Copyright© AE&M all rights reserved. 82 byanITT.be measured levelscan to ,GHandcortisol responses subjects(4).Ashormonal GH, andACTHinnormal , of ,epinephrine, norepinephrine, administration, lowbloodglucose triggersthesecretion 20to60minutesafterinsulin levels. Approximately administration leadingtoadeclineinbloodglucose byintravenousinsulin in 1960(3),isperformed of theHPA axis(1,2).TheITT, whichwasdeveloped usedprimarilytoassessthefunctionalintegrity test are (ACTH)stimulationtest,andmetyrapone hormone T INTRODUCTION DOI: 10.20945/2359-3997000000200 Accepted onJuly/3/2019 Received onJan/24/2019 [email protected] Kayseri, Turkey, 38039 Department ofEndocrinology, Erciyes University MedicalSchool, Yasin Simsek Correspondence to: Kayseri, TurkeyEndocrinology, School, Departmentof 1 original article original Erciyes Medical University stimulation test (GST), adrenocorticotropic stimulation test(GST),adrenocorticotropic he insulintolerancetest(ITT),glucagon Is biochemical hypoglycemia tolerancetest;hypoglycemia;;dynamictest Keywords effective asbiochemically confirmed hypoglycemia duringanITT. were found. were comparedintermsofpeakcortisol andGHresponses,nostatisticallysignificantdifferences group thaninthenonhypoglycemic group(19.3 and52.0mg/dL,respectively). When thetwogroups were foundtobesimilar. The meanbloodglucoselevelwas significantlylowerinthe hypoglycemic responses. mg/dL or>40duringanITT, andthegroupswerecomparedintermsoftheirGHcortisol hypoglycemic andnonhypoglycemic groupsaccordingtowhethertheirplasmaglucoselevel≤40 obtained after clearsymptoms ofclinicalhypoglycemia developed. The patientswereenrolledinthe wereincludedinthestudy.patients withpituitarydisorders Samples forbloodglucose levels were hypoglycemia during an ITT were compared. this study, theGHandcortisol responsesofpatientswhoachieved andfailedtoachieve biochemical at abloodglucoselevel≤40mg/dLtoeffectively andcorrectly assesstheHPA andGH-IGF-1 axes.In pituitary-adrenal (HPA) axis. The goalofthetestistoachieve clinicalandbiochemical hypoglycemia growth factor(IGF-1)the integrityofgrowthhormone(GH)–insulin-like axisandthehypothalamic- Objective: ABSTRACT https://orcid.org/0000-0002-2861-4683 Fahrettin Kelestemur https://orcid.org/0000-0003-2024-7433 Kursad Unluhizarci https://orcid.org/0000-0001-8277-6774 Fatih Tanriverdi https://orcid.org/0000-0003-2519-5978 Halit Diri https://orcid.org/0000-0003-3241-2352 Zuleyha Karaca https://orcid.org/0000-0003-1654-6422 Yasin Simsek insulin tolerance test? an during necessary 1 Results: The insulin tolerance test (ITT) has been accepted as the gold standard test for assessing The insulintolerancetest(ITT)hasbeenacceptedasthegoldstandardforassessing Conclusion: 1 1 1 The mean age, body mass index and waist circumference of the two patient groups 1 1 The datapresentedsuggestthat clinically symptomatichypoglycemia isas contraindicated in elderly patients and in patients with contraindicated in elderly patients and in patients with andthe testis isrequired, by experiencedmedicalstaff close medicalsupervision therefore, sideeffects; from deficiencies (3,8-10). testfordiagnosingGHandcortisol the goldstandard healthy subjects(8).Currently, theITTisconsidered toanITTin response 15 and23µg/dLforanormal have beensuggestedforITTs, andtheyrangebetween (5-7). Various levels valuesforthepeakcortisol cut-off withapeakGHexceeding5µg/L shown torespond 3 µg/LonanITT, whilehealthysubjectshavebeen response lessthan in adultsisdefinedasapeakGH An ITT is unpleasant for patients and is not free An ITTisunpleasantforpatients andisnotfree GHdeficiency guidelines,severe to recent According Subjects and methods: Arch EndocrinolMetab. 2020;64(1):82-8 Arch Metab. Endocrinol 2020;64/1 One hundred thirty-five

Arch Metab. Endocrinol 2020;64/1 and after30, 60, 90and120minutes.An additional after symptomatic hypoglycemia began(minut insulin (minute-15),aswellimmediately regular of 0.1U/kg(0.2if BMI >30kg/m obtainedpriortotheintravenous administration were andGH measurements cortisol blood samples for serum questionable. responses inhormone of thedifference A, makingthecalculationofstatisticalsignificance to 118 in group consisted of only 17 patients, compared 2(BG>40mg/dL) > 40mg/dL(n:17).Group had than 40mg/dL(n:118),andthesecondgroup had glucoselevelslower the first group created: were achievedduringthetest,twogroups 40 mg/dLwere whether plasmaglucoselevelslowerorhigherthan analyzedduringthesesymptoms. According levels were speech andvisionduringtheITT, andbloodglucose hunger, confusion,headache,andimpaired drowsiness, anxiety, sweating,faintness,weakness,dizziness,nausea, symptoms ofhypoglycemia,includingtachycardia, conducting thestudy. Allpatientsdevelopedclear thelocalEthicsCommitteewasobtained before from included in the study.hypopituitarism were Approval forsuspected male) inwhomanITTwasperformed analysesof135patients (83 female,52 Retrospective SUBJECTS ANDMETHODS duringanITT.responses and GH to achieve accurate peak cortisol is required suitableorbiochemical hypoglycemia manifestations are study, weaimedtoshowwhetherhypoglycemia-related complicated.Inthis more would makethetestresults ontheglucoselevel,it tohavenoeffect been reported infusion has finishing. Although dextrose the test, before during infusionmaybenecessary intravenous dextrose hypoglycemia,andan administration maycausesevere insulin give asecondinjectionofinsulin(15).Further to ≤ 2.2mmol/l)isnotachieved,itwouldbenecessary adequate biochemicalhypoglycemia(plasmaglucose, level forthebiochemicalcriterionworldwide(1,14).If a 2.2mmol/llevelhasbeenwidelyusedasthethreshold hypoglycemiaduringanITT, suggestedforeffective were mmol/l (45 mg/dL), and 2.8 mmol/l (50.4 mg/dL) Although glucoselevelsof2.2mmol/l(40mg/dL),2.5 assessment oftheHPA andGH-IGF-1axes(12,13). ≤ 2.2mmol/l(40mg/dL)duringanITTforeffective (11). disease disease,epilepsyorischemicheart cerebrovascular The ITT was performed after an overnight fast,and afteranovernight The ITTwasperformed

In general, the goal is to achieve a blood glucose level In general,thegoalistoachieveabloodglucoselevel 2 ) soluble e 0),

respectively. level,theassaymethod, cortisol Fortheserum Immunotech SAS(Marseille,France),and6.3%6.8%, asfollows:IRMA, ofvariationsfor IGF-1were coefficients of assay, kit,andintraassayinterassay commercial 1.5%and14%,respectively.of variationswere Themethod and the values of the intra-assay and interassay coefficients and Immunotech SAS (Marseille,France),respectively, theimmunoradiometricassay(IRMA) GHwere serum responses totheITT(1,13). acceptedassufficient were GHlevel≥3.0µg/L level ≥18.0µg/dLandaserum cortisol Aserum by theplasmaglucosemeasurement. biochemical hypoglycemiawasdetermined whereas anxiety), (especially palpitation,sweating,tachycardia, by clinicalfindings hypoglycemia wasdetermined developed hypoglycemiasymptoms.Symptomatic nor hypoglycemiasymptomsbutnottopatientswho biochemicalhypoglycemia(≤40mg/dL) sufficient dose ofinsulinwasgiventopatientswhohadneither hypogonadotropic hypogonadism and 3 lymphocytic hypogonadism and3lymphocytic hypogonadotropic 2 traumaticbraininjury,syndrome, 3idiopathic 6Sheehan’s failure, sella, 9congenitalpituitary of thepatientshadnontumoral causes( and5 Rathke’s cleft cyst), and33 16 acromegaly causes (27 nonfunctioningadenoma, 37 prolactinoma, 1,85ofthepatientshadtumoral status. Ingroup including tumoralornontumoral,andoperational disorders, of pituitary also had similar ratios in terms (Table compared were the 2groups 1).Bothgroups similarwhen The demographicsofthepatientswere RESULTS statisticallysignificant. considered Apvalueof<0.05was a 95%confidenceinterval. within performed (Chicago, USA). All analyses were withSPSS20.0software performed analyses were Allstatistical tothetrapezoidformula. according (AUC)wascalculated underthecurve The area usedfortheanalysis ofratios.and Fisher’stestwere forquantitativevariables. Chi-squared the groups usedforcomparisons betweenWhitney Utestswere deviation orerror, frequency, Mann– andpercentage. Descriptive statisticsincludedthemean,standard Statistical analysis (Czech Republic),and5.8%9.2%,respectively. radioimmunoassay,of variationswere Immunotechsro kit, and intraassay and interassay coefficients commercial The

assay method and commercial kit used for the kitusedforthe assay methodandcommercial Deep hypoglycemia for aninsulintolerance test? 10 empty 10 empty 83

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 84 Data wereexpressedas themean±SEM;F: cortisol; AUC: areaunder thecurve. Table 5. Data wereexpressedasthemean±SEM; AUC: areaunderthecurve. Table 4. Data wereexpressedasthemean±SEM; AUC: areaunderthecurve. Table 3. TSH: thyroid-stimulatinghormone;ft4: freethyroxine;IGF-1: insulin-likegrowthfactor-1. Table 2. BMI: bodymassindex. Table 1. ofhypopituitarism.Themean ofthefrequencies terms similarin were The twogroups surgical treatment. duetomedicalor inremission tumorswere pituitary hypogonadism).Allpatientswith hypogonadotropic and1idiopathic 1traumaticbraininjury syndrome, had nontumoralcauses(1emptysella,2Sheehan’s and1Rathke’scleftcyst),5patients acromegaly 1 causes (8nonfunctioningadenoma,2prolactinoma, 2,12patientshadtumoral hypophysitis). Ingroup Deep hypoglycemia for aninsulintolerance test? P value Group 2n: 17 Group 1n: 118 Minutes P value Group 2n: 17 Group 1n: 118 Minutes P value Group 2n: 16 Group 1n: 102 Minutes Blood glucose(mg/dL) Cortisol (5–25µg/dL) IGF-I (64–336ng/mL) fT4 (0.88–1.72ng/dL) TSH (0.57–5.6lU/mL) Waist circumference(cm) BMI (m Weight (kg) Height (cm) Age (years) Female Male 2 /kg) Demographic dataofthegroups Cortisol responses(µg/dL)ofthepatientsduringanITT GH responses(µg/L)ofallpatients(withorwithoutacromegaly) GH responses(µg/L)forthepatientswithoutacromegalyonly Mean serumglucose(athypoglycemia)andbasalhormonelevelsofthe patients 10.0 ±1.5 10.1 ±0.5 0.97 -15 0.9 ±0.5 0.3 ±0.0 0.9 ±0.5 0.2 ±0.9 0.14 0.12 -15 -15 11.6 ±2.0 10.1 ±0.6 0.40 1.6 ±1.0 0.6 ±0.3 1.7 ±0.1 0.6 ±0.3 0 Group 1n:118 Group 1n:118 151.7 ±105.3 0.50 0.49 95.7 ±12.7 79.5 ±15.6 162.6 ±8.8 42.6 ±10.8 19.3 ±0.9 10.0 ±6.1 73 (61.9%) 45 (38.1%) 30.0 ±6.1 0 1.1 ±0.2 1.5 ±1.1 0 14.7 ±2.0 10.7 ±0.6 0.46 1.3 ±0.4 0.9 ±0.2 1.4 ±0.5 0.9 ±0.2 30 0.11 0.09 30 30 14.0 ±2.0 8.8 ±0.6 0.02 0.5 ±0.2 0.7 ±0.2 0.5 ±0.2 0.7 ±0.2 60 0.33 0.33 60 60 significant differences were found(Table were 5). significant differences no statistically of peak cortisol, in terms compared were (Tables 3and4).Inaddition,whenthetwogroups even considering acromegaly between the 2 groups, ofpeakGHlevelsduringtheITT interms difference (Tablegroups wasnostatistically significant 2).There similarinboth levelsofthepatientswere basal hormone (52.0±2.3mg/dL).The nonhypoglycemic group ± 0.9mg/dl)wassignificantlylowerthanthatofthe (19.3 blood glucoselevelofthehypoglycemicgroup 133.3 ±100.2 Group 2n:17 Group 2n:17 97.8 ±13.9 78.6 ±18.9 164.9 ±9.8 43.5 ±12.4 52.0 ±2.3 10 (58.8%) 28.7 ±6.6 9.8 ±5.6 1.1 ±0.1 1.1 ±1.2 7 (41.2%) 12.0 ±1.9 7.8 ±0.4 0.04 0.4 ±0.1 0.5 ±0.1 0.4 ±0.2 0.4 ±0.2 90 0.43 0.31 90 90 10.1 ±1.4 7.0 ±0.4 0.04 120 0.1 ±0.0 0.3 ±0.0 0.1 ±0.0 0.2 ±0.0 0.88 0.97 120 120 Arch Metab. Endocrinol 2020;64/1 16.4 ±2.2 12.1 ±0.7 Peak F 0.05 1.5 ±0.5 1.3 ±0.2 1.6 ±0.5 1.3 ±0.2 Peak GH Peak GH 0.62 0.56 < 0.001 p value p value 0.59 0.33 0.96 0.22 0.55 0.47 0.84 0.36 0.73 0.81 0.81 1897.1 ±266.8 1394.4 ±78.5 137.1 ±56.3 142.8 ±60.5 98.3 ±23.0 96.4 ±26.0 0.03 AUC 0.32 0.26 AUC AUC Arch Metab. Endocrinol 2020;64/1 BG: blood glucose; GH: growthhormone. Figure 2. BG: bloodglucose;GH: growthhormone. Figure 1. was 120th minute5.8%ofthepatients.Nocorrelation minute 41.1%,atthe60thand achievedatthe0thminutein11.7%,30th were levels 2,peakcortisol 7.8% ofthepatients,andingroup the 90thminutein7.8%,andat120th 30th minutein35.9%,atthe60th6.1%, 1atthe0thminutein42.4%, achieved ingroup levelswere minute in5.9%ofthepatients.Peakcortisol 41.1%, atthe60thminuteinand120th 0th (basal)minutein11.8%,atthe30th achievedatthe 2,peakGHlevelswere and ingroup 9.5%, andatthe120thminutein14.7%ofpatients, at the60thminutein15.6%,90th (basal) minutein14.7%,atthe30th45.5%, GH (μg/L) In group 1, peak GH levels were achievedatthe0th 1,peakGHlevelswere In group GH (μg/L) -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 GH responsesinpatientswithacromegaly. GH responsesinpatientswithoutacromegaly. 0.2 0.9 ITT-15GH ITT-15GH 0.9 0.3 1.7 0.6 ITT-OGH ITT-OGH 0.6 1.6 ITT-3OGH ITT-3OGH 0.9 1.3 0.9 1.4 ITT-6OGH ITT-6OGH 0.5 0.7 0.7 0.5 group 1(p<0.05)(Tablesgroup 1to3). 3and4)(Figures however, 2hadhigherAUClevelsofGHthan group ofacromegaly; regardless similarinbothgroups were 3). Peak GH responses 1 (Figure 2 than in group group significantlyhigherin levelsandAUCvalueswere cortisol 2. levelsearlierthangroup GH andcortisol ITT. 1achievedpeak group totheseresults, According atthe30th-60thminuteof measured levels were atthe30th-60thminute,andcortisol measured were 2,peakGHlevels at the0thminute;ingroup measured levels were at the 30th minute, and peak cortisol andGHlevels(p>0.05). at peakcortisol detected amongbloodglucoselevelsafterinsulinand The mean cortisol responses of every test minute, peak testminute,peak ofevery responses The meancortisol mostly measured 1, peak GH levels were In group ITT-9OGH ITT-9OGH 0.4 0.5 0.4 0.4 Deep hypoglycemia for aninsulintolerance test? ITT-12OGH ITT-12OGH 0.1 0.3 0.2 0.1 BG >40mg/dL BG <40mg/dL BG >40mg/dL BG <40mg/dL 85

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 86 BG: blood glucose; F: cortisol. Figure 3. theactivation (18). Asbloodglucoselevelsdecrease, plasma glucoselevel<70mg/dL(3.9mmol/L) symptoms. Hypoglycemiaisusuallydescribedasa between blood glucose levels and hypoglycemia mmol/L duringtheITT. study (84.6%)developedbloodglucoselevels<2.2 value forITTs, andmostofthepatientsinpresent we also use this cut-off our department, be essentialatthebeginningofanITT(3,7,12,13).In whichmight response, (40 mg/dL)toactivateastress to2.2mmol/L that bloodglucoseshoulddecrease studies reported system (17). Most previous nervous andGHlevels,activationofthesympathetic cortisol ofthebody, response stress in ACTH, withincreases induce excessivehypoglycemia,whichleadstoamajor intendedto organ axis(16).Insulininjectionsare It canevaluatethewholehypothalamus-pituitary-end thegoldstandard. theITTisconsidered secretions, testsofGHandcortisol Among variousprovocative DISCUSSION levels(p:0.56,p:0.84,respectively). and cortisol ofGH interms betweengroups significant difference wasnostatistically inthetests,there adequate responses patients with less than 18.0 µg/dL), after removing levels less than 3 µg/L and peak cortisol response levels (i.e., peak GH to GH and cortisol responses Deep hypoglycemia for aninsulintolerance test?

Cortisol (µg/dL) maybediscordance conditions,there Under certain When comparingthepatientswithinadequate 12.0 14.0 16.0 18.0 10.0 0.0 2.0 4.0 6.0 8.0 Mean cortisolresponsesinITT. ITT-15F 10.0 10.1 ITT-OF 11.6 10.1 ITT-3OF Minutes oftheITT 14.7 10.7

ITT-6OF Additionally, in theydemonstratedthatdifferences concentrations. plasmaACTHandcortisol increases ofeuglycemia, to healthypersons,eveninthepresence showed thatintravenousinfusionofhighdosesinsulin functions(23,24).Schultesandcols. on pituitary subsequent episodesofhypoglycemia(21,22). euglycemiaduring torestore necessary response thecounterregulatory glucose levelthatprecipitates the hypoglycemiahasbeenshowntoreduce recurrent blood glucose(20).Inpatientswithdiabetesmellitus, in symptomswithasignificantdecrease warning the appearance of autonomic before neuroglycopenia isdescribedastheonsetof hypoglycemia unawareness (19). Ontheotherhand, blood glucoseleveltonormal ofthe ofthesymptomsafterrestoration and thereversal anxiety, ofhypoglycemia whichallows theperception symptoms suchaspalpitations,sweating,hunger, and system leads to neurogenic of the autonomic nervous effect of insulin on HPA secretory activity, ofinsulinonHPAeffect secretory preventing stimulatory Another studydemonstratedtheprolonged (26). to moderate hypoglycemic stress response the HPAsuggested thatinsulinalsoincreases secretory activity (25). An experimental study on HPA secretory ofinsulin effect themoderatestimulatory have covered ofhypoglycemiamight effect stimulatory The strong (25). influenceontheadrenals toadirect be related may release in ACTHlevels;insulin-inducedcortisol insulin infusioncouldnotbeexplainedbydifferences levelsbetweenthehighandlowdosesof cortisol 8.8 14 Several studies revealed that insulin has direct effects effects that insulin has direct Several studiesrevealed ITT-9OF 7.8 12 ITT-12OF 10.1 7 Arch Metab. Endocrinol 2020;64/1 BG >40mg/dL BG <40mg/dL Arch Metab. Endocrinol 2020;64/1 inpatients administration maynotberecommended ≤ 40mg/dLduringanITT. insulin further Therefore, glycemiclevels in placeofbiochemically confirmed clinically symptomatic hypoglycemia may be used involved (35). subjects, andnopatientswithhypopituitarismwere however,an ITT; theirstudyincludedonly16healthy during and GH responses did not change peak cortisol thatthelowdoseinfusionofglucose and cols.reported (2).Borm was muchlowerthanthetarget required found thatthehypoglycemiaachievedduringanITT Ajalaandcols.also both thepatientsandmedicalstaff. anditisanunpleasanttestfor is potentiallydangerous, hypoglycemia, which inevitably leadstouncontrolled glucose <2.2mmol/l)duringanITT(34).The to achieve adequate biochemical hypoglycemia (blood ofthedose ofinsulinrequired determinant important cols., fastingbloodglucosewasfoundtobethemost on thedepthofhypoglycemia.InastudybyLeeand systemtohypoglycemiawasnotdependent regulatory study, of thecounter themagnitude of the response to this According levels than the other groups. cortisol patients hadlowerpeakandAUCvaluesforGH study, 1 despitehavinglowerglucoselevels,thegroup inglucoselevels (33).Inthis on theextentofdrop andGHwasnotdependent ofcortisol that theresponse achieved (32,33).However, Amielandcols.revealed depends on thedepthofhypoglycemia this response delayed(30,32).The magnitudeof hypoglycemia are during hormone andgrowth ofcortisol the effects of glucagonandcatecholaminesonglucoseregulation, (31).Despitetherapideffects catecholamines increase and glucose levelcontinuestofall,glucagonisreleased, insulin levels. When the glucose levelsisdecreasing response tofallingblood givenstepbystep.Thefirst are tohypoglycemia responses (3.5 mmol/l).Hormonal glucoselevelfallsbelow63mg/dL whentheserum starts glands. the adrenal of insulinon effect in the brainanddirect receptors inthedistributionofinsulin to individualdifferences glucose levelsmaybe related at different responses (30).Eventually,directly thecauseofsimilarcortisol functions pituitary insulin seems to affect Therefore, (28,29). hippocampus, hypothalamus,andpituitary foundinthe brain barrier, were anditsreceptors theblood- (27).Insulincrosses failure regulatory the developmentofhypoglycemia-associatedcounter In conclusion, the present datasuggestthat In conclusion,thepresent tohypoglycemia response The counterregulatory

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