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European Journal of Endocrinology -18-0197 levels. suggesting thattheliverandgutplaykeyrolesindeterminingfastingpostabsorptivecirculatingglucagon axis. Thisarticlesummarisesthephysiologicalregulationofglucagonsecretioninhumansandconsidersnewfindings mediated byincreasedcirculatingaminoacidsconstituteacompleteendocrinefeedbacksystem:theliver–alpha cell induced hepaticglucagonresistance(andreducedaminoacidturnover)andcompensatorysecretion ‘pancreacentric’ and‘glucocentric’understandingofhyperglucagonaemialedtothehypothesisthatsteatosis- strongly correlateswithobesity, liverfatcontentandcirculatingaminoacids,hasmadeusquestionthecommon cells. Furthermore,ourobservationthatfastinghyperglucagonaemiaisunrelatedtothediabeticstate,but may alsobesecretedfromextrapancreatictissues–mostlikelyproglucagon-producingenteroendocrine polypeptide promoteshyperglucagonaemiaandthatglucagon,hithertoconsideredapancreas-specifichormone, the roleofgut-derivedfactorsindiabetichyperglucagonaemiaandshownthatglucose-dependentinsulinotropic factors aspotentialmediatorsofdiabetichyperglucagonaemia.Inaseriesclinicalexperiments,wehaveelucidated isoglycaemic intravenousglucoseadministrationinthesepatients,wehavebeenfocusingonthegutandgut-derived oral glucoseinpatientswithtype2diabetesisexchangedbynormalsuppressionofplasmaglucagonlevelsfollowing suppressive effects ofglucoseandinsulin.Sinceweobservedthatthewell-knownhyperglucagonaemicresponseto Hyperglucagonaemia isusuallyvieweduponasaconsequenceofpancreaticalphacellinsensitivitytotheglucagon- component ofdiabetesandisfoundtocontributesubstantiallythehyperglycaemicstatediabetes. Hyperglucagonaemia (inthefastingaswellinpostprandialstate)isconsideredacorepathophysiological Abstract European SocietyforEndocrinologyMeetingatBarcelona,Spain. This articleisbasedonthepresentationfor of Copenhagen,Denmark 3 2 1 Filip K Knop A gutfeelingaboutglucagon EJE PRIZE2018 Novo NordiskFoundationCenterforBasicMetabolicResearch,FacultyofHealthandMedicalSciences,University Department ofClinicalMedicine,FacultyHealthandMedicalSciences,UniversityCopenhagen,Denmark, Clinical MetabolicPhysiology, StenoDiabetesCenterCopenhagen,GentofteHospital,UniversityofHellerup, Denmark, https://doi.org/ www.ej Review Review journals andisamemberof numerousprofessionalsocietiesand committees as a referee for several international authored 270 scientific peer-reviewed publications. He serves particularly interested in the integrative role of the gut in human (patho)physiology and has of Copenhagen, Denmark. Prof. Knop has been involved in diabetes research since 1999. He is Clinical MetabolicPhysiologyatStenoDiabetesCenterCopenhagen, GentofteHospital,University Filip KKnop,MDPhD Invited Author’s profile e-online.org 10.1530/EJE 1 , 2 , 3 -18-0197 6 ,
is aconsultantendocrinologist,ProfessorofEndocrinology andHeadof © 2018EuropeanSociety ofEndocrinology F KKnop European JournalofEndocrinology Printed inGreatBritain Glucagon andthegut Published byBioscientifica Ltd. PrizeLecture2018atthe . Downloaded fromBioscientifica.com at10/02/202109:25:40AM (2018) Endocrinology European Journal of [email protected] Email to FKKnop should beaddressed Correspondence 178
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R267 –R280 via freeaccess European Journal of Endocrinology www.eje-online.org proglucagon. corresponding toaminoacidpositions inthe160aminoacid GLP-1 andGLP-2.Numbersindicate aminoacidpositions intervening peptide2(IP2)and totheglucagon-likepeptides: which isfurtherprocessedinto oxyntomodulinandGRPP, (MPGF)), whereasPC1/3processesproglucagonintoglicentin, intervening peptide1 (IP1) and a majorproglucagonfragment fragments (glicentin-relatedpancreaticpolypeptide(GRPP), glucagon andthreepresumablybiologicallyinactive the enteroendocrineLcells.PC2processesproglucagoninto PC2 beingrestrictedtothepancreaticalphacellsandPC1/3 which hithertohavebeenbelievedtobetissue-specificwith the presenceandactivityofenzymesPC1/3PC2, The posttranslationalprocessingofproglucagonisbasedon convertase 2(PC2)andprohormone1/3(PC1/3). Differential processingofproglucagonbyprohormone Figure 1 origin isbasedonpancreas-specificexpressionofPC2 ( glucagonotropic glucagon-likepeptide2(GLP-2)( like peptide1(GLP-1)andtheintestinotrophic the glucose-loweringandsatiety-inducingglucagon- by PC1/3leadingtoseveralactivepeptidesincluding of proglucagoninenteroendocrineLcellsisundertaken glucagon byprohormoneconvertase2(PC2),processing cells inwhichproglucagonisprocessedto29aminoacid intestinal epithelium( also producedinenteroendocrineLcellsfoundthe findings outlinedinthepresentpaper, proglucagon is in theisletsofLangerhans( a pancreas-specific hormone secreted from alpha cells encoded bytheglucagongene( glucagon, derivedfromtheprecursorproglucagon For almost a century, the 29 amino acid hormone Introduction Fig. 1 Review ). Thus,thenotionofglucagon’s pancreas-specific 4 ). Incontrasttopancreaticalpha 2 , 3 ). Ofimportanceforthe F KKnop 1 ), hasbeenconsidered 5 ) adrenaline andnoradrenaline( system and elevated levels of in the sympathetic nervous during stressandcoldexposure( supply isneededtosustainphysiologicalfunctions,e.g. are elicited during situations where increased energy factors addition tohypoglycaemia,otherstimulatory concentrations fallbelownormalfastinglevels( glucagon concentrations increase when blood glucose and ithasbeenknownfordecadesthatcirculating coordinationofglucagonsecretion, strict regulatory ( system and muscles, when needed the central nervous and energy-richglucosetobodilytissues,particularly fundamental roleinsecuringsupplyofeasilyaccessible effects onhepaticglucoseproductionand,thus,playsa maintains glucosehomeostasisviaitsstimulatory itself. rather thanpancreas-specificexpressionofproglucagon cells contributes importantly to diabetic hyperglycaemia that hypersecretionofglucagon frompancreaticalpha ( who typicallyarecharacterised byhyperglucagonaemia concentrations arewellknown inpatientswithdiabetes, perturbations intheregulationofplasmaglucagon producing pancreaticalphacells( outlined aboveconvergesatthelevelofglucagon- system controllingcirculating glucagonconcentrations glucagon-induced endogenousglucoseproduction. signs ofenergyabundanceandminimisedneedfor ( glucagon concentrationsinaglucose-dependentmanner GLP-1 inhibitsalphacellsecretionandreducescirculating the insulinotropic and satiety-promoting gut hormone cells, respectively( and somatostatinfromneighbouringbetadelta itself andbyglucose-stimulatedsecretionofinsulin glucose onalphacellsismediateddirectlyby concentrations ofglucagon( administration ofglucoseisknowntoreducecirculating with diabetes.Hyperglycaemiaelicitedbyintravenous(iv) glucagon secretioninhealthyindividualsandpatients ( insulinotropic polypeptide(GIP)( administration oftheguthormonesglucose-dependent cause hypoglycaemia ( most aminoacids,whichwithoutglucagonreleasewould insulin secretion,e.g.proteinmealsandadministration of stimulated by non-carbohydrate nutritional stimulators of Glucagon andthegut 6 6 25 16 ). Thiscriticalroleofglucagonobviouslyrequiresa ). Andformorethanfourdecades, ithasbeenargued , , Glucagon isrecognisedasahormonethatprimarily It is the general belief that the complex regulatory It is the general belief that the complex regulatory 17 26 , , 18 27 ), respectively, hasbeenshowntostimulate ). These glucagon-suppressive factors are all 19 , 20 10 Downloaded fromBioscientifica.com at10/02/202109:25:40AM , , 21 11 6 , 8 ). Furthermore, exogenous ). This inhibitory effectof ). Thisinhibitory , 22 9 12 ). Glucagonreleaseisalso , 7 ) andincludeactivity 23 , 13 178 , , 24 6 14 :6 ). Importantly, ). Furthermore, , 15 ) andGLP-2 R268 6 ). In via freeaccess European Journal of Endocrinology hyperglucagonaemia constitutes acentraldeterminant stating thatthecombination ofinsulindeficiencyand and Orci toproposetheir‘bihormonal hypothesis’ hyperglycaemia of type 1 diabetes ( essential roleforglucagoninthedevelopmentof 43 concentrations inthecontextofhyperglycaemia( rich mealresultinginundesirablyhighplasmaglucagon tolerance test (OGTT) or after ingestion of a carbohydrate- appropriately orevenincreaseduringanoralglucose are typicallyelevatedinthefastingstateandfailtodecrease In patientswithtype2diabetes,glucagonconcentrations Hyperglucagonaemia indiabetes conceptions ofglucagonbiology. of thetraditional‘pancreacentric’and‘glucocentric’ hyperglucagonaemia will be discussedinthe context the liverinregulationofglucagonsecretionand recent findingsinvolvingthegastrointestinaltractand pathophysiological phenomenonwillbeoutlined,and stimulating pancreaticglucagonsecretion( and, possibly, contribution of glucagonotropic gut factors occurs on the basis of gut-derived glucagon secretion ( 39 discovered liver–alphacellaxis( occurs duetosteatosis-induceddisruptionofthenewly evidence tosuggest( of hyperglucagonaemia ( of whichwehavedelineatedthecausalityandaetiology findings havespurredarangeofclinicalstudiesonthebasis explaining fastinghyperglucagonaemia ( glucagonsecretion resistance andcompensatory associated steatosisintheliverleadstohepaticglucagon than the diabetic state ( hyperglucagonaemia is moretightly related toobesity ( after nutrientingestioninpatientswithtype2diabetes determinants ofthehyperglucagonaemiaobserved pointing tothegutand/orgut-derivedfactorsasmajor hypoinsulinaemia pathognomonicfordiabetes( insulin, respectively, combinedwithabsoluteorrelative alpha cellstothesuppressiveeffectsofglucoseand and areusuallyexplainedbyresistanceofpancreatic hyperglucagonaemia remainincompletelyunderstood ( 30 28 Review ). Pioneering studies by Gerich , ), andafewyearslater, thatfasting weobserved ). However, the mechanisms underlying diabetic In thepresentpaper, hyperglucagonaemiaasa In 2007,wereportedthefirsthumanfindings 40 ) and( 2 ) thatpostprandial hyperglucagonaemia 1 ) thatfastinghyperglucagonaemia 11 31 , ) and suggested that obesity- 34 , 32 36 F KKnop , , 33 37 t al. et 44 , , 34 38 ) leading Unger pointed to an , ) and provided 18 35 ). 32 , 36 ). These 29 , 37 ). , 41 42 38 ) , , hyperglucagonaemia ( alpha cellsecretionisthoughttocontributediabetic and ensuingreducedinsulin-mediatedinhibitionof ( the development of hyperglucagonaemia in diabetes insulin, respectively, constitutesacriticalfactorfor to theglucagon-suppressiveeffectsofglucoseand earlier, thecurrentdogma states that alpha cell resistance diabetic hyperglucagonaemia are not clear. As alluded Despite theseendeavours,themechanismsunderlying characterising patientswith type2diabetes. important roleinthepostprandial hyperglucagonaemia stimulation ofthegastrointestinal tractmayplayan gastrointestinal tractorfactors originatingfromglucose insulin secretionaspreviouslythoughtandthatthe insulin ‘blindness’ofthealphacellsorcompromised diabetic hyperglucagonaemiawasnotglucoseand/or ( receptor-blocking capabilitieshavebeendeveloped( lowering drugswithglucagon-loweringorglucagon has beenpursuedasatherapeutictarget,andglucose- with diabetes( and postprandialhyperglycaemiacharacterisingpatients ( stimulate endogenousglucoseproductionintheliver been establishedthatelevatedglucagonconcentrations for diabetic hyperglycaemia ( glucose curve from the oralglucose challenge ( glucose curve glucose infusion(IIGI)administeredtocopytheplasma concentrations afteranisoglycaemicintravenous with anormalsuppressionofcirculating glucagon glucose administration(OGTT),but,surprisingly, react indeed exhibitahyperglucagonaemicresponsetooral human datashowingthatpatientswithtype2diabetes activity ( to diminished or defect suppression of alphacell secretory pancreatic problemofincreasedglucagonsecretiondue generally, diabetichyperglucagonaemiaisconsidereda type 2 diabetic postprandial hyperglucagonaemia. Thus, control subjects) ( of patients with type 2 diabetes (compared to healthy insomecohorts inhibiting guthormoneGLP-1observed concentrations ofthebetacell-stimulatingandalphacell- ( of glucagon(e.g.gammaaminobutyricacidandamylin been suggestedtoinhibitpancreaticalphacellsecretion paracrine influenceofotherbetacellproducts,whichhave beta cellfunctionindiabetesmayinvolveareduced Glucagon andthegut 29 30 45 51 , ), and, thus, contribute significantly to the fasting ). Thisstronglysuggestedthatthegenesisoftype2 , As alludedearlier, in2007,wereportedthefirst 49 52 ). Furthermore,compromisedbetacellfunction )). Additionally, reducedpostprandialplasma 6 ). 46 , 53 47 ) could,hypothetically, contributeto ). Accordingly, hyperglucagonaemia 29 Downloaded fromBioscientifica.com at10/02/202109:25:40AM , 50 28 ). Likewise,compromised ). Over the decades, it has 178 www.eje-online.org :6 R269 i. 2 Fig. 48 via freeaccess ). ) European Journal of Endocrinology www.eje-online.org suppression ofcirculatingglucagon concentrationsafterIIGI administration, but,surprisingly, aseemingly normal patients withahyperglucagonaemic responsetooralglucose revealed adifferential glucagon responseinthediabetic type 2diabetes(T2D)andmatched healthycontrols(CTRL)(A) intravenous glucoseinfusion(IIGI)performedinpatientswith Oral glucosetolerancetest(OGTT)andisoglycaemic Figure 2 Review F KKnop et al baseline-subtracted areaunder curve.AdaptedfromKnop glucose challenge(BandC).NS, non-significant;bsAUC, administered tocopytheplasma glucosecurvefromtheoral also investigatedpatientswithchronicpancreatitisand be expectedtoresultingreatersuppressionofglucagon anything, thelargerinsulinresponsetooralglucosewould incretin effectintype2diabetes( incretin hormonesGIPandGLP-1( during IIGIduetothestronginsulinotropiceffectsof responses duringOGTTaremarkedlyhigherthanthose alpha cellseemtoexplainthisphenomenonasinsulin with type 2 diabetes. Neither did insulin resistance of the glucagon responsesafteroralglucoseingestioninpatients of the alpha cell plays a majorrole in the exaggerated seemed unlikelythatimpairmentofglucosesensing Due to the isoglycaemic conditions in these studies, it of type 2 diabetic postprandial hyperglucagonaemia. ( as in healthy subjects during IIGI was reproduced by us 2 diabetesisaggravatedbyOGTT, butsuppressedsimilarly in2007thathyperglucagonaemiatype Our observation The OGTT/IIGIphenomenon glucose stimuli as observed intype2 diabetes ( glucose stimuliasobserved showed similarpatternsofglucagonresponsestothetwo in C-peptide-negativepatientswithtype1diabetesand glucagon responses,Hare insulin signallingasanexplanationoftheparadoxical In ordertoeliminatepotentialdifferencesinintra-islet than beingaspecificpathogenetictraitoftype2diabetes. to occurasaconsequenceofthediabeticstaterather OGTT andIIGI,respectively, suggestingthephenomenon ( diabetes (maturity-onsetoftheyoungtype3) ( diabetestochronicpancreatitis patients withsecondary OGTT andIIGIinotherformsofdiabetesfoundthat phenomenon, weinvestigatedglucagonresponsesto IIGI, respectively, occurasatype2diabetes-specific differences inglucagonresponsestoOGTTand hyperglucagonaemia' and'Gut-derivedglucagon'). 'Potential gutfactorscontributingtopostabsorptive in postprandialglucagonsecretion(seesectionson that thegastrointestinaltractplaysanimportantrole Taken together, ourfindingsin2007stronglysuggested responses compared to IIGI; but the opposite occurred. Glucagon andthegut 54 58 54 ) andothers( ) alsoexhibitedtheparadoxicalglucagonresponsesto ) andpatientswithhepatocytenuclearfactor1a . ( In ordertoestablishwhethertheparadoxical 30 ). 55 , 56 ) andmadeusreconsiderthegenesis Downloaded fromBioscientifica.com at10/02/202109:25:40AM et al . performedOGTTandIIGI 30 30 178 ) (despiteareduced , 54 :6 , 57 )). Thus,if 59 R270 ). We via freeaccess European Journal of Endocrinology It is well acknowledged that reduced incretin effect limits fatty liverdiseaseandpsoriasis patients)( normal glucosetolerance, patients withnon-alcoholic type 2diabetes(e.g.obeseinsulin-resistant subjectswith 66 insubjectswithprediabetes ( as ithasbeenobserved be anearlyconsequenceofdisturbedglucosemetabolism of diabetes( in type2diabetes( glucose, whereastheincretineffectisseverelyreduced for 50–70%oftheinsulinsecretedinresponsetooral in healthysubjects.Theincretineffectisresponsible comparing insulinresponsestoOGTTandIIGI and GLP-1( by stimulationofinsulinotropicguthormones,i.e.GIP potentiation ofglucose-inducedinsulinsecretionelicited As alludedearlier, theincretineffectdescribes glucagon secretion Implications ofgastrointestinal-stimulated still obscure. of gastrointestinallymediatedglucagonsecretionwere However, theunderlyingmechanismsandderivedeffects in healthysubjectswhenlargerglucoseloadsareused. phenomenon indiabeticpatientsthatcanalsobeevoked mediated glucagonsecretionseemedtobeaconsistent loads areingested( in non-diabeticcontrolsubjectswhenlargerglucose in glucagonsecretionbetweenOGTTandIIGIispresent Interestingly, thesestudiesalsoshowedthatthedifference or constitutesamorepotentglucagonotropicsignal( that greaterstimulationofthegastrointestinaltractelicits when largeroralglucoseloadswereemployedsuggesting responses toOGTTandIIGI,respectively, intensified diabetes and showed that the paradoxical glucagon suppressed circulating glucagonlevels. with differenttypesofdiabetesandthatIIGIinallcases constituted acommonphenomenonamongpatients findings suggestedthatpost-OGTThyperglucagonaemia i.e. independentlyofglucosetolerance)( was suppressednormallybyivglucoseinallgroups, increased glucagonresponsestooralglucose(glucagon diabetic glucosetoleranceinthesepatients–drivenby glucose toleranceoverimpairedtoovert oral andivglucose,respectively, increasesfromnormal and showedthatthedifferenceinglucagonresponseto endocrineinsufficiency different degreesofsecondary Review ) andinotherconditionswith highriskofdeveloping We then went back to study patients with type 2 54 54 , , 58 57 , ). Theincretineffectismeasuredby 64 30 61 ). Reducedincretineffectseemsto , 54 , , 62 55 ). Thus,gastrointestinally , 57 F KKnop , 63 ) andother forms 31 , 38 60 , ). These 67 , 61 68 65 ). ). , The incretineffectmostlikelyconstitutesanimportant an OGTTiscausedbytheoralrouteofadministration. percentage ofanindividual’s glucosedisposal during to the glucose ingested orally. GIGD explains what fromtheOGTTcurve to mimictheplasmaglucosecurve the amount of glucose needed to be infused intravenously of glucoseingested(throughthegastrointestinaltract)and with IIGI by relating the difference between the amount factors onglucosedisposalfollowingOGTTcompared in 2010( term ‘gastrointestinallymediatedglucosedisposal’(GIGD) differentially affectglucosedisposal,weintroducedthe disposal duringOGTTvsIIGI. any sizewill,inevent,contributetoimproveglucose reduced incretineffect.Nevertheless,aneffectof the contextofinsulinresistanceoftenaccompanyinga disposal hasbeendifficulttodisentangle–especiallyin postprandial insulinsecretion,butitseffectonglucose ( exhibit aseverelyreducedGIGDintherangeof~10–30% 56 In healthysubjects,GIGDtypicallyamountsto~60%( factors arealsotakenintoaccountwhencalculatingGIGD. glucose concentrationsand/oratthepresentunknown glucose uptake,differencesinportalandvenousblood intheintestinalmucosa,first-passhepatic afferent nerves including differencesinglucagonsecretion,activationof glucose concentrationsdifferentlyduringOGTTandIIGI, contributor toGIGD,butotherfactorsaffectingplasma compromised inthetype 2 diabeticpatientsandto stimuli). Interestingly, GIGDwasfoundtobesignificantly exhibited similarglucagon suppression tobothglucose glucagon concentrations normally (healthycontrols response to75 incretin effect,butexhibitedahyperglucagonaemic patients withtype2diabeteswereshowntohaveanormal pathognomonic fordiabetes. may contributetopostabsorptivehyperglycaemia that gastrointestinallymediatedglucagonsecretion stimulating hepaticglucoseproduction.Thissuggested circulating glucagonconcentrations)mostlikelyby glucose disposalduringOGTTvsIIGI(whichsuppressed elicited bytheoralglucoseadministrationdeteriorated to Interestingly, meanGIGDcameoutnegative(amounting GIGD in the context of abrogated incretin effect ( with type1diabetesandwere,thus,abletodescribe performed OGTTandIIGIinC-peptide-negativepatients Glucagon andthegut 31 , − , 6%) suggestingthatthehyperglucagonaemicresponse In ordertobetterunderstandhoworalandivglucose In aKoreanstudy, leanandwell-controlled Asian 65 56 , , 67 59 57 , ). GIGDdescribestheimpactofgastrointestinal , 68 58 g OGTT, whereasIIGIsupressedcirculating , , 69 64 , ). Asmentionedearlier, Hare 70 ), whereaspatientswithdiabetes Downloaded fromBioscientifica.com at10/02/202109:25:40AM 178 www.eje-online.org :6 R271 t al et 59 31 via freeaccess ). , . European Journal of Endocrinology www.eje-online.org the OGTT-induced hyperglucagonaemia in diabetic glucagonostatic effectofGLP-1 couldcontributetoexplain 1, and we speculated that reduced secretion or attenuated candidate was the glucagonostatic incretin hormone GLP- glucagon-modulating gut-derived factors.Anobvious in patientswithdiabetes,wedirectedourattention to the paradoxicalglucagonresponsestoOGTTandIIGI insulin (duetotheincretineffect)didnotseemexplain As glucose (due to the isoglycaemic conditions) and postabsorptive hyperglucagonaemia Potential gutfactorscontributingto further investigation. hyperglucagonaemia arenotcompletelyclearandwarrant and pathophysiologicimplicationsofpostabsorptive seems tobeaconsistentphenomenon,buttheeffects of nutrientstimulationthegastrointestinaltract together, hyperglucagonaemiaarsingasaconsequence complicate theinterpretationoftheseresults.Taken mechanisms elicitedbyglucagonreceptorantagonism specificity of LY2409021 andpossiblecompensatory glucose excursions ( test, respectively, havelittleornoeffectonpostabsorptive hyperglucagonaemic responsestoOGTTandmixedmeal glucagon receptor antagonist LY2409021 suggest that the datafromstudiesusingthe glucose levels,preliminary IIGI translateintomeaningfuleffectsoncirculating that thedifferentialglucagonresponsestoOGTTand production) duringOGTT. Despitetheseindications concentrations (knowntodiminishendogenousglucose incretin effect) and, presumably, higher portal glucose during IIGI even with higher levels of insulin (due to the glucose productionwashigherduringOGTTthan fashion, and,importantly, weshowedthatendogenous whereas IIGIsuppressedglucagonlevelsinanormal duringOGTT,high glucagonresponseswereobserved As expected from ourpreviousstudies, inappropriately diabetic controlsusingglucosetracermethodology( IIGI in patients with type 2 diabetes and matched non- and endogenous glucose production during OGTTand excursions, Lund IIGI (suppression)influencepostabsorptiveglucose glucagon secretionduringOGTT(hypersecretion)and handling intype2diabetes. glucagon secretioncontributestotheimpairedglucose This stronglysuggeststhatgastrointestinal-stimulated correlate significantly withOGTTglucagonresponses( Review In ordertofurtherevaluatewhetherdifferencesin et al. 72 investigatedglucosedisappearance , 73 ). However, potential lack of F KKnop 71 56 ). ). from ourownorotherstudiesindicatedincreasedOGTT- with GLP-1 in equimolar amounts ( hormones GLP-2andGIP. AsGLP-2issecretedtogether equation, weturnedtothetwoglucagonotropicgut control subjects( patients andfoundittobesimilarasinmatchedhealthy the glucagonostaticpotencyofGLP-1intype2diabetic responses toOGTTindiabeticpatients.We thenevaluated OGTT didnotseemtoexplaintheexaggeratedglucagon GLP-1 responses( and meta-analysisofthedatadisclosednodifferencesin patients withtype2diabetesandhealthycontrolsubjects review of studies comparing GLP-1 responses between ( subjects suppressingglucagonnormallyduringOGTT hyperglucagonaemic patientswithdiabetesandhealthy no differenceinGLP-1responsestoOGTTbetween ‘hypo-GLP-1-aemia’ intype2diabetes( patients vshealthycontrols.Despitethegeneralnotionof been undertaken with inconsistent and conflicting results humans (referencedindetail byLund several studies in totally pancreatectomised animals and the gastricmucosaofrabbits anddogs( a ‘glycogenolyticsubstance’ couldbeextractedfrom agobySutherland&deDuvewhoshowedthat 70 years Extrapancreatic glucagon secretionwassuggested Gut-derived glucagon be aresultofglucagonsecretiondirectlyfromthegut. thought thatOGTT-induced hyperglucagonaemia could in type2diabetes.However, wecould not escapethe hyperglucagonaemic responsetoorallyingestedglucose GIP may play apredominantrole in theinappropriate IIGI) ( decreased circulating glucagon concentrationsduring effect onplasmaglucagonlevels(asexpected,GLP-1 were glucagon responsesduringIIGI,whereasGLP-2hadlittle and respectively) able toshowthatGIPinfusionsignificantlyincreased infusions, GIP +GLP-1GLP2 (with concomitantsaline,GIP, GLP-1,GLP-2and we designed a study involving an OGTT and five IIGIs worsened postprandialhyperglycaemia( glucagon responses in type 2 diabetes and, consequently, exogenous GIPadministrationincreasedpostprandial OGTT responses.Interestingly, Chia an underlyingmechanismofthehyperglucagonaemic increased secretionofGLP-2and/orGIPconstituted induced responsesofGIP( Glucagon andthegut 30 , 54 18 , ). Onthebasisoftheseresults,wesuggestedthat 58 , 59 , 63 27 53 , 71 ). With GLP-1eliminatedfromthe ). Thus,reducedGLP-1responseto ). We alsoperformedasystematic Downloaded fromBioscientifica.com at10/02/202109:25:40AM 75 ), wefounditunlikelythat 5 et al. ) and no clear signals 178 :6 74 t al et hadshownthat 77 76 ), we observed ), weobserved ). Sincethen, ). Therefore, . ( 41 )) have R272 via freeaccess European Journal of Endocrinology presumably biological inactive fragments intervening presumably biologicalinactive fragmentsintervening idea thatprocessing of proglucagon to glucagon (and the specific notionofglucagon secretionisrelatedtothe of adulthumans( not reconfirmedinmucosal biopsiesfromthestomach the foetalhumanstomach( resembling glucagon-positivecellswereidentified in of extrapancreaticglucagon( ventricle and the ileum could constitute places of origin had suggestedthatthemucosainantrumof extrapancreatic glucagonsecretion?’. physiological and/orpathophysiologicalimplications of glucagon secretionregulated?’and‘Whatmaybethe and how is it brought about?’, ‘How is extrapancreatic the localisation(s)ofextrapancreaticglucagonsecretion a numberofexcitingquestionsaroseincluding‘Whatis new pieceofevidencegut-derivedglucagonsecretion, in man–mostlikelyoriginatingfromthegut.With this emphasised theexistenceofextrapancreaticglucagon pancreatectomised patients,thesefindingsstrongly and pancreaticpolypeptide)wereabsentinourtotally 62 applying 75 extent duringIIGIasexpectedfrompreviousstudies levels inresponsetobothglucosestimuli,butagreater ( undetectable levelsintotallypancreatectomisedpatients whereas IIGIdecreasedcirculating glucagontoalmost circulating glucagonconcentrations inresponsetoOGTT, proteomics, wewereabletoshowadramaticincreasein forms ofglucagon( eliminating, cross-reactivitywithelongatedortruncated N-terminal antiglucagonantibodies,andthus,intheory sandwich ELISA utilising a combination of C and control subjects( pancreatectomised patients and 10 matched healthy human plasma( detection oflow-abundantpeptides,suchasglucagon,in proteomicsallow within massspectrometry-based dramatically ( sensitivity aswellspecificityofglucagonassays Importantly, newanalyticalendeavourshaveimproved or presence of extrapancreatic glucagon impossible. ( accuracy ofmanycurrentandpreviousglucagonassays glucagon, duetoimportantshortcomingsandlow in measuringthe29aminoacidproglucagonproduct, (most likelyduetospeciesdifferencesanddifficulties Fig. 3 78 Review ). Asotherpancreas-relatedproducts(e.g.C-peptide )) making decisive statements about the absence Studies indepancreatiseddogsfromthe1970s Lund ). Thehealthysubjectssuppressedplasmaglucagon et al g OGTTandIIGIinhealthysubjects( . performed75 79 80 ), and, furthermore, technical advances ). 79 84 ). Applyingarecentlydeveloped 79 ). Asalludedearlier, thepancreas- ), and mass spectrometry-based ), andmassspectrometry-based g OGTTandIIGI in 10totally 83 81 ), whilethisfindingwas F KKnop , 82 ). Later, alphacell- 61 , ( subjects (CTRL).Asterisks(*)indicatesignificantdifferences pancreatectomised patients(PX)andnon-diabeticcontrol intravenous glucoseinfusion(IIGI)intotally oral glucosetolerancetest(OGTT)andisoglycaemic Plasma responsesofglucose(A)andglucagon(B)during75 Figure 3 and immunohistochemical PC2-positive enteroendocrine controls andwereabletoshow ( hyperglucagonaemic responses) andmatchedhealthy with type2diabetes(exhibiting grosslypostprandial hypothesis, wesampledjejunal biopsiesfrompatients and IIGI,respectively( explain theparadoxicalglucagonresponsestoOGTT following luminalnutrientstimulationand,therefore, L cell products and 29 amino acid ‘pancreatic’ glucagon peptide 2( GLP-1, GLP-2,glicentin,oxyntomodulinandintervening thought toprocessproglucagonexclusivelybyPC1/3 to that PC2 expression in enteroendocrine L cells, which are restricted tothepancreas( peptide 1andmajorproglucagonfragment)byPC2 is Glucagon andthegut P
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0.05). AdaptedfromLund 5 ), wouldresultinco-secretionof‘traditional’ Downloaded fromBioscientifica.com at10/02/202109:25:40AM 86 85 et al ). Inordertoexplorethis ). In2009,itwashypothesised 1 ) thepresenceofPC2mRNA . ( 41 ). 178 www.eje-online.org :6 R273 g via freeaccess European Journal of Endocrinology www.eje-online.org glucagon-secreting cellsis currently beinginvestigated. ensuing diminishedstimulation ofenteroendocrine of gastricemptying/upper gastrointestinal motilityand direct effectoraresultoflixisenatide-induced deceleration receptor agonistlixisenatide ( excursions) bysingledosingoftheshort-actingGLP-1 (concomitantly withreducedpostprandialplasmaglucose glucagon responsesthatcanbesignificantlysuppressed test intotallypancreatectomisedpatientselicitsclearcut alpha cells.Also,Juel extrapancreatic glucagon is different from pancreatic stimulus–secretion couplinginthecellsresponsiblefor pancreatectomised patients( validated sandwichELISAmentionedearlier)intotally (as assessedbytherecentlydevelopedmassspectrometry- had noimpactoncirculating glucagonconcentrations stimulator ofpancreaticglucagonsecretion,arginine, a recentstudy, Juel suppress extrapancreaticglucagonsecretion( stimulus, whereasivglucoseseemstobeable patients, itisclearthatoralglucoserepresentsastrong From Lund these cellsmaynotbeasspecificpreviouslythought. glucagon andsuggeststhatprocessingofproglucagonin small intestineasapossiblesource ofextrapancreatic current evidencepointstoenteroendocrinecellsinthe processing by PC1/3) should be kept open. Held together, glucagon byotherprocessingenzymes(e.g.unspecific possibility ofproglucagonprocessingto29aminoacid evident insmallintestinalmucosabiopsiesand,thus,the study, however, noco-stainingofglucagonandPC2was glucagon (Jorsal gastric mucosabiopsiesfoundnoornegligiblesignsof sandwichELISAonhuman mass spectrometry-validated antibody andpeptideextractionwithapplicationofa using a new highly glucagon-specific monoclonal Jorsal andcolleaguesincludingimmunohistochemistry with healthy individuals ( intestine of individuals with type 2 diabetes compared expression ofthegeneencodingPC2, significantlygreater furthermore, werecentlyobserved and obesenon-diabeticpatients,respectively( fromobesepatientswithtype2diabetes bypass surgery) mucosa biopsies(obtainedduringRoux-en-Ygastric confirmed thesefindingsinastudyinvestigatingjejunal diabetic patientsascomparedtohealthycontrols( PC2-positive cellsinthejejunalepitheliumoftype2 and theproglucagonproductGLP-1( cells, ( Review How isextrapancreaticglucagonsecretionregulated? 2 ) immunohistochemicalco-localisationofPC2 t al et et al .’s studiesintotallypancreatectomised ., unpublished observation). Inthis ., unpublishedobservation). t al et et al . haveshownthatamixedmeal . showedthatthewell-known 4 ). Recent investigations by 90 89 ). Whetherthiseffectisa F KKnop ) suggestingthatthe PCSK2 3 , inthesmall ) 50%more 88 41 87 ), and ). In ). We nutrients todistalpartsofthesmallintestinewhere rerouting who haveundergonegastricbypasssurgery mechanism maybeofparticularimportanceinpatients landing’ ofpostprandialglucoseexcursions.Such oral ingestionofcarbohydrates,ensuringa‘smooth of endogenousglucoseproductionunleashedby induced insulinsurges)andthestrongsuppression the potent glucose-lowering mechanisms (e.g. incretin- extrapancreatic glucagoncanbethoughttocounteract glucagon secretionremainsuncertain.Hypothetically, being investigated. and drugsknowntoinfluenceglucagonsecretionare somatostatin. Furthermore,theeffectsofhypoglycaemia GLP-1, GLP-2,oxyntomodulin,insulin,amylinand state-of-the-art glucagonanalyses;theseincludeGIP, secretion intotallypancreatectomisedpatientsusing range offactorsknowntoregulatepancreaticglucagon Additionally, wearecurrentlyevaluatingtheeffectsofa potentially, play animportantroleinthepostabsorptive have far-reachingpathophysiological implicationsand, ( aftergastricbypasssurgery the reducedappetiteobserved such as GLP-1 and peptide YY – a view compatible with mediated satiety signals alongside other gut hormones may alsoactasnutrientsensorsandconveyglucagon- hypoglycaemia, glucagon-secretingcellsinthegut of gut-derivedglucagontoprotectionfrompostprandial Inadditiontothepotential contribution observation). plasma glucagonconcentrations(Jorsal correlating with postoperative increments in postprandial all biopsiesretrievedpostoperativelyvspreoperatively – glucagon antibody)andextractableappeared in identified inmucosabiopsies(usingahighlyspecific increased andglucagonwasimmunohistochemically ProglucagonmRNA aftergastricbypasssurgery: observed the paradoxicalpostprandialhyperglucagonaemia glucagon secretionfromthegutcouldhelptoexplain Jorsal secretion ( are known for their suppressive effects on alpha cell massive secretionofGLP-1andinsulin,bothwhich induced improvement in glycaemic control involving which seemscounterintuitiveinthecontextofsurgery- accompanied bypostprandialhyperglucagonaemia, metabolicbenefitsaretypically patients, surgery-induced risk ofpostprandialhypoglycaemia( the amountofcarbohydrateingested,increasing in aGLP-1-mediatedovershootofinsulinrelativeto GLP-1-secreting Lcellsareabundantandoftenresult Glucagon andthegut 93 ). Perhaps more intriguingly, gut-derived glucagon may Presently, thephysiologicaleffectofextrapancreatic et al . alludedtoabovesuggestthatextrapancreatic 86 ). Interestingly, datafrom thepreliminary Downloaded fromBioscientifica.com at10/02/202109:25:40AM 178 et al 91 :6 , ., unpublished 92 ). Inthese R274 via freeaccess European Journal of Endocrinology hepatic insensitivitytoglucagon andthatthisprovides response to steatosis-induced occurs as a compensatory hyperplasia), led us hypothesise that hyperglucagonaemia in the liver results in hyperglucagonaemia (and alpha cell showing thatselectiveknockoutoftheglucagonreceptor combined withelegantstudiesbyLonguet tolerant obese and insulin-resistant subjects ( hyperglucagonaemia in completely normoglucose- On thisbasis,our findings in2012showing fasting necessarily involveperturbationsinglucosehomeostasis. and lackofglucagonsignalling,respectively, donot ( cell hyperplasiawithgrosshypersecretionofglucagon these patientsexhibitapancreaticswellingduetoalpha with disturbancesofglucosemetabolism( the glucagonreceptorareneithernecessarilyassociated glucagonoma patients( inabout30%of diabetic hyperglycaemiaisonlyobserved and overt erythema skin lesion, the necrolytic migratory tumours (glucagonomas)themostconspicuoussignisa ( about changescompletelycompatiblewiththisevidence and lackofglucagonsignalling,respectively, donotbring ( pathogenesis offastinghyperglycaemiaintype2diabetes the pivotalroleoffastinghyperglucagonaemiain of hepaticglucoseproduction,andthus,demonstrated plasma glucagonlevelscontributetoincreasedbasalrate Baron patients withtype2diabetes( became a well-established fact among the majority of grew insizeandnumbers–fastinghyperglucagonaemia appeared normal( type 2diabetes,fastingplasmaglucagonconcentrations In earlystudiesinvolvingrelativelyleanpatientswith liver-alpha cellaxis Fasting hyperglucagonaemiaandthe Further studiesareneededtoaddresstheseissues. dose andconditionexamined( of glucosesuppressesglucagonlevelsindependently secretion ofglucagonfromthegutasivadministration hyperglycaemia ( carbohydrates and its contribution to postabsorptive the hyperglucagonaemic response tooralingestionof hyperglycaemia pathognomonicfordiabetes.Thus, 33 33 45 Review ). Thus, extreme phenotypes of glucagon excess ). For instance, in patients with glucagon-producing ). Nevertheless, in humans,extreme glucagon excess t al et . providedevidencethatelevatedfasting 46 95 , ), butoverthedecades–aspatients 94 33 ) maycompletelydependon ). Andinactivatingmutationsof 30 F KKnop , 43 54 , , 55 96 , ). Furthermore, 56 , 33 58 t al et ); rather, ,
61 . ( , 62 31 34 ). ), ) hepatic steatosisoftenobserved afterpancreatectomy. pancreatectomy mayconstitute amajordeterminantofthe glucagon. Also,thelackofpancreatic glucagonaftertotal (i.e. theenteroendocrineLcells)resultinginformationof amino acidsseemtotargetotherproglucagon-producingcell and secretionfromthepancreas.Butwithoutapancreas, compensatory alphacellgrowthandglucagonsynthesisin which undernormalcircumstanceswouldprovide acid turnoverisreducedgivingrisetohyperaminoacidaemia, processes (e.g.ureagenesisandlipolysis).Consequently, amino abolished, whichcompromisesglucagon-dependenthepatic stimulation oftheliverbypancreaticglucagoniscompletely axis isdisruptedonthebasisoftotalpancreatectomy, hyperglucagonaemia. Lowerpanel:Whentheliver–alphacell for thedisruptionofbalance,leadingtofasting in turnstimulatesalphacellsecretionordertocompensate glucagon resistance)resultinginhyperaminoacidaemia,which amino acidturnoverisreduced(duetosteatosis-induced disrupted byfattyinfiltrationoftheliver, ureagenesisand ureagenesis. Midpanel:Whentheliver–alphacellaxisis controlling aminoacidclearanceintheliverbyaccelerating glucagon, whichinturnseemstoplayavitalrole amino acidsseemtomaintainandregulatethesecretionof its disruption.Upperpanel:Undernormalcircumstances, Proposed mechanismsunderlyingtheliver–alphacellaxisand Figure 4 Glucagon andthegut Downloaded fromBioscientifica.com at10/02/202109:25:40AM 178 www.eje-online.org :6 R275 via freeaccess European Journal of Endocrinology www.eje-online.org system involvingtheliver andthepancreas: of disruptionahitherto unrecognisedendocrine the contextofobesityand type 2diabetesarisesaresult support thenotionthatfasting hyperglucagonaemiain fat combinedwithhyperglucagonaemia( glucagon receptorantagonist-inducedbuild-upofliver Furthermore,recent reports showing observation). to lean non-steatotic subjects (Suppli in obesesubjectswithbiopsy-verifiedsteatosis compared glucagon resistanceatthelevelofaminoacidturnover datafromourgroup showing hepatic by preliminary hyperglucagonaemia ( cell axisrepresentsanimportantdeterminantoffasting suggesting thatliver-specificdisruptionoftheliver–alpha relate toliverfatcontentandcirculating aminoacids( state ( hyperglucagonaemia occursindependentlyofthediabetic (with and without type 2 diabetes) showthat fasting studies inpatientswithnon-alcoholicfattyliverdisease in obese normal glucose-tolerant subjects, our recent alpha cellsdetermineglucagonlevels( that specificaminoacidsandacidtransportersin recently beencorroboratedinrodentstudiesshowing between theliverandalphacellsofpancreashas by acceleratingureagenesis( vital roleincontrollingaminoacidclearancetheliver the secretionofglucagon,whichinturnappearstoplaya of amino acids, thus, may be to maintain and regulate fluctuating plasma glucose levels( mediators ofliver-pancreascross-talkcomparedtoever- amino acidscanbethoughttoconstitutemorerelevant from transamination of amino acids ( removing from the body the ammonia that results glucagon ( with theurine)–processescriticallycontrolledby and deamination,tofinallyproduceurea(eliminated acids throughprocessesincludingtransamination ( signal betweentheliverandalphacells( circulating aminoacidscouldconstitutethefeedback alpha cells, andthus, suggested that single or several acids, whichinturninduceproliferationofpancreatic amino acidturnoverandincreasedplasmalevelsof that inhibitionoftheglucagonreceptorleadstoreduced ( alpha cells,leadingtofastinghyperglucagonaemia( a feedbackmechanismactingatthelevelofpancreatic Fig. 4 Fig. 4 Review Similar to observations offastinghyperglucagonaemia Similar toobservations The liveriscrucialforthemetabolismofamino ). 38 ). FindingsfromSolloway ). Rather, fastinghyperglucagonaemiaseemsto 97 ). In this way, glucagon is responsible for i. 4 Fig. ). Thisnotionissupported i. 4 Fig. F KKnop et al 33 ). Thisfeedbackloop ). A normal function . ( et al 36 35 , 97 ) demonstrated 37 ., unpublished ). Therefore, 98 ). ) strongly 32 , 40 34 32 ), ), ) )
Histology showedmarkedfattyinfiltrationoftheliver. From liver wasfoundtobeenlargedandbrightyellowincolour. Death occurred60 daysafterpancreatectomy. Atautopsy, the balanced dietandtreatedadequatelywithinsulin(right). depancreatised dog(right),approximatelythesamesize,feda Photograph ofnormalliverdog(left)andthea Figure 5 Dragsted cell mass, as observed inobesehumans( cell mass,asobserved in hypersecretionofglucagon, butalsoincreasedalpha 37 cells ( stimulating glucagon secretion from pancreatic alpha ultimately resultsinhyperaminoacidaemiapotentially acid turnover( glucagon resistance( related toobesity( to be independent of the diabetic state and rather in thesepatients( proglucagon-producing cells,i.e.enteroendocrineL perhaps explainingthehyperactivityof extrapancreatic turnover and, thus, results in hyperaminoacidaemia deficiency, whichinturnreduceshepaticaminoacid associated hepatic steatosis may be a result of glucagon of clinicalcases( studies ( after pancreatectomy( dogs fromthe1930sshowingincreasedliverfatcontent disease (assuggestedfromstudiesindepancreatised role inthepathophysiologyofnon-alcoholicfattyliver concept thatglucagonmayplayahithertounrecognised development ofhepaticsteatosis( total pancreatectomyisrobustlyassociatedwiththe axis is to remove pancreatic alpha cells. Interestingly, liver–alpha cellaxis( Glucagon andthegut ), thehyperaminoacidaemic state maynotonlyresult Taken together, fastinghyperglucagonaemiaseems Fig. 4 102 et al ). Assuggestedfromstudies in rodents( ) inadditiontoafewandsporadicreports . ( 100 39 103 ). Fig. 4 , 31 40 32 Fig. 4 , , Fig. 5 104 ). Reducedaminoacidturnover ) ( , 105 Downloaded fromBioscientifica.com at10/02/202109:25:40AM 38 41 )). Thistotalpancreatectomy- ). Anotherwaytodisruptthis ) andensuingreducedamino ), steatosis-associatedhepatic ). ) ( 100 , 99 101 178 ) andsupportsthe ) andlaterrodent :6 106 ). R276 35 , 36 via freeaccess , European Journal of Endocrinology References invaluable contributionstothearticlesformingfoundationofthispiece. Wewer Albrechtsen, Jens J Holst and Tina Vilsbøll are thankedfortheir Asger Lund,MikkelChristensen,JonatanIBagger, Tina Jorsal,NicolaiJ Acknowledgements funding agencyinthepublic,commercialornot-for-profit sector. The workwiththisarticlewasnotfundedbyanyspecificgrantfrom Funding perceived asprejudicingtheimpartialityofthisreview. The authordeclaresthatthereisnoconflictofinterestcouldbe Declaration ofinterest need tobeconsidered. alphacellsecretion amino acid-mediatedcompensatory hyperglucagonaemia, hepaticglucagonresistanceand be takenintoaccountandwhenevaluatingfasting gut-dependentglucagonsecretionshould is observed, cells). Thus,whenpostabsorptivehyperglucagonaemia glucagonsecretionfromalpha (triggering compensatory acids as essential mediators of liver–alpha cell cross-talk axis (hepaticglucagonresistance)involvingamino associated disruptionoftheemergingliver–alphacell of thediabeticstateandrathertoberelatedobesity- fasting hyperglucagonaemiaseemstooccurindependently stimulation ofthegastrointestinaltract.Furthermore, or glucagonotropic factors elicited by intraluminal consequence of gut-derived glucagon secretion and/ that postabsorptivehyperglucagonaemiaoccursasa diabetic hypoinsulinaemia).Thisnewevidencesupports suppressive effectsofglucoseandinsulincombinedwith diabetes (i.e.reducedalphacellsensitivitytotheglucagon- understanding ofpostabsorptivehyperglucagonaemiain and IIGI experiments have challenged the traditional and humanphysiologyexperimentsapplyingOGTT plasma glucagonconcentrationshasaccumulated hitherto underestimatedroleindeterminingpostprandial Over thelastdecade,evidencethatgutplaysa Conclusions 3 2 1 Review Kimball CP &Murlin JR.Aqueousextracts ofpancreasIII.Some Banting FG, Best CH,Collip JB,Campbell WR &Fletcher AA. Bell GI, Sanchez-Pescador R,Laybourn PJ&Najarian RC.Exon 58 precipitation reactionsofinsulin. Medical AssociationJournal Pancreatic extractsinthetreatment ofdiabetesmellitus. Nature duplication anddivergenceinthehumanpreproglucagongene. 337–346. 1983 304 368–371. 1922 (https://doi.org/10.1038/304368a0) 12 Journal ofBiologicalChemistry Journal 141–146. F KKnop Canadian 1923 5
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