Summary Ch 79 outline: Guyton and Hall Textbook of Medical Physiology, ISBN: 9780323597128 PBL

PhysCh79:Insulin,glucagon,diabetesmellitus
IntroductionPancreassecretesinsulin&glucagon:crucialfornormalregulationofglucose,lipid,andproteinmetabolism
●Pancreatictissues
○Acini:secretesdigestivejuicesintoduodenum
○Isletsoflangerhans:secreteinsulin&glucagondirectlyintoblood
■1-2Mineachpancreas
■Contains:
●Alphacells:25%-secreteglucagon
●Betacells:60%-secreteinsulin&amylin
●Deltacells:10%-secretesomatostatin
●PPcells:veryfew-secretepancreaticpolypeptide
■Allowscell-cellcommunication&directcontrolofsecretionInsulin
●Affectsfat,protein,andcarbohydratemetabolism
●Associatedwithenergyabundance
○Dietofabundantfood
→abundantenergy
→increasedinsulinsecretion
○Excesscarbs
→carbsstoredasglycogen
■Convertedintofats&storedinadipose
○InsulinpromotesAAuptakebycells&convertingthemtoproteins
■Inhibitsbreakdownofproteinsalreadyincells-Chemistry
●2chainsconnectedbydisulfidelinkages
○Whensplit,functionalactivityofinsulinlost
●Synthesis:
β
-
cells
○TranslationofinsulinRNA(ribosomesonER)
→preproinsulin
→cleavedinER
→proinsulin
→cleavedingolgi
→insulin
■A&Bchainsconnectedbydisulfidelinkages
■Cchainpeptide
○Cpeptide&insulinpackagedintogranules
→secretedinequimolaramounts(1:1)
■5-10%secretedasproinsulin
○Cpeptide:
■BindsGPCRsoncellmembranes
→activatesNa/K-ATPases&endothelialNOsynthase
■Measuredbyradioimmunoassayinsulin-treateddiabeticpatients(determineshowmuchoftheirowninsulintheyareproducing
●PtswithType1(cannotproduceinsulin)havegreatlydecreasedCpeptidelevels
○Insulincirculatesunboundinblood(½life:6m)
■Clearedfromcirculationwithin10-15m
■Insulinthatbindstoreceptorsontargetcellsdegradedbyinsulinase(inliver)-Activatingtargetcellreceptors
●Insulinreceptor:enzymelinkedreceptor;4subunitsheldbydisulfidelinkages
○2
α
:outsidecellmembrane
○2
β
:crossesmembraneandprotrudesintocellcytoplasm ●Insulinbinds
α
-
subunit
→
β
-
subunitsautophosphorylated
→tyrosinekinasesactivated
→phosphorylatesintracellularenzymes
○Insulin-receptorsubstrates(IRS):mediateseffectsonglucose,fat,andproteinmetabolism
●Insulinstimulationcauses:
○80%ofbodycellstoincreasetheirglucoseuptake
●Especiallyfat&muscle;notneurons
■Glucosetransportviatranslocationofintracellularvesiclestocellmembrane
●Wheninsulinunavailable,vesiclesseparatefromcell&movebacktocellinterior
■Glucoseenterscell
→phosphorylatedtobecomeasubstrateforcarbohydratefunctions
○CellmembranepermeabletoAAs,K+,PO-
→increasedtransportofionsintocell
○Slowereffects(hrs-days):changedtranslationrateormRNAtoformnewproteins
■Allowsinsulintoachieveitsmetaboliceffects-Effectofinsulinoncarbmetabolism
●Promotingmuscleglucoseuptake
○MuscletissuedependsonFAsforenergy
■Normalrestingmusclemembraneslightlypermeabletoglucose(exceptwhenmusclestimulatedbyinsulin)
■Insulincanincreaserateofglucosetransportintorestingmuscleby15-fold
○Whenmusclesuseglucose:
■Moderateorheavyexercise
●Doesnotrequirelargeamountsofinsulin
●MusclecontractionincreasestranslocationofGLUT4tofacilitatediffusionofglucoseintocell
■Firstfewhrsafterameal
●Bloodglucosehigh&pancreassecretinglargeamountsofinsulin
●Extrainsulincausesrapidtransportofglucoseintomusclecells
○MusclecellsuseglucoseinsteadofFAs
●Storageofglycogeninmuscle
○Excessglucosestoredasglycogen(2-3%concentration)
■Usedforlaterenergy
○Glycogen:
■Usefulforshortperiodsofextremeenergyusagebymuscles
■Providesspurtsofanaerobicenergyforafewminutesatatimeviaglycolyticbreakdownofglycogentolacticacid(canoccurwithoutoxygen)
●Liveruptake,storage,useofglucose
○Insulincausingglucoseuptakeinliver:
■Insulininactivatesliverphosphorylase
→preventsbreakdownofstoredglycogen
●Phosphorylasecausesliverglycogentosplitintoglucose
■Insulinenhancesuptakeofglucosebylivercellsbyincreasingactivityofglucokinase