity.Gcggfp/gfpmicemayserveasanovelmodeltoanalyzetheeffectofmildhyperglycemiaduring lategestationalp