2 185

A Hinrichs and others Transient in GHR 185:2 R35–R47 Review deficiency

MECHANISMS IN Transient juvenile hypoglycemia in growth receptor deficiency – mechanistic insights from Laron syndrome and tailored animal models

Arne Hinrichs1,2 , Simone Renner1,2,3 , Martin Bidlingmaier4 , John J Kopchick5 and Eckhard Wolf 1,2,3,6

1Chair for Molecular Animal Breeding and Biotechnology, Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany, 2Center for Innovative Medical Models (CiMM), LMU Munich, Oberschleißheim, Germany, 3German Center for Research (DZD), Neuherberg, Germany , 4Endocrine Laboratory, Medizinische Klinik Correspondence und Poliklinik IV, Klinikum der Universität München, Munich, Germany, 5Edison Biotechnology Institute Heritage should be addressed College of Osteopathic Medicine and Molecular and Cellular Biology Program, Department of Biomedical Sciences, to A Hinrichs Ohio University, Athens, Ohio, USA, and 6Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Email Munich, Munich, Germany [email protected]. uni-muenchen.de

Abstract

The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provided additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In

European Journal of Endocrinology the Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of is reported. Reduced in GHRD is discussed to cause juvenile hypoglycemia and a counter-regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.

European Journal of Endocrinology (2021) 185, R35–R47

Introduction low serum levels of insulin-like growth factor 1 (IGF1) and elevated levels of GH. Phenotypically they have a small Growth deficiency (GHRD) – the stature and are somewhat obese (1). In the Israeli cohort of human Laron syndrome (LS) – is a hereditary disorder LS patients (2), several inactivating mutations of the GHR leading to diminished growth hormone (GH) binding gene have been reported (1), while a cohort in is and intracellular signal transduction. LS patients have more uniform with only one inactivating GHR mutation

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-21-0013 European Journal of Endocrinology https://eje.bioscientifica.com healthy phenotype with increased insulinsensitivity healthy phenotypewith – ranging from insulinresistance ( have ofLS patients between cohorts various beendescribed ( symptom get ofLSbutvanishes adult patients when the ofadiposetissue. andincreased accumulation retardation phenotypeofpostnatal growth characteristic show the 3 ( of disruption EN, enhanced;IM,impaired;NO,normal. Beta-cell mass Glucose response ITT HOMA-IR Energy expenditure Caloric intake Insulin response Glucose response GTT offasting after longerin infantsandchildren periods ( cohorts from both Juvenile hypoglycemia isamajor symptom inLSpatients Laron syndromepatients receptor deficiency Glucose homeostasisingrowthhormone transient juvenile hypoglycemia are discussed. involved potentially Mechanisms phenomenonof inthe andinrodent andpig GHRD.of LSpatients modelswith ofglucosehomeostasisalterations in different cohorts even ( inobeseLSpatients Insulin Glucose adults. young accordingto( reaching normoglycemiaasadult.In human LSpatients(IsraeliandEcuadoriancohort),prepubertal,hypoglycemicarereferredtoasyoung,afterpuberty, Table 1 established byin inducingaframeshift mutation mouse model for LS–the approximatelywith 100 affected individuals( largest isthe innumbers, cohort Ecuadorian of which the ( 1 3 , ). In total, just 350 LS patients are estimated worldwide, just). Intotal, 350LSpatients Review 7 8 ). Similar to human LS patients, these animalmodels these ). Similarto humanLSpatients, Juvenile hypoglycemia is commonly as observed a key , 9 GHR- ). Nevertheless, differences). Nevertheless, inglucosehomeostasis Parameters ofglucosemetabolismindistinctagegroups.Agegroupsaredividedaccordingtoglycemicstatus.In KO pigsarereferredasyoungattheageof3monthsandadults atpubertywith6monthsofage. Ghr exon 4( 36 IM ( ↑ ↔ IM ( EN –NO( ↑ ↓ ), startingfrom11monthsofage,reachingnormoglycemiaaccordingto( 8 ( ↑ ( 8 ( ( , 1 ) 8 10 ) 10 10 11 ) Ghr Young ) , , 6 ) and has clinical implications ) andhasclinical 9 19 18 ). Aporcine LSmodelhasbeen ). This review summarizes the ). This review the summarizes -KO mouse – was produced by 10 ) ) Israeli cohort , 17 A Hinrichsandothers Ghr ) 10 ↓ NO ( ↑ ↑ ↔ IM ( EN ( ↑ ↓ -KO mice,animalsuptoanageof9.5months,exhibitinghypoglycemiaarereferredas ( ( ↔ ↔ ) to ametabolically ↔ ( 10 53 ( 17 ( ↑ 53 ( 10 10 ( 8 10 ) ) 8 8 , , ) Adult ) ); NO–EN , 19 10 ) , 17 19 ) , ) 16 ) GHR ) 4 , 5 exon ). A Ecuadorian cohort ↓ Young ( 11

) observed in patients aged 40years inpatients observed andolder( and even occasionalcasesofhyperglycemia have been Fasting glucoselevels ( atpuberty tend to normalize age-matched control subjects. The difference appeared insulin levelsand their were always in higher than Israeli cohort, ofthe peak was inLSpatients observed ( and decrease inadulthood increase atpuberty, earlier inmales, infemales than a lifelong increased insulinsensitivity was assumed( hyperglycemicIsraeli cohort, values were and notreported, glucoselevels fasting normal ( adult significance disappeared at age 5 statistical ( years always although lower childhood, incontrols during than glucosevalues werecohort, found widely to butwere vary , andlossofconsciousness( ( reported ( intolerance was revealed by oral ( relatives were ( reported ofcontrol siblingsand range ofthose ofone-third the of different insulinlevels ages; inadultLSpatients, in didnotfocus onacomparison LScohort Ecuadorian was ( observed atrend ofrelativeand inadultpatients, insulinopenia age, ofhyperinsulinemia decreased with degree the from age 6to 10 years from age 11 than to 22years. Thus, earlier malesandwas infemales more pronounced than deficiency Transient hypoglycemiainGHR ↓ ↓ IM ( NO ( ↓ ↔ Table 1 ( ( ( ( Adult 9 9 9 9 ) ) , Under physiological insulin levels conditions, In Israeli LS patients, ahighIn Israeli incidenceofglucose LS patients, 9 ) 9 14

) ) Ecuadorian LS patients (age LSpatients Ecuadorian ) ). Hypoglycemic glucoselevels of3040mg/dLwere 8 ↓ IM ( ↓ ↑ ↑ IM ( EN ( ↓ ↓ ), leadingto heavy sweating, pallor, headache, ( ( ( ( ( ( 35 36 55 37 36 35 35 39 39 , ) ) , , , 8 Young 39 56 37 36 , ) , , 64 40 10 ) ) ); ) ) ) ↔ , Ghr ( 16 35 -KO mouse ). Studies of insulin levels in the Downloaded fromBioscientifica.com at10/01/202108:54:59PM 9 ) , 37 14 IM ( ↓ ↑ ↑ EN ( ↓ ↔ ( ( ( ( ), animalsarereferredtoas 15 ( 36 57 37 35 ). 37 41 41 ). Asimilarage-dependent ) ) , , 9 , 57 36 , , Adult ) 38 17 74 14 ) , ); ) andintravenous ( 37 ) < 12 ). Incontrast to the 185 ↑ 20 years) 20 revealed ) ( , 36 13 :2 ) ). In the Israeli ). Inthe ↔ IM NO ↔ ↓ Young GHR-

↓ ↓ 8 KO pig ). Young 1 9 R36 ↔ IM NO ↔ ↔ , Adult ).

10 10 ↑ ↓ 18 ( via freeaccess 7 ), ). ) ) European Journal of Endocrinology Adult LS patients from the Israeli cohort treated with Israeli cohort from the Adult LSpatients after overdosage state oradministration inafasting ( adverse effect of treatment isIGF1-induced hypoglycemia in fatmassandhyperlipidemia ( over adipogenic effects time of rhIGF1 lead to anincrease and hyperlipidemia to first months ( in the years craniofacies ( not fully restores velocity –lineargrowth the andmodifies atinfancyaccelerates –but treatment starting Long-term ( inLSpatients 30 years andcanbeusedasatherapeutic Recombinant human (rh) IGF1is available for more than on glucosehomeostasis Treatment ofLaronsyndromepatientsandeffects background. genetic are related respective tobetween LS cohorts the various the ( high of consanguinityIn view degree in LS patients of the risk ( the disease associated gene affecting variants T2D- identified 400 componenta genetic more than with contextsensitivity –inthe oftype2diabetes (T2D)–has age of36yearsinsulin resistance atthe ( ( mutation this sharing supervision under Zvi of Moroccan heritage one Israeli patient Laron`s The E180 seemsto lowerfor risk mutation diabetes, as the E180 mRNA incommon( precursor splicemutation ( Israeli cohort Several ofthe mutations homeostasis ( phenotypeinglucose contrary discussed to causethe differences have indiet betweenthe cohorts been sensitivity ( compared to healthy controls, arguingfor increased insulin forthose insulin were lower significantly the LS patients in valuescurve for different, glucose was not significantly but intolerance was Inoral observed. GTTs, area underthe the BMI- andage-matched control relatives, nosign ofglucose ( cohort in this ( insulin-resistant diabetes with werepresenting reported ( peaks (11–22 years) ( patients in young adults(23–30years) inpubertal than to controls ( glucose loadwas commonly lower compared inLSpatients age with ( first at observed early puberty,the incidence increased and glucose tolerance tests (GTTs) ( 19 21 Review ), highlighting the broad variability among patients broad variability), highlightingamongpatients the ), it is likely that the differences), it islikely inglucosehomeostasis the that While environmental circumstances, especially 17 ) and rising insulinlevels) andrising age inLSpatients with 19 9 10 ). The amplitude of insulin response following ). 26 , 20 1 18 ). Treatment decreases fatmass ofchildren 8 8 ), whereasfrom Ecuadorhave patients the ), genetic causes appear ), justgenetic as likely. ). However, casesofhyperinsulinemic ). Comparing Ecuadorian LS patients to LSpatients ). Comparing Ecuadorian ) and decreased with age, that is,was lower age,) anddecreased that with GHR 10 gene are described in the inthe gene are described ). Glucoseintolerance was A Hinrichsandothers 27 ). The most prevalent 21 ) didnotdevelop 22 ). Insulin 23 2 ) but , 24 25 3 2 ). ). ). ). ). with rhIGF1 appears desirable for all LS patients as the rhIGF1 desirablewith appears for asthe allLSpatients hypoglycemic incidents ( velocityof growth asignificant increase of without showed LSpatients Ecuadorian apromotion prepubertal events ( insulinlevelsdecreased serum hypoglycemic without to adultsfor 7days successfully suppressed GHlevels and increasing adultheight ( potential and osseous maturation, decrease fatmass accumulation andshowed trials areduced dosagein clinical could that rhIGF1 replacementLS patients, therapy hasbeenused persistently decreased ( hypoglycemicepisodes without episodesandinsulinlevels werestabilize as patients more likely able to tolerate fasting ( Israeli LScohort in the reversed insulinresistance andimproved glucosetolerance of treatment ( and hyperlipidemia, which reversed upondiscontinuation rhIGF1 for showed alimited time offatmass areduction 36 (referredup to to anage as'young'; of9.5months ( levelsLow serum ofglucosewere for reported The approval ( by authorities highdue to cost the costs ofrhIGF1 for andthe obtaining therapy isnotavailable the Nevertheless, for allLSpatients improves. Israeli cohort from the phenotype ofpatients metabolic andthe stature normalizes phenotype ofshort the liverthe have elevated bloodglucoseandinsulin levels, For GHRin instance, micelacking secretion/action. show inglucosehomeostasis alterations andinsulin been generated (reviewed in tissues have GHRinspecific lacking mutants conditional revealing glucoseintolerance ( old levels young invery animals(3days; controls ( mice andalways remained lower inage-matched than levels ( levels similarto controls ( in 'old' mouse model. Inconsistent results have beenobtained levels inthe hasnotbeenobserved atpuberty ofglucose In contrast normalization to humanLSpatients, deficiency Transient hypoglycemiainGHR )) butbecamesimilarto controls atage 11 ( months In addition to global In addition GTTs,During ofinsulinin~2-month- secretion the Insulin levels were to below reported inyoung Ghr Ghr 36 -KO theglucose, micewas clear notsufficient to Ghr 31 -KO mouse ). 35 ). Administration of rhIGF1 over 12 to months -KO mice (21 which showed months), glucose , 28 36 ). Long-term rhIGF1). Long-term replacement therapy , 37 ). Only onestudy normal observed 10 29 33 Downloaded fromBioscientifica.com at10/01/202108:54:59PM 32 ). Glucoselevels were to reported 38 ). In the Ecuadorian cohort of cohort Ecuadorian ). Inthe Ghr ). ). In conclusion, the treatment the ). In conclusion, ) oreven higher significantly 42 -KO lines of mice, multiple 39 , https://eje.bioscientifica.com , 43 40 ). Many lines ofthese , 35 185 41 30 ). ). ). 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Low insulinlevels are similarto findings however, but glucoselevels atpuberty donotnormalize The fromwhile Ecuadorappearmetabolically healthy. patients tend to Israelidevelop cohort syndrome,the metabolic the 52 Review ). In the following, ). Inthe mechanisms potential we outline The porcine Ghr 50 -KO mouseresembles juvenile hypoglycemia; ). Under physiological acute the conditions, GHR -KO resembles model closely the Fig. 3 ). 51 A Hinrichsandothers ). Insulinantagonizing GHR -KO pig that alterations ofbodycomposition alterations maythat affect energy in blood glucose levels. changes the It has been discussed supply with correlate in energy do alterations Neither significantly increased in significantly hypoglycemic expenditureenergy ( size, was interpreted ascompensation ofanincreased for smaller their aftermice, observed normalization high fat diet ( insulin sensitivityin cannotbeforeseen, increased cohort asthe Ecuadorian ( western diet comparable isongoing Israeli cohort to the can beassumedfor past, while the atransitiontoward a a traditional diet cohort, for Ecuadorian that the noticed, expenditure energy resting isincreased ( their subjects, but than normal more energy significantly forcorrected body weight do not consume – patients –when showing Israeli that LScohort, assessed inthe causesforare potential increasing bloodglucoselevels. Increased food expenditure intake and/orreduced energy Changes infoodintakeandenergyexpenditure is notconclusively dueto apositive balance( energy age 21 weeks ( consumption –was seeninhypoglycemic expenditureincrease inenergy –measured by oxygen elevated atage 9( animals atage 2( deficiency Transient hypoglycemiainGHR 4 ). Nevertheless, the effect of a high caloric diet on the effect diet ofahigh on the ). Nevertheless, caloric Therefore, adiposity inGHRD that it can beconcluded Food expenditure intake andenergy have been 55 54 ). Increased food consumption of ), 7–12 ( months to drawaconclusion. enough clinicalorexperimental evidence indicates thatthereiscurrently not mechanism isprobablynotrelevant. '?' mechanism, while' evidence fortherelevanceofthis models ofGHRD.' cohorts ofLSpatientsandinanimal glucose levelstowardadulthoodin involved inthenormalizationofblood Overview ofmechanismspotentially Figure 3 37 37 ) and 3 months ( ) and3months ) and17 ( months 55 Ghr ). Caloric intake was found). Caloric to be Downloaded fromBioscientifica.com at10/01/202108:54:59PM ‑KO micepersists after feeding a https://eje.bioscientifica.com 58 ) and17 ( months   ' indicatesthatthereis 185 ' indicatesthatthe 56 8 57 :2 , ) andremained Ghr 53 ). Asignificant Ghr ). Ithasto be -KO miceat - KO mice Ghr R39 57 -KO ). 8 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com observed ( observed no commonobesity-associated comorbidities have been fat depotsleadingto 'healthy '. Consequently, results inanenlargement ofpreferentially subcutaneous in LS patients, negative effects ( onmetabolism levels andelevated leptin obvioustissue without serum pigs, which have fat increased subcutaneous significantly depot ( subcutaneous especially inthe of increased adiposetissue, presence can result inincreased insulinsensitivityinthe mice ( levelsadiponectin) were found to beelevated in low andhigh (both molecularweightand adiponectin enhancing insulinsensitivity ( in 'healthy obesity' ( fatdepotsin subcutaneous diabetes mellitus ( ofdeveloping risk fatdecreases the type2 subcutaneous insulin resistance while of apreferential accumulation promotesrole asvisceral inmetabolism, fataccumulation ( patients Ghr vssubcutaneous visceral fat depots, have in beenobserved is,apreferential enlargement of that accumulation, several publications. especially onglucosehomeostasis –have beenaddressed in obesity ( inGHRDleadsto progressive GHaction oflipolytic The lack Increasing obesity sexual canbeexpected. maturation RMR during and in patients inLaronof leanmassdecreases toward both puberty proportion ofbodyfatincreases andthe proportion As the maturation. adjusted increasing pubertal BMR/RMRwith several studies noted a decrease in lean or fat-free mass- adolescents( inprepubertal than pubertal expenditure dailytotal energy (TDEE)were higher in absolute rate metabolic basalorresting (BMR/RMR)and the that in healthy nonobeseadolescentsconcluded expenditure puberty inenergy changes andintake during to smallerbodysize( due utilization to increased energy seen as an adaptation expenditure, consumption canbe andincreased energy Review Ghr -KO mice( Based on the findings in the Ecuadorian cohort of cohort the Ecuadorian findingsin Based onthe tissue offat Differencesthe distribution in A recent systematic review of12 studies investigating 66 -KO miceshow analtered activity, secretory even 68 ), as in LS patients ( ), asinLSpatients 8 62 ). A similar situation canbeexpected). Asimilarsituation for 68 , , 20 63 ). Progressive accumulation of adipose tissue ). Progressive ofadiposetissue accumulation 60 , ). The plays site offataccumulation amajor GHR , Ghr 54 61 64 63 ), and the effects – onmetabolism ), andthe ) andwere alsosuggested for humanLS -KO miceand -KO pigs, a relative decrease in BMR/ 8 , ). Furthermore, visceral fatdepots ). Furthermore, , 65 58 ). Therefore, enlargement of the ). 67 Ghr ). Elevated levels adiponectin -KO micecanbeseenasa 7 64 ). A Hinrichsandothers ). For instance, leptin GHR -KO pigs, GHRD 59 ). However, GHR Ghr -KO -KO substrate for gluconeogenesis inyoung individuals( can leadto adecrease offree fattyacidsandglycerol asa in potentially the and and decreased cohort Ecuadorian inthe accompanied byaction diminished insulin resistance ( a progressive lipidswas reported increase ofserum Israeli cohort, from the age. InLSpatients with normalize in young in adipocytes levels leads lipid tosynthesis low serum The triglycerides preferential useofcirculating for storage of bloodglucoselevels following juvenile hypoglycemia. unlikelyis thus to play amajor role for normalization the children up to the age of5.5years upto the children didnot recover from was age-dependent Israeli ( cohort the to insulin-inducedhypoglycemia) from inLSpatients are established inpig routinely models ( that hyperinsulinemic-normoglycemic clamp experiments old need to insulinsensitivityin3-and6-month- determine ofglucoselevels.the normalization Future reflects studies insignificant increase inHOMA-IR from age 3 to 6months value (2.0)forthreshold insulinresistance inhumans.The animals( 6-month-old normalization ofglucoselevelsnormalization inadults. substrate poolfor to gluconeogenesis the andcontribute levels after assemblingstorage lipidscanincrease the lipid ofcirculating hand,normalization other On the ( cohort Ecuadorian from the patients while low levels oftriglycerides were for described adult corresponded to 0.25 corresponded 15, and21 In months. lowerwith inage-matched controls at9.5, scores than results have for been reported the HOMA-IR isnotvalidatedthe for animals( gender- healthy controls and BMI-matched ( displayed low HOMA-IR scores compared to age-, mellitus were ( reported years ( indicate insulinresistance uptoLS patients anage of40 insulin resistance (HOMA-IR) values above 2.0inIsraeli hyperglycemia, andhomeostasis modelassessmentfor ( ( cohort LS Ecuadorian onehandandthe onthe Israeli LScohort majorInsulin sensitivityisthe difference betweenthe Changes ininsulinsensitivity deficiency Transient hypoglycemiainGHR 7 ) on the other hand. Hyperinsulinemia, developing hand.Hyperinsulinemia, other ) onthe The outcome ofinsulintolerance tests (ITTs; leading In contrast, LS patients from the Ecuadorian cohort cohort Ecuadorian In contrast, from the LSpatients GHR 8 ). In addition, casesofinsulin-dependentdiabetes). Inaddition, 9 -KO pigs controls using andcorresponding ), the ), the Ghr -KO mice( Ghr -KO mouse( Ghr ± 7 -KO mouse and the 16 ) andwere clearly below thus the 0.20 and0.70 0.20 Downloaded fromBioscientifica.com at10/01/202108:54:59PM 54 GHR ). ) and -KO pigs, HOMA-IR scores 54 GHR ), and the ), andthe Ghr 185 9 -KO pigs ( ). Enhancedinsulin 8 ± :2 -KO mouse ( , 0.20 in3-and 0.20 10 71 GHR , GHR 70 ). 19 9 ), similar 7 ). While ). While -KO pig ) which -KO pig R40 69 36 1 via freeaccess ), ). ), European Journal of Endocrinology 2-month-old 2-month-old islets was found 28%and68%reduced in10-day-old and Ghr islets ofLangerhans have beenextensively studied inthe consequences ofGHRDfor sizeandcomposition ofthe the the are lacking, pancreas inLSpatients endocrine of the mass.beta-cell ( score was described (HOMA-assessment modelfor function beta-cell reduced homeostasis asignificantly LS patients, insulin resistance ( was exhaustion discussedasasignofbeta-cell dueto ofhyperinsulinemiainsulinopenia seenafter aperiod mass maythe relative beaffected. InIsraeli LSpatients, isonly beta-cell indirectevidence LSthere that with ( and insulinsecretion transcription proliferation,GH stimulates beta-cell insulingene Changes inbeta-cellmassandsecretorycapacity andinanimalmodelsfor LS. LScohort Ecuadorian the casein isnotthe whileglucose inIsraeli this LSpatients, ofblood normalization toage the canindeed contribute respective controls. recovery ofglucoselevels in amoreobserved pronounced decrease andadelayed ( months (discussed below). of GHRD-associated transient juvenile hypoglycemia are ofspecialinterest contextnorepinephrine inthe and epinephrine ofglucocorticoids, patterns secretion (ACTH) are secreted inresponse to hypoglycemia, the ( to function assesspituitary–adrenal in endocrinology hypoglycemia test tool isfrequently usedasadiagnostic to hypoglycemia.mechanisms The insulin-induced suggest age-dependent differences incounter-regulatory normoglycemia was completely restored. These outcomes recovery ofglucoselevels, atearly andinchildren puberty, hypoglycemia, (6–8years) olderchildren showed aslight even when for corrected bodyweight ( mice was markedly reduced ( 10- to 11-month-old animals.The massof beta-cell analysisdetailed was in performed of islet cell populations Ki67 was in3-day-old observed of islet cellsstaining positively for proliferation marker the controls. Moreover, decreased proportion a significantly 72 Review , -KO mousemodel( While detailed morphological and functional analyses andfunctional While morphological detailed decreasing insulinsensitivity with In conclusion, In 73 ). As GH and the adrenocorticotropic hormone hormone adrenocorticotropic ). AsGHandthe Ghr 64 -KO mice,ITTs were atage performed 5.5 ), 7 months ( ), 7months Ghr -KO micecompared to age-matched 10 9 35 ). Ininsulin-sensitive Ecuadorian ), which may imply in areduction ). The average pancreatic sizeofthe 35 Ghr ), and1year ( − 80% compared to controls), -KO micecompared to the A Hinrichsandothers Ghr -KO mousepups.A 35 , − 75 50% compared 74 ). In patients ). Inpatients ). Allstudies Ghr -KO β )

need to be interpreted with caution, as the used mouse as the need to caution, be interpreted with in response to ahigh-fat diet. study The results from this proliferation and beta-cell stimulated insulin secretion for cellsisimportant GHRinbeta glucose- that concluded ofglucosehomeostasis ( deterioration andfurther glucose-stimulated insulinsecretion, inanoverallresulting reduced mass,blunted beta-cell GHR showed cells lacking beta reduced proliferation, was impaired ( glucose-stimulated insulinsecretion their nevertheless, reduced masswhen beta-cell onachow diet; maintained cellsdidnotshowthe beta GHRspecifically a in lacking Igf1 mice couldberescued by beta-cell-specific expression ofan for bodyweight.correction The reduced islet sizein (100%)significantly the increased different between to controls). The alpha-cellmasswas notsignificantly with the onset ofpuberty. the with Notably, show LSpatients Avitzur and Klinger ( hasalreadymetabolism been proposed by Laron, A linkbetween sexual development and glucose Metabolic changesduringpuberty ( receptorpolypeptide (GIPR)function impairedmodel with glucose-dependentinsulinotropic youngerthe age aspreviously group, inapig observed have more pronounced effects oncellproliferation in ( higher in11-week-old compared animals to 5-month-old proliferation rate the cellsinpigs ofbeta that ismarkedly representative samples ( sampling recovery to performed ensureis routinely the of old inpancreas samplescell populations from 3-to 6-month- sterological investigations endocrine cellsandother ofbeta specific beta-cell- the mousemodelwith was notaddressed inthe phenomenon oftransient juvenile hypoglycemia inGHRD ofislet cellsunderly composition andfunction the question whether abundance, age-related inthe changes massandinsulincontentbeta-cell ( islets and induces genepancreatic expression augmenting receptorLocally in prolactin expressed hGH signals via the (hGH)minigene. hormone also harbors ahumangrowth rat insulingene promoter ( line expressing control ofa Cre recombinase underthe deficiency Transient hypoglycemiainGHR 78 ). Thus, the lack of a growth stimulus isexpected stimulus to ofagrowth lack ). Thus, the transgene ( In contrast aglobal to micewith It will thus beinteresting to quantitative perform It willthus GHR Ghr -KO andcontrol pigs. Random systematic -KO ( 48 39 48 ). When challenged with ahigh-fat). When with challenged diet, ). ). Ghr 10 -KO andcontrol mice,andthus 77 Downloaded fromBioscientifica.com at10/01/202108:54:59PM ) as the hypoglycemia) asthe vanishes ). Ourprevious studies showed RIP- Cre https://eje.bioscientifica.com transgenic mouseline) 185 Ghr 78 76 48 :2 ). ). Moreover, the -KO after group ). The authors ). The authors Ghr -KO, mice Ghr R41 -KO via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com normalization of glucose levels and puberty in both LS ofglucoselevels inboth normalization andpuberty ( mice, even GHaction absenceoflipolytic inthe preference for fatoxidation was suggested inolder offattyacids forimport beta-oxidation ( palmitoyltransferase reduced mitochondrial 1A andthus suggestedto ofcarnitine free carnitine reduced activity Moreover, acylcarnitines of long-chain a decreased ratio and, asatendency, reduced free fattyacidlevels. glycerol reduced serum had significantly concentrations Normoglycemic disrupted. 6-month-old in effect (reviewed in aglucosesparing is decreased, resulting of fattyacidsandglucosefor substrates –glucoseoxidation competition fatty acidoxidation isreduced and–dueto the effectinsulin resistance. Thus, of insulin the to suppress to increase in GH/IGF1 contributes pubertal subjects, the human generation. In normal and energy respiration relative useoffattyacidsvs glucoseasfuelsfor cellular isthe ofglucoselevels puberty normalization during insulinsensitivity( hepatic protects females against insulinresistance andincreases insulin sensitivityandreduces bodyfatinmenandestrogen development ofinsulinresistance, as testosterone improves ( values while to insulinsensitivity returns prepubertal andremain higher inadulthood, puberty resistance during nor estradiol levels level are the associated with ofinsulin puberty, dramatically during changing testosterone neither Tanner the during ( stages ofpuberty andfall of insulinresistance andshow ofrise asimilarpattern GH/IGF1 axis.IGF1levels thelevel arerelated significantly to sensitivity are notmediated by butby sexual the ( atpuberty patients ( secretion increaseinsulin sensitivity and a compensatory in insulin ( age of6months sexual atthe maturity of glucose levels with normalization pigs occurred and the havedeficits in reproduction in beenobserved ( reported of malesandfemales andareduced litter sizewere asdelayed such and deficits in reproduction maturation at 38daysalready occurred (investigated in female mice) ( months ofglucoselevels atagenormalization was 11 reported ( but preserved fertility hypogenitalism, andadelay inpuberty 84 Review ). Furthermore, sexual hormones protect against sexual hormones the ). Furthermore, 80 Another potential factor contributing to the to the factor contributing potential Another isphysiologicallyPuberty adecrease associated in with In line with observations in LS patients, noobvious inLSpatients, observations In linewith Although there is a clear temporal isaclear between there association Although ). In GHRD this mechanism is at least partially isatleast partially mechanism ). InGHRDthis 37 79 15 ) while sexual maturity – although delayed) while sexual –although maturity – ). , 80 , 81 82 ), with clinical implications for diabetic implications for clinical diabetic ), with ). Interestingly, ininsulin changes the 1 ). In the ). In the 85 , 86 , 87 A Hinrichsandothers Ghr ). ). 83 -KO mouse model, ). Incontrast, while 7 ). 88 GHR ). However, a -KO pigs

54 GHR Ghr ). -KO -KO

levels dehydrogenase ofretinol 16 (RDH16) andretinoic induced diabetes ofyouth (MIDY) ( of liver samples from apig modelfor mutant AKT pathway (reviewed in gluconeogenesis andglycogenolysis PI3K/ the through uptake andglycogen while synthesis, basalinsulininhibits glycogenolysis (reviewed in rates ofgluconeogenesis the and modulating hormones isregulatedEndogenous by glucose production multiple Altered endogenousglucoseproduction homeostasis. energy complex betweenthe relationships GHRD, and puberty and age-matched controls may provide new insights into vs fattyacidoxidation in3-and6-month-old remain unclear.mechanisms Systematic studies ofglucose andinthe patients glucagon levels were lower incontrol mice( than ( in LSpatients causeforwas discussedasapotential juvenile hypoglycemia can alsostimulate glycogenolysis (reviewed in STAT5 the through gluconeogenesis, partly pathway, and glycolysis (reviewed in glycogenolysis andby decreasing glycogenesis and glucose output by increasing gluconeogenesis and stimulated gluconeogenesis ( linkbetweenacid asmechanistic insulindeficiencyand and serum samples derivedand serum from 6-month-old aged bloodglucose levelsgluconeogenesis cannormalize in ofsuggested counter-regulatory activation that from tissue (G6PC) wereglucose-6-phosphatase increased in liver as phosphoenolpyruvatesuch carboxykinase and (PCK1) mRNAand the levels for key enzymes of gluconeogenesis factor forkheadtranscription box protein O1(FOXO1) gluconeogenic abundance of the the In addition, were measured in21-month-old contrast, oreven normal elevated levels ofglucagon in reduced gluconeogenesis. resulting potentially In which catalyzes arate-limiting step ofglycolysis ( pyruvate kinase(PKLR,liver andred bloodcellisoform), in gluconeogenesis butadecreased abundance of pigs showed abundances ofenzymesinvolved normal deficiency Transient hypoglycemiainGHR Postprandial glucose promote hepatic insulinpeaks In 2-month-old hypoglycemicIn 2-month-old glucoseproduction/gluconeogenesis Reduced hepatic In contrast to insulin,glucagon promotes hepatic Proteomic investigations and metabolomic of liver Ghr -KO mice( Ghr 10 -KO vs control mice.These observations , 69 8 ). ). ). GHR Downloaded fromBioscientifica.com at10/01/202108:54:59PM -KO underlying pig model,the 93 89 ). Similarly, GHstimulates 92 90 ). ). ). A multi-omics analysis). Amulti-omics 91 185 Ghr ) revealed increased :2 -KO mice( Ghr GHR -KO mice, 89 INS ). GHR -KO pigs gene- R42 38 35 88 -KO via freeaccess ). ). ), ).

European Journal of Endocrinology to beconsidered. While differences in food consumption glucose levels normalizing factors therefore, need other models, insulinsensitivity ispreserved orincreased; animal aswell asinboth LScohort Ecuadorian In the lead to hyperglycemia ofpatients. Israeli cohort inthe ofglucoselevels normalization ormayexplains the even contextinsulinopenia inthe syndrome ofmetabolic animal models.Decreasing insulinsensitivityandrelative andinboth ofLSpatients cohorts deficiency inboth Juvenile hypoglycemia isamajor consequence ofGHR Conclusions andperspectives liver samples.profiling ofcorresponding andserum gluconeogenic enzymes andsubstrates by multi-omics the rate two ofgluconeogenesisthe ageusing inthe groups unique model for hypothesis by testing this quantifying butnormoglycemic providesmonths atage 6months, a The inthe bysupported observations levels by anage-related increase ingluconeogenesis are ofglucose normalization This conceptandthe LS patients. causeforassumed aspotential juvenile hypoglycemia in byproduction gluconeogenesis hasbeendiscussed( by low glucose levels ofhepatic promotion ofinsulin,the Ghr so far, elevated were levels in reported ofglucocorticoids levelsWhile epinephrine were notinvestigated inGHRD effect ofglucagon the ( andthereby intensifying tissues ofgluconeogenic substratesmobilization from peripheral a state ofhypoglycemia, gluconeogenesis by promoting the levels Epinephrine are known toglucocorticoids. increase in and (especially catecholamines epinephrine) include ofglucoselevels normalization inGHRDuponpuberty in vivo gluconeogenesis by canbedetermined the gluconeogenesis. Importantly, rate pig, of the inthe provide changes and metabolome hintsfor reduced 3-month-old need to similaranalyses perform ofliver from tissue providing substrates for gluconeogenesis. Future studies wereamino acidmetabolism found to beupregulated, enzymes involved multiple In addition, GH action. in ofglucoselevels absenceof normalization inthe to the of substrates for gluconeogenesis and therefore contribute inPKLRlevelsA reduction preservation canresult inthe Review -KO miceatanormoglycemic age ( Taken together, impaired gluconeogenesis hasbeen involved potentially hormones Additional inthe 2 GHR H ( 2 94 O-method and by quantifying the abundances of the and byO-method quantifying -KO pig model,which ishypoglycemic atage 3 , 95 ). GHR -KO pigs and controls to see if proteome A Hinrichsandothers Ghr -KO mousemodel. 8 ). Accompanied 2 H 2 O-method O-method 54 ). 96 ). glucagon andcatecholamines. likely andcanbemediated by several including hormones, –especially byproduction gluconeogenesis most –appears investigation.further Anincrease inendogenous glucose deserve changes andmetabolic mechanisms regulatory and in LSpatients ofglucoselevels normalization between andthe puberty temporalpig isaclear model.While there association nor in the LS patients mice but not in Ecuadorian insulin, which results inglucoseintolerance in can lead to capacity a decreased for secretory GH action absenceofproliferativeA reduced massinthe beta-cell animalmodels. andboth patients sensitivity inEcuadorian fat does not lead tosubcutaneous a decreasing insulin of GHRdeficiency, ofhealthy butapreferred accumulation ofbodyfatisacommonhallmarkincreased accumulation canbeconsidered asminor. normalization An on the expenditureand energy have influence beenassessed,their the humanbrain high requiresthe amounts particularly components (reviewed in( of neurotransmitters, neuromodulators, andstructural oxidativeproduction, stress management, and synthesis depends onglucoseasafuelforbrain critically ATP hypoglycemia inLaron syndrome. The mammalian consumption plays arole intransient juvenile puberty. associated changes metabolic with GH/IGF1 axis in the generally, roles ofsex steroids helpto the dissect andofthe and,more presence ofsexage hormones dependsonthe recovery if the of normoglycemia at pubertal can clarify of castrated inclusion the Furthermore, cells modulate glucoselevels inanage-dependent manner. capacity (c) whether ofbeta differencesthesecretory in age; glucose with and normalizing mechanism regulatory of gluconeogenesis as serves a counter-(b) if stimulation togluconeogenesis juvenile contributes hypoglycemia; (a)to which extent insufficient age canclarify groups a stereological examination massinboth ofbeta-cell by applying the The 6 months. normoglycemic with animalsagedof 3months atleast pigs needsto compare hypoglycemic age animalsatthe normoglycemia andpuberty. Therefore, astudy in of capacity forsecretory association insulinandthe the more than closely cohort Ecuadorian phenotype of the animal modelisrequired. The in differentgroups, age wherefore a study inasuitable deficiency Transient hypoglycemiainGHR Ghr By now, parameters no coherent study assessed these Another interesting question isifbrain glucoseAnother -KO mouseregarding glucosetolerance, potentially in vivo GHR 2 H 2 quantification ofgluconeogenesis quantification O-method in combination with with in combination O-method -KO underlying pigs, the counter- Downloaded fromBioscientifica.com at10/01/202108:54:59PM 97 GHR )). Dueto its large size, https://eje.bioscientifica.com -KO pig resembles the 185 :2 GHR -KO pigs GHR GHR Ghr R43 -KO -KO - KO KO via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com 2206/2-1 toAHandTRR127EW) andtheDZD(toEW). (HI Forschungsgemeinschaft Deutsche the by supported was study This Funding be could that interest of conflict perceived asprejudicingtheimpartialityofresearchreported. no is there that declare authors The Declaration ofinterest in different ( age cohorts requires systematic studies ofbrain glucoseconsumption are relatedbrain to in LS patients juvenile hypoglycemia the changes of and structural iffunctional clarification andCA1 hippocampus regions of the ( gyrus cingulate regions and showed trends toward larger dentate hadlarger areas inseveral surface LS patients and frontal and porcine models ( increased relative the brainwith weight of rodent ( a protective effect delaying cognitive aging( proper glucosesupply, and enhancedcognitive function ensuring LScohort, increased insulinsensitivity inthis GHR andhippocampalparietal, regions compared their with task-related andgreater performance infrontal, activation revealing cohort, Ecuadorian enhancedcognitive the latter study investigated young from adultLSpatients unrelated factors to GHRD(discussedin other effects ofspecific and below-average intelligence ( brain ofparenchymal appearance degrees loss to varying mixed intelligence results from normal ( Studies ofintelligence GHRDrevealed inhumanswith hypoglycemia brain couldaffect development. normal hypoglycemia Conversely, inLSpatients. juvenile young to transient couldcontribute juvenile children ( childhood peakglucoseuptake during is just 50%ofthe brain daily glucoseuseofthe Inadulthumans,the growth. weight expenditure reducing gain, energy onsomatic thus age ofslowest the with closely uptake corresponds body adolescence. Interestingly, peakinbrain glucose the and inlate childhood pruning activity-dependent development ofneuronal processes andsynapses before high costs energetic the extensive associated with ishighest)body ratio butaround age 5years, reflecting brain (when to the glucose consumption notatbirth Thisand MRIdata. study revealed peakofbrain the usingpositron emissiontomography(PET)adulthood to humanbrain from birth glucose consumption ofthe of glucose.Kuzawa andcolleagues( 98 Review ). Thus, the increased brain). Thus, glucoseconsumption in the -intact relatives-intact ( GHR 7 ) of GHRD, young adult Ecuadorian mutations, genetic background, or background, genetic mutations, 101 98 ). This was explained by the ). ). A Hinrichsandothers 100 ), probably dueto 98 ) calculated the ) calculated the 99 ) and normal ) andnormal 101 4 101 ). Inline ). Final ). The 102 ) References manuscript andrevisedthedraft. A H wrote the original manuscript, S R, M B, J J K and E W commented on the Author contributionstatement

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