European Journal of Endocrinology 10.1530/EJE-16-1062 The diagnosisofhypoglycemiarequiresfulfillment of lowering agentssuchassulfonylureasorinsulin( usually occursinthesettingoftreatmentglucose- In contrast,hypoglycemiaisrelativelyuncommonand Symptoms ofhypoglycemiaarecommonandnon-specific. Introduction management ofhypoglycemiainthesesituations. illness andfactitioushypoglycemia.We provideanoverviewofthe pathogenesis and includemedications,non-isletcelltumors,hormonaldeficiencies,critical to insulinomabutassociatedwithhighlevelsofinsulinantibodiesandplasmainsulin.Otherimportantcauses of pancreatogenous hypoglycemiasyndrome.Autoimmunesyndromeisclinicallyandbiochemically similar of endogenoushyperinsulinemichypoglycemiaincludeinsulinoma,post-bariatricandnoninsulinoma performed. Likewise,ifsymptomsoccurafteramealthenmixedstudymaybethetestofchoice.Thecauses under whichsymptomsoccur. Incaseswheresymptomsoccurinthepostabsorptivestate,a72-hfastshouldbe of spontaneousoccurrencesymptoms.Ifthisisnotpossiblethenonewouldwanttocreatethecircumstances on anevaluationforhypoglycemia.Whenpossible,ofhypoglycemiashouldbecarriedoutatthetime such itisimportanttoconfirmhypoglycemiabyestablishingthepresenceofWhipple’s triadbeforeembarking -lowering agentssuchassulfonylureasorinsulin.Thesymptomsofhypoglycemiaarenon-specificand as mechanisms, hypoglycemiaisuncommonandusuallyoccursinthesettingoftreatmentdiabetesusing glucose concentrations.Whenthesemechanismsfailoraredefective,hypoglycemiaensues.Duetorobust Glucose isthemainsubstrateutilizedbybrainandassuchmultipleregulatorymechanismsexisttomaintain Abstract Division ofEndocrinology, ,MetabolismandNutrition,MayoClinic,Rochester, Minnesota,USA Nana Esi Kittah hypoglycemia Pathogenesis andmanagementof M DOI: 10.1530/EJE-16-1062 www.eje-www.eje-online.org disorders suchasinsulinomaand hypoglycemiapost-Roux-en-YGastricBypass. affecting beta-cellfunction.His clinicalinterestsincludethediagnosisandmanagement of hypoglycemic understanding theroleofcommongeneticvariationsin pathogenesisofprediabetesandotherfactors Endocrinology & . He directs a program funded by the National Institutes of Health aimed at Clinic Rochester, USA since June 2001. Currently, Dr Vella as the research serves chair for the Division of Dr AdrianVella Invited Author’s profile Review ANAGEMENT OFENDOCRINEDISEASE online.org

and isaProfessorofMedicineintheMayoClinicCollege andhasbeenatMayo Adrian Vella © 2017EuropeanSociety ofEndocrinology © 2017EuropeanSociety ofEndocrinology N EKittahandAVella Printed inGreatBritain 1 , 2 ). Only afterWhipple’s triadisfulfilledshouldworkupfor symptoms or signs when hypoglycemia is corrected. at thetimeofsuspectedhypoglycemia;resolution of with hypoglycemia;alowplasmaglucoseconcentration Whipple’s triad( of hypoglycemia Pathogenesis andmanagement Published byBioscientifica Ltd. 3 , 4 ): symptoms,signsorbothconsistent Downloaded fromBioscientifica.com at09/26/202106:38:39AM (2017) Endocrinology European Journal of [email protected] Email to AVella should beaddressed Correspondence 177 177 : 1 177 :1 , R37–R47

R37 –R47 via freeaccess European Journal of Endocrinology defective, hypoglycemiaensues. responses ( be significantcontributorstothecounter-regulatory however, in acute hypoglycemia, they do not appear to mechanisms; areimportantcounter-regulatory In casesofprotractedhypoglycemia,cortisolandgrowth below thephysiologicrange(68 epinephrine increasewhenglucoseconcentrationfalls becomes significant( the responseisinadequatedoesroleofepinephrine presence ofglucagon.Onlywhenglucagonisdeficientor hypoglycemia, butdoesnotappeartobeessentialinthe Epinephrine is also an important factor in preventing inadequate, hypoglycemia persists without improvement. glucagon secretion ( mechanism topreventhypoglycemiaistheincreasein ( (4.5 mmol/L) 81 mg/dL occur ataplasmaglucoseconcentrationofapproximately decline ( the pancreaticBcellsasplasmaglucoseconcentrations hypoglycemia isthecessationofinsulinsecretionfrom cognitive impairmentoccurs( glycemic thresholdsthatarehigherthanthoseatwhich shown thattheactivationofthesemechanismsoccurat that canbeutilizedforcerebralmetabolism.Ithasbeen processes suchaslipolysisthatgeneratealternativefuels maintain glucoseconcentrationsoralternativelyfacilitate fuel utilizedbythebrainandassuchmultiplemechanisms processes generatingenergyforhomeostasis.Itisthemain Glucose isanimportantsubstrateforthemetabolic hypoglycemia Mechanisms ofdefenseagainst of thecommoncauseshypoglycemia( ofthepathogenesisandmanagement provide anoverview hypoglycemia beinitiated.Thisreviewisintendedto www.eje-online.org Non-islet celltumors Organ failure-liver, kidney deficiencies autoimmunehypoglycemia syndrome Non- pancreatogenous hypoglycemiasyndrome Prescribing error/dispensingerror Post bariatrichypoglycemia Insulinoma Factitious hypoglycemia Outpatient setting Table 1 Review Causes ofhypoglycemia. 7 , 7 8 ). Whentheabovemechanismsfailorare ). Decreasedinsulinsecretionappearsto 7 ). When glucagon production is 7 ). Thelevelsofglucagonand 9 ). Thenextmostimportant 5 , 6 mg/dL (3.8 ). Thefirstdefenseagainst N EKittahandAVella Table 1 mmol/L)) ( ). Causes ofhypoglycemia 9 ). Non-islet celltumors Hormone deficiencies Organ failure-, kidney Critical illness/sepsis Prescribing/dispensing error Drug-induced hypoglycemia Inpatient setting concentrations lessthan55 of both( symptoms, postprandialsymptomsoracombination patients withinsulinomamayhavepostabsorptive important indeterminingetiology( ( and measuredinareliablelaboratory Whipple’s triadbemeasuredfromavenousblooddraw glucose concentrationsusedtoestablishanddocument hypoglycemia iscorrected.Itimportantthatplasma hypoglycemia; resolutionofsymptomsorsignswhen low plasmaglucose concentration at the timeofsuspected symptoms, signsorbothconsistentwithhypoglycemia;a symptoms ishighlysuggestiveofhypoglycemia. occur ininstanceswhenhypoglycemiaisprotracted( consciousness and coma.Braindeath has beenknownto lightheadedness, , lethargy, seizure, loss of changes, visual changes, , dysarthria, / Neuroglycopenic symptomsincludeweakness,behavioral that includesweating,warmth,nauseaandhunger( tachycardia, , tremors;andcholinergicsymptoms into: adrenergicsymptomsthatincludepalpitations, or less ( concentrations ofapproximately50 neuroglycopenic symptomsoccuratplasmaglucose of approximately60 symptoms occuratplasmaglucoseconcentrations autonomic andneuroglycopenic( The symptomsofhypoglycemiacanbedividedinto Diagnosis ofhypoglycemia hypoglycemia ( expensive testinginpatientswhodonothavetrueclinical embarking onanevaluationtopreventunwarrantedand by establishing the presence of Whipple’s triad before specific. Assuchitisimportanttoconfirmhypoglycemia However, one must notethatthese symptoms arenon- of hypoglycemia Pathogenesis andmanagement The relationshipofhypoglycemiatomealsisnot The presence of autonomic as well as neuroglycopenic 5 ). Autonomic symptoms can further be divided 14 ). Patientswithspontaneousplasmaglucose 12 ). Whipple’s triad( Downloaded fromBioscientifica.com at09/26/202106:38:39AM mg/dL (3.3 mg/dL (3 10 mg/dL (2.8 177 13 mmol/L) whereas 12 , 4 ). Thisisbecause :1 , 11 ). 3 ). Autonomic ) consistsof: mmol/L) on mmol/L) R38 9 10 ). via freeaccess ). European Journal of Endocrinology glycogenolysis with preservation ofhepaticglycogen glycogenolysis withpreservation because increasedinsulinconcentrations inhibithepatic glucose hypoglycemia duetoan insulinoma, anincreaseof 30 glucose concentrationsarethenmeasuredat10,20and and 1 and circulating oralhypoglycemicagentsaremeasured insulin, C-peptide, proinsulin, beta-hydroxybutyrate the fastisconcluded, plasma concentrations of glucose, glucose concentrationsasdescribedabove( symptoms orsignsofhypoglycemiadecreasedplasma (2.5 symptoms and plasma glucose concentration is 45 1–2 every (3.3 till thebloodglucoseconcentrationdropsto60 6 proinsulin, beta-hydroxybutyrateareobtainedevery while awake( and patientsareadvisedtocontinuetheirnormalactivity beverages ( the patientisallowedtohavenon-caloricandcaffeine-free prior meal and ingestion of calories ( inpatient facility. Theonsetofthefastissetatlast but needstobecompleted,whennecessary, inan 95% within48 hypoglycemic andsymptomaticin12 fastwillbecome 43% ofpatientsundergoingasupervised etiology ofhypoglycemia.Hirshberg symptoms andtoendeavordeterminethecause/ confirm hypoglycemiaasacauseofthepatient’s symptoms occur. would wanttorecreatethecircumstances underwhich ( fasting plasmaglucoseislessthan55 5.0 mL (0.2 plasma C-peptideconcentrationofatleast0.6 insulin concentrationofatleast3 for endogenoushyperinsulinemiaareaplasma and plasmaglucoseismeasured.Diagnosticvalues is reversedbygiving1 agents. Oncethesehavebeenobtained,hypoglycemia beta-hydroxybutyrate andcirculating oralhypoglycemic obtained forglucose,insulin,C-peptide,pro-insulin, spontaneous occurrence of symptoms ( of hypoglycemiashouldbecarriedoutatthetime venous bloodwarrantforfurtherworkup.Evaluation 12 Review min afterinjection.Incases ofhyperinsulinemic ). Ifspontaneoussymptomsdonotoccurthenone pmol/L, betahydroxybutyrate The fastcanbeinitiatedduringoutsideofficehours 72-h fast is to The main aim of the supervised mmol/L) orlessafter72 mmol/L) orlessatwhichpointtheyareobtained mg ofglucagonisgivenintravenously( nmol/L), proinsulin concentration of at least ≥ h. Thefastisconcluded once thepatienthas 25 16 mg/dL (1.4 ). Noncrucialmedicationsarediscontinued h and100%within72 16 ). Plasmaglucose,insulin,C-peptide, mg ofglucagonintravenously mmol/L) isexpected.This is h ifthepatienthashadno N EKittahandAVella < 2.7 µU/mL (18 16 h ( h, 67%within24 t al et mg/dL (3 mmol/L whenthe ). During the fast, 15 13 ). . showedthat ). Plasma is 16 16 ). Plasma mmol/L) pmol/L), ). Once mg/dL mg/dL ng/ h, h test ( 50 of healthypeoplecanhaveaplasmaglucoselessthan of hypoglycemia( an oralglucosetolerancetesthasnoroleintheevaluation 30 and then every insulin, C-peptide,proinsulinandareobtainedatbaseline is requiredwithnocaloriesinliquidform.Plasmaglucose, undergone aRoux-en-Ygastricbypass,standardizedmeal upper gastrointestinal anatomy, such as patients who have provokes theirsymptoms.Inpatientswhohavealtered overnight fast.Patientsaregivenamealsimilartowhat may bethetestofchoice.Thisisperformedafteran possible postprandial hypoglycemia, a mixed meal study suggests thatsymptomsoccuraftermeals,indicativeof stores. Oncethishasbeendone,thepatientisfed. hepaticglycogen and releaseofglucosefrompreserved stores. Administrationofglucagonwillcausemobilization arterial calciumstimulation ( sampling, selectiveangiographyandpancreatic with fine-needleaspiration,transhepaticportalvenous receptor scintigraphy, endoscopicpancreatic ultrasound ( tomography, MRI and transabdominal ultrasonography of metastases.Non-invasiveimagingincludescomputed the extentofdiseaseandevaluateforpresence hyperinsulinemic hypoglycemia. there isconvincingbiochemicalevidencetosupport concentration. Localization studies are carried out once insulin concentrationfortheprevailingplasmaglucose hyperinsulinemic hypoglycemiawithaninappropriate patient years( study, itoccurswithanincidenceof4permillion in 1927( neuroendocrine tumorofthepancreas,firstdescribed Insulinoma ( Insulinoma oral hypoglycemicagentsrespectively. hypoglycemia syndromeandcausedby (insulin secretagogues)toruleoutinsulinautoimmune of hypoglycemia) screen for oral hypoglycemic agents essential totestforinsulinantibodiesand(atthetime and tumorenucleationisthe mainstayoftherapy( once thediagnosisofhypoglycemia hasbeenconfirmed insulinoma ( CT with68Ga-DOTA-exendin-4 hasbeenused tolocalize of hypoglycemia Pathogenesis andmanagement 21 mg/dL (2.8 , In contrast, in cases where the history obtained In contrast, in cases where thehistory Imaging is essential to locate the tumor, determine 18 22 ). Duringtheevaluationofhypoglycemia,itis ). Invasivetechniquesincludesomatostatin 19 24 i. 1 Fig. mmol/L) during an oral glucose tolerance ). Accordingtoapopulation-based , 20 25 17 ). Itischaracterizedbyendogenous min for 5 ) is the most common functioning ). Surgicalexplorationiscarried out ). Thisisbecauseapproximately10% Downloaded fromBioscientifica.com at09/26/202106:38:39AM h. It is important to note that 21 , 23 ). MorerecentlyPET/ 177 www.eje-online.org :1 R39 21 via freeaccess ). European Journal of Endocrinology www.eje-online.org previously ( they examinedthespecimens ofthepatientsdescribed did notfindevidenceof isletcellhyperplasiawhen pathology ( partialpancreatectomyand exhibitedsimilar underwent described 3patientswithasimilarpresentationwhoalso nesidioblastosis. Subsequently, thestudyby Patti specimen suggestedappearancescompatiblewith symptoms. Pathological examinations of thesurgical partialpancreatectomy tocontroltheir who underwent hyperinsulinemic hypoglycemiafollowingRYGB ( by Service symptoms. Thepathogenesisofthisdisorderisuncertain. is variablebutpatientstypicallypresentwithpostprandial than inmen.Thetimeofonsetsymptomsaftersurgery patients ( uncertain buthasbeenestimatedtooccurin0.2–1%of function. Theprevalenceofpost-RYGB hypoglycemiais which bypassthepylorus,oralteruppergastrointestinal gastric bypass (RYGB) ( Hypoglycemia isaknowncomplicationofRoux-en-Y Post bariatrichypoglycemia for surgicaltherapy. have beenused( such asoctreotideandlanreotide,ethanolablation the use of diazoxide, long-acting somatostatin analogs instances ( Laparoscopic procedureshavebeenusedinmany Review The conditionrosetoprominenceafterthestudy 31 26 t al et 32 ) andappearstobemorecommoninwomen 33 , 27 ) ashavingnesidioblastosis ( ). In contrast, the study by Meier . described6patientswithendogenous 21 , 28 , 30 , 29 ) inpatientswhoarenotcandidates ). Medicalmanagementincluding i. 1 Fig. ) and other procedures N EKittahandAVella 34 ), merelyan t al et t al et 32 ) . . concluded thatalowcarbohydrate diet waslesslikelyto diet, hypoglycemiawasameliorated. Theinvestigators When thesamesubjectsconsumed alowcarbohydrate duringthe highcarbohydratemeal. after mealingestion.Twelve of14patientsdeveloped were measuredatbaselineandthen30-mininterval on day2.Plasmaglucoseandinsulinconcentrations carbohydrates onday1andameallowin These patientsweregivenamixedmealhigh in studied 14patientswithhyperinsulinemichypoglycemia. as demonstrated in the studyby Kellogg modification bariatric bypasshypoglycemiaisdietary increase inthenucleardiameterofbetacellswhen post-prandial glucosenadirinaffectedpatients( antagonism oftheGLP-1receptorcanameliorate study bySalehi role inglucosedisposalafterRYGB ( this hypothesis( ( by excesssecretionofglucagon-likepeptide-1(GLP-1) e.g.caused and aberrantresponsetobariatricsurgery suggestions thatthisconditionmayrepresentanexcessive the ameliorationoftype2DM( histology afterRYGB. lack of a clear definition of what constitutes abnormal might altercellular size inautopsyspecimen–andthe been argued,forexamplethatpost-mortemautolysis conclusions mightarisefromthecontrolsused–ithas compared toautopsyspecimen( of hypoglycemia Pathogenesis andmanagement 37 , The firstlineoftherapyinpatientswithpost Given theeffectsofRYGB onglucosemetabolism and 38 ). Therearesignificanttheoreticalobjectionsto et al 39 (−) linesrepresentaninhibitoryeffect. lines representastimulatoryeffect, the hypoglycemia invarioussituations.The(+) Mechanisms ofthepathogenesis Figure 1 ) andultimately, GLP-1 plays asmall . havedemonstratedthatcompetitive Downloaded fromBioscientifica.com at09/26/202106:38:39AM 35 34 , 40 36 177 ). Thisdisparityin , ), therehavebeen 41 :1 et al ). However, the . ( 42 44 , ), who R40 43 ). via freeaccess

European Journal of Endocrinology In refractory cases of post-RYGBIn refractory hypoglycemia, reversal of remnant stomach alleviates symptoms of hypoglycemia. ral feeding( treatment ofpost-RYGB hypoglycemia. this procedurehasbeenlargelyabandonedforthe continue tohavesymptomsafterpartialpancreatectomy, and persistentsymptoms( one patient requiring total pancreatectomy for severe recurrent symptomsafterpartialpancreatectomywith of priorbariatricsurgery. Forty-one (87%)patientshad ( had undergonepartial pancreatectomy forhypoglycemia described pancreaticresectionofupto50–100%( resection of 80% ( ( resection of 80% of the parenchyma in eight of nine patients in theliteraturewithMathavandescribingpancreatic ( 10 months RYGB hypoglycemiawhoremainedfree ofsymptomsat distalpancreatectomyinapatientwithpost- preserving study byAlvarez 77% developedrecurrenceintheirsymptoms( initially;however,of theirsymptomsafterthesurgery All of the nine patients had resolution to open surgery). andonehadaconversionoflaparoscopicsurgery surgery extended distalpancreatectomy(eighthadlaparoscopic hypoglycemia ( retrospectively studied15patientswhohadpostbypass of post-RYGB hypoglycemia( hypoglycemia. the longitudinaleffectoftherapyonpost-RYGB is adearthofstudieswhichhaverigorouslyexamined and insulinomahavebeenused( diazoxide thatisusedinthetreatmentofhypertension ameliorate postprandialsymptoms.Insomeinstances, motility andpostprandialsplanchnicvasodilation compounds inhibitinsulinsecretionanddecreasebowel and post-RYGB interventions hypoglycemia when dietary such asoctreotideandlanreotidehavebeenusedtotreat effects offlatulenceanddiarrhea.Analogssomatostatin glucose andinsulinbuttheiruseislimitedbyadverse These compoundsdecreasethepostprandialrisein symptoms, patients ( cause hypoglycemiaandimprovedsymptomsinthese 47 51 Review ), thestudybyThompson ). The majority of the patients (64%) had a history ). Themajorityofthepatients(64%)hadahistory The casereportshavesuggested thatcontinuousente­ However, Vanderveen Pancreatectomy has been used for the treatment Pancreatectomy hasbeenusedforthetreatment donotalleviate interventions When dietary α -glucosidase inhibitorsareineffective( 44 52 ). α 48 -glucosidase inhibitorshavebeenutilized. ) byinsertion of agastrostomy tubeintothe ). The extent of pancreatic resection differs ). The extent of pancreatic resection differs 47 t al et ). Nine underwent surgery involving involving surgery ). Nineunderwent 49 ) and the study by Harness . describedalaparoscopicspleen- 51 et al ). Asthemajorityofpatients 32 t al et . studied75patientswho 46 N EKittahandAVella , ). Unfortunately, there . described pancreatic . describedpancreatic 33 ). Mathavan 45 50 47 ). These ). ). The ). The t al et t al et . . the RYGB has been described. The study by Himpens often confusedwithpostbypasshypoglycemia;however described inthestudybyService syndrome (NIPHS) ( Non-insulinoma pancreatogenoushypoglycemia hypoglycemia syndrome Non-insulinoma pancreatogenous symptomsofhypoglycemia. severe refractory may beareasonabletherapeuticoptioninpatientswith per weekdecreased. This suggeststhat reversal ofRYGB neuroglycopenia and the number of hypoglycemic events months),therewerenofurtherepisodesof (range 3–22 and neuroglycopenia. At ameanfollow-up of 12 months hyperinsulinemichypoglycemia patients withrefractory more recentseries( dumping syndromewithouthypoglycemia( first describedthereversalinapatientwithsevere for thepresenceofinsulinantibodies andplasmainsulin presentation ofhypoglycemia causedbyinsulinomabut ( described asacauseofhypoglycemia byHiratain1972 Insulin autoimmunehypoglycemia syndromewasfirst syndrome Insulin autoimmunehypoglycemia recommended treatmentofchoice( symptoms,distalpancreatectomy isthe with refractory cases ( of thepancreas( insulin responseispositiveinmultiplevascularterritories stimulation withhepaticveinsamplinginwhichthe patients ( with congenitalnesidiobalstosiswasdetectedinthese no geneticmutation( ( typically occursinthepostprandialperiod. negative localizingimagingstudies.Hypoglycemia hyperinsulinemic hypoglycemiainthesettingofa ofgastricbypassandpresentwithendogenous a history NIPHS shouldbeconsideredinpatientswhodonothave and intraoperativeultrasoundarenegative( as trans-abdominalultrasound,abdominalCT, MRI,EUS bypass surgery. Imagingofthepancreaswithstudiessuch ofgastric patients withNIPHSdonothaveahistory of hypoglycemia Pathogenesis andmanagement 58 55 ). Thisisclinicallyandbiochemically similartothe ). Imagingwasnegativeforinsulinoma.However, Diaxozide hasbeenusedtomanageNIPHSinsome Diagnosis usuallyrequiresselectivearterialcalcium Surgical specimensexhibitfeaturesofnesidioblastosis 57 ). Inseverelysymptomaticpatientsor 55 ). 49 , 54 55 i. 1 Fig. ), reversalwasperformedinthree , 56 KCNJ11 Downloaded fromBioscientifica.com at09/26/202106:38:39AM ). ) isararecondition first and et al 49 177 ABCC8 . in1999( , 55 www.eje-online.org :1 ). 49 ) associated , 55 53 55 ). Thus, ). Ina ). Itis R41 et al via freeaccess .

European Journal of Endocrinology www.eje-online.org It willhowevernotalwaysbe practicaltoavoidprescribing ( patient shouldbeevaluated forpossiblehypoglycemia unconscious is acommonphenomenonand assuchevery drug-induced hypoglycemia.Drug-inducedhypoglycemia Alcohol causeshypoglycemia( of thesefactorsandthusareatriskforhypoglycemia( patients onmultiplemedicationsareatriskforanumber a riskfactorfordrug-inducedhypoglycemia.Hospitalized Seltzer in1972and1989( liver diseaseandrenalasshowninthestudyby drug-induced hypoglycemiaarerestrictedfoodaccess,age, low( was moderatetovery supporting theassociationofthesedrugswithhypoglycemia hypoglycemia ( agents andIGFwerethemostcommondrugsthatcaused quinine, betablockers,angiotensin-convertingenzyme treat hyperglycemia showed thatquinolones,pentamidine, of 448studieshypoglycemianotcausedbydrugsusedto pentamidine. However, most recently a systematic review antagonists suchaspropranolol,salicylatesand quinine, disopyramide,nonselectivebeta-adrenoceptor have beenimplicated in causing hypoglycemia and include A numberofmedicationsnotusedtotreathyperglycemia the mostcommondrugsthatcausehypoglycemia( Insulin orinsulinsecretagogues,aloneincombinationare Drug-induced hypoglycemia asatreatmentmodality( pancreatic surgery ( 3 years to decreaseinsulinantibodiesandtheeffectlastedfor rituximab havebeenused( azathioprine, plasmapheresis,6-mercaptopurine and tosteroidsothertherapiessuchas In casesrefractory frequently usedinthemanagementofhypoglycemia. syndrome appears to be self-limiting ( also contributestohypoglycemia( insulin causes hypoglycemia. Dissociation of antibodies antibodies-binding capacityisexceededandunboundfree stimulating the secretion of insulin. At some point, the ( ( these antibodiesmaybetriggeredbydrugsand viruses with HLA-DR4positivity( autoimmune diseases.Ithasbeenshowntobeassociated be morecommoninAsians( levels typicallyhigherthan1000 75 Fig. 1 66 Review , , Hypoglycemia in insulin autoimmune hypoglycemia Prevention ofdrug-induced hypoglycemiaisthekey. 76 67 ) ( ). , 68 69 72 ). Theantibodiesbindtoinsulinandproinsulin ). Thisresultsininitialhyperglycemiafurther ). Therehavebeenreportsintheliteratureof 74 ). However, thequalityofevidence 75 62 71 74 60 , 78 , , ). Factors that predispose to ). Factorsthatpredisposeto 63 76 72 , ) and is also a risk factor for ) andisalsoariskfactorfor pmol/L ( N EKittahandAVella 61 ). Poly-pharmacy is also ). Poly-pharmacyisalso , ). Rituximabwasshown 69 64 ) andinpatientswith ). , 65 70 ). Appearanceof 59 ). Steroids are ). Itappearsto 73 ). Fig. 1 77 ). ). ).

epithelial, hematopoietic and rarely neuroendocrine epithelial, hematopoieticandrarelyneuroendocrine with benign or malignantsolidtumors of mesenchymal, In rarecases,recurrenthypoglycemiamayoccurinpatients Non-islet celltumors may resultinfurtherhypoglycemicepisodes. needed forseveralhoursasprematurediscontinuation then usedtomaintainbloodglucoselevelsandmaybe warranted. Aninfusionof10%dextroseat100 then correctionwith50%dextroseorglucagonis cannot takeoralglucoseorhaveseverehypoglycemia, severe symptomswith15 orally inpatientswhoareconsciousanddonothave drug andreversing acute hypoglycemia.Thiscanbedone hypoglycemia usuallyinvolvescessationoftheoffending with liverandrenaldiseases.Treatment ofdrug-induced be takeninprescribingpotentialoffenderstopatients medications that may cause hypoglycemia. Caution must frequency andsymptoms of hypoglycemia.Insome frequent carbohydratesnacks canalsohelpinreducing be giveninseverecases( administration ofintravenous dextrose.Glucagoncan management ofacutehypoglycemia involvesthe leads tothediagnosisofmalignancy. of malignancy( Hypoglycemia insomecasesisthefirstpresentingsymptom often seenincasesoftumorsthatcausehypoglycemia. infiltration oftheliverbytumor. Large tumorbulkis decreased productionofglucosefromtheliverdue to for hypoglycemia caused by non-islet cell tumorsinclude ratio of10ormoreisdiagnostic( discussed above,‘Big’IGF2levelsarehigh.AnIGF2:IGF1 is inhibitedbytheinsulin-likeactionsof‘Big’IGF2.As There isanormalresponsetoglucagonasglycogenolysis Growth hormone,IGF1( C-peptide levelsandsuppressedbeta-hydroxybutyrate( hypoinsulinemia withlowbloodglucose,insulin, in the postabsorptivephaseand is characterized by Hypoglycemia innon-isletcelltumorsusuallyoccurs muscles and peripheral tissues with resultant hypoglycemia. increased uptake of glucose from the systemic circulation by results indecreasedglucoseproductionfromtheliverand IGF2 bindstotheinsulinreceptorandIGFreceptors.This and stimulatestheinsulinreceptor( of IGF2( is anincompletelyprocessedposttranslationalprecursor express highmolecularweightIGF2(‘Big’IGF2),which origin as a paraneoplastic syndrome ( of hypoglycemia Pathogenesis andmanagement As inothercasesofhypoglycemiadiscussedabove, 81 , 82 80 ). IGF2 is similar in structure to insulin ). IGF2issimilarinstructuretoinsulin ) and workup for hypoglycemia invariably ) andworkupforhypoglycemiainvariably Downloaded fromBioscientifica.com at09/26/202106:38:39AM 83 86 g ofglucose.Inpatientswho ) andIGFBP3arealsolow( ). Encouragingpatientstoeat 80 , 85 79 i. 1 Fig. 177 ). Other mechanisms ). Othermechanisms , 80 :1 ). As such ‘Big’ ). Assuch‘Big’ ). These tumors ). These tumors mL/h is R42 84 83 via freeaccess ). ). ). European Journal of Endocrinology ketogenesis, proteolysisand decreasesglucoseutilization. insulin signaling,increases ,lipolysis, mechanisms thatprotectagainst hypoglycemia.Itimpairs Cortisol hasanimportantrole inthecounter-regulatory Hypoglycemia inadrenal insufficiency been associatedwithincreasedmortality( such situationsashypoglycemiaincriticalillnesshas rarely prominentandshouldbesoughttreated in can beapartofthepresentationincriticalillnessbut is resulting inadrenalinsufficiency( are atriskofbilateraladrenalhemorrhageorinfarction septic orhavethrombocytopeniafroma variety ofcauses with corticosteroidsynthesis( including medicationssuchasetomidatethatinterferes adrenal insufficiencyhasmanypotentialetiologies Critical illnessincreasesphysicalstress.Relativeorabsolute glucose utilizationpredisposetohypoglycemia( impaired gluconeogenesis and increased peripheral In criticallyillpatients,decreasedglycogenstores, Sepsis andhypoglycemia tumor hypoglycemiawithsomesuccess( been reportsofuseimatinibincasesnon-isletcell potential tumorgrowthcausedbyGH( term useofgrowthhormoneandthereistheconcernfor tumors ( management of hypoglycemia mediated by non-islet cell have alsobeenusedaloneorincombinationthe receptors ( somatostatin receptors or lack functional somatostatin glucose likelyduetothefactthattumorsdonothave other casestherehasbeennoimprovementinblood been usedwithsuccessinsomecases( limited success ( of hypoglycemiainnon-isletcelltumorsthoughwith hypoglycemia. Diaxozidehasbeenusedinthetreatment is not possible, medications may be used to control For casesinwhichcompleteresectionofthetumor burden andsubsequentlylimitepisodesofhypoglycemia. chemotherapy mayalsobeneededtodecreasetumor the tumor is unresectable ( Embolization has also been carried out in cases where resected mayalsoreducehypoglycemicepisodes. ( Complete resectionofthetumorifpossible,iscurative instances, total parenteral nutrition may beneeded ( 81 Review ). Debulkingoflargetumorsthatcannotbecompletely 94 93 , 95 , 94 , 96 ). Glucocorticoids and growth hormones 91 , 97 , , 92 98 ). Somatostatin analogs have , 88 99 , 103 ). Costmaylimitthelong- 89 N EKittahandAVella , , 90 104 105 ). Radiotherapy and ). Patientswhoare 93 ). Hypoglycemia 100 87 106 ). However, in ). Therehave ). , 107 101 , , 108 102 87 ). ). ). adrenocortical failure could result in hypoglycemia ( decreased endogenousglucoseproduction,implyingthat close to70%,increased glucose oxidation by 50%,with acute withdrawalofcortisolincreasedinsulinsensitivity The study by Christiansen Addison’s diseaseareatincreasedriskofhypoglycemia. insufficiency isuncommon,althoughpatientswith andhypothalamusrespectively.the pituitary adrenalinsufficienciesareduetodisordersof and tertiary due to adrenalhemorrhage( ( adrenalinsufficiency are animportantcauseofprimary ever indevelopingcountriesinfectionssuchastuberculosis is autoimmunediseaseindevelopedcountries( 3–5 days ( insufficiency usingcontinuousglucosemonitoringfor Meyer somatostatin infusionmaybe required. (in hypoglycemiacausedby aninsulinsecretagogue)a infusion tomaintainnormal bloodsugars.Occasionally, with 50%dextrose,orglucagon andsubsequentdextrose offending medication, reversal of hypoglycemia acutely ( partner’s oralhypoglycemicagentoradispensingerror older patientsitmaybeduetoinadvertentuseof a meglitinides ( insulin orsecretagoguessuchassulfonylureasand hypoglycemia isusuallyduetothesurreptitioususe of is positiveatthetimeofhypoglycemia.Factitious lowering medications,and,ideallyadrugscreenthat toprove access toglucose- and requiresadetailedhistory Factitious hypoglycemiamaybechallengingtoprove Factitious hypoglycemia hypoglycemia isdoneusingintravenousdextrose. hydrocortisone isgiven( and incasesofadrenalcriseshigh-doseintravenous corticosteroids split twice or three times daily ( involves replacement with a physiological dose of oral in youngchildrenwithhypopituitarism.Thetreatment adrenalinsufficiencyandisalsoseen with secondary episodes ofhypoglycemia( dosing waschangedtolateevening,therewerenofurther than 50 hypoglycemia withabloodglucoseconcentrationofless of hypoglycemia Pathogenesis andmanagement 110 119 Hypoglycemia in adult patients with primary adrenal Hypoglycemia inadultpatientswithprimary adrenalinsufficiency The commonestcauseofprimary Hypoglycemia isencounteredmoreinpatients ). Other causes of primary adrenal insufficiency may be adrenalinsufficiencymaybe ). Othercausesofprimary ). Treatment inthesecases involves cessationofthe t al et mg/dL. Whenthepatient’s lasthydrocortisone 112 . studied 13 patients with primary adrenal . studied13patientswithprimary ). Onepatientwasdetectedtohavenocturnal 16 , 115 , 116 Downloaded fromBioscientifica.com at09/26/202106:38:39AM 114 , 112 117 105 ). Immediatecorrectionof t al et ). , ) or infarction. Secondary ) or infarction. Secondary 118 . demonstrated that ). Incasesinvolving 177 www.eje-online.org :1 109 ); how­ R43 111 113 via freeaccess ). ) European Journal of Endocrinology www.eje-online.org References the public,commercialornot-forprofitsector. This reviewdidnotreceiveanyspecificgrantfromfundingagencyin Funding sponsored byXOMApharmaceuticals,Berkeley, CA,USA. Dr Vella isalocalPIinmulticenterstudyofpost-RYGB hypoglycemia Declaration ofinterest irreversible neurologicalsequelae. sequelae ofprolongedhypoglycemiathatmayresultin Treatment ofacutehypoglycemiaisimportanttoprevent true hypoglycemiaexistsbyfulfillingWhipple’s triad. of hypoglycemia,itisimportanttoestablishthat which causesignificantmorbidity. Beforetheevaluation There arehoweveruncommoncausesofhypoglycemia treatment ofdiabeteswithglucose-loweringmedications. Hypoglycemia isacommonphenomenoninthesettingof Conclusion 11 10 9 8 7 6 5 4 3 2 1 Review JCI31669) ofClinicalInvestigation Journal edrv-7-2-131) diabetes mellitus. systemstopatientswithinsulin-dependent counterregulatory NEJM198507253130405) ofMedicine England Journal and intensiveinsulintherapyindiabetesmellitus. Investigation are higherthanthethresholdforsymptoms. systems thresholds foractivationofglucosecounterregulatory dysfunction. hormonesecretion,symptoms,andcerebral for counterregulatory P&GerichJ.HierarchyDurrant J,Cryer ofglycemicthresholds Association Journal Chiropractic Medicine 2272–2279. failure indiabetes. America Metabolism ClinicsofNorth Cryer PE. Hypoglycemia, functional failure, and brain death. Cryer PE,WhiteNH&SantiagoJV.Cryer Therelevanceofglucose PE&GerichJE.Glucosecounterregulation,hypoglycemia, Cryer PE.Glycemic Schwartz NS,ClutterWE,ShahSD&Cryer Mitrakou A,RyanC,Veneman T, MokanM,JenssenT, KissI, Whipple AO.Isletcelltumorsofthepancreas. Whipple AO.Thesurgicaltherapyofhyperinsulinismus. PE.Diversecausesofhypoglycemia-associatedautonomic Cryer Guettier JM&GordenP. Hypoglycemia. 287 ofPhysiology:EndocrinologyandMetabolism American Journal sympathetic neural,ratherthanadrenomedullary, activation. system: neurogenicsymptomsarelargely theresultof PE.Hypoglycemiaandthesympathoadrenal DeRosa MA&Cryer 1993 cholinergic) ratherthanneuroglycopenicsymptoms. of hypoglycemia.Perception ofneurogenic(predominantly Towler P. DA,HavlinCE,Craft S&Cryer Mechanismofawareness E32–E41. 42 1791–1798. 1987 (doi:10.1056/NEJMra031354) American Journal ofPhysiology American Journal 1952 Endocrine Reviews 79 New England Journal ofMedicine New EnglandJournal 1938 777–781. (doi:10.2337/diab.42.12.1791) 66 1985 3 334–342. 237–276. 2007 (doi:10.1172/JCI112884) 313 2006 N EKittahandAVella 1986 117 232–241. 868–870. Endocrinology and 35 7 1991 131–139. 753–766,viii–ix. Journal ofClinical Journal Canadian Medical (doi:10.1056/ 260 2004 (doi:10.1172/ New E67–E74. (doi:10.1210/ Diabetes 350 Journal of Journal 2004

of hypoglycemia Pathogenesis andmanagement 18 17 16 15 14 13 12 20 19 28 27 26 25 24 23 22 21 diab.30.12.996) hypoglycemia. Lev-Ran A&AndersonRW. Thediagnosisofpostprandial Press, 1987. Andreani D&MarksV. NEJM199504273321707) ofMedicine Journal FJ.Hypoglycemicdisorders. Service Metabolism diagnostic testforinsulinoma. Doppman JL,SkarulisMC&GordenP. Forty-eight-hourfast:the Hirshberg B,LiviA,BartlettDL,LibuttiSK,AlexanderHR, and Metabolism at theMayoClinic,1987–2007. in thepresentationandmanagementoffunctioninginsulinoma Charboneau JW, AndrewsJC,LloydRV FJ.Seculartrends &Service Placzkowski KA,Vella A,ThompsonGB,GrantCS,ReadingCC, 8529(05)70086-4) America disorders. FJ.DiagnosticapproachtoadultswithhypoglycemicService 94 Guideline. hypoglycemic disorders:anEndocrineSocietyClinicalPractice FJ.Evaluationandmanagementofadult Seaquist ER&Service PE,AxelrodL,GrossmanAB,HellerSR,MontoriVM, Cryer 711–719. of patients:a60-yearstudy. insulinoma –incidence,recurrence,andlong-termsurvival FJ,McMahonMM,O’BrienPC&BallardDJ.Functioning Service jama.1927.02690050014007) American MedicalAssociation Carcinoma oftheislands ofthepancreas. Wilder RM,AllanFN,PowerMH&Robertson HE. G. Robot-assistedlaparoscopicmiddle pancreatectomy. Giulianotti PC,SbranaF, BiancoFM,Addeo P&Caravaglios (doi:10.1097/SLE.0b013e3182a4bf69) Endoscopy andPercutaneous Techniques pancreatectomy: areviewof51cases. Machado MAC,EpsteinMG&Makdissi FF. Laparoscopiccentral 015-2976-x) World ofSurgery Journal forbenigntumoursofthepancreas:asystematic review.surgery Beger H,SiechM,PochB,MayerB&SchoenbergM.Limited 84 CT tolocalizeanoccultinsulinoma. Raraty M&Wild D.ApplicationofGa(68)-DOTA-exendin-4 PET/ Cuthbertson DJ,BanksM,KhooB,AntwiK,ChristE,CampbellF, (doi:10.1210/jc.2006-1479) Clinical EndocrinologyandMetabolism or beta-cellhyperplasiainadultpatients. emission tomographyasatooltolocalizeaninsulinoma Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron A, AlanenK,ParkkolaR,SolinO,BergmanJ,SaneT Kauhanen S,SeppanenM,MinnH,GullichsenR,Salonen Metabolism cell tumours. medicine inthedetectionandmanagementofpancreaticislet- Virgolini I,Traub-Weidinger T&DecristoforoC.Nuclear 2005 Best PracticeandResearch: ClinicalEndocrinologyandMetabolism localization ofislet-celltumoursthepancreasonCTandMRI. Noone TC,HoseyJ,FiratZ&SemelkaRC.Imagingand bpg.2005.05.008) Gastroenterology Grant CS.Insulinoma. 709–728. 789–791. 19 1999 195–211. (doi:10.1016/S0025-6196(12)62083-7) Endocrinology andMetabolismClinicsofNorth 2000 2005 Journal ofClinicalEndocrinologyand Metabolism Journal (doi:10.1210/jc.2008-1410) (doi:10.1111/cen.12973) Best PracticeandResearch: ClinicalEndocrinologyand 28 2009 Diabetes 2005 85 19 519–532,vi. 1995 (doi:10.1016/j.beem.2004.11.013) 3222–3226. 213–227. 94 19 2015 Best PracticeandResearch: Clinical 1981 1069–1073. Downloaded fromBioscientifica.com at09/26/202106:38:39AM Hypoglycemia 332 783–798. 1927 Mayo ClinicProceedings 1144–1152. 39 30 (doi:10.1016/j.beem.2004.09.001) Journal ofClinicalEndocrinologyand Journal (doi:10.1016/S0889- 1557–1566. Journal of Clinical Endocrinology ofClinicalEndocrinology Journal 996–999. (doi:10.1210/jcem.85.9.6807) 89 (doi:10.1016/j. New England (doi:10.1210/jc.2008-2031) 348. . NewYork, NY, USA:Raven Clinical Endocrinology 2013 Surgical Laparoscopy 2007 177 (doi:10.1056/ Journal of the ofthe Journal (doi:10.1001/ (doi:10.2337/ Journal ofJournal 23 :1 (doi:10.1007/s00268- 92 486–490. 1237–1244. 1991 et al Journal Journal 66

2009 2016 . R44

via freeaccess European Journal of Endocrinology 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 Review (doi:10.1053/j.gastro.2013.11.044) after gastricbypass. like peptide1receptorcorrectspostprandial hypoglycemia Salehi M,GastaldelliA&D’AlessioDA. Blockadeofglucagon- s11154-014-9291-y) Endocrine andMetabolicDisorders to mediateglycemiceffectsofweightlosssurgery. Salehi M&D’AlessioDA.Effectsofglucagonlikepeptide-1 2062–2069. type 2diabetesaftergastricbypasssurgery. GLP-1 actionandglucosetoleranceinsubjectswithremissionof Jiménez A,CasamitjanaR,Viaplana-Masclans J,LacyA&Vidal J. 483–493. metabolism afterRoux-en-Ygastricbypass. Contribution ofendogenousglucagon-likepeptide1toglucose C, CobelliRizzaRA,CamilleriM,ZinsmeisterAR&Vella A. Shah M,LawJH,MichelettoF, SathananthanM,DallaMan (doi:10.1210/jc.2007-2260) of ClinicalEndocrinologyandMetabolism problemorredherring? bypass hypoglycemia–primary Vella FJ.Incretinhypersecretioninpost-gastric A&Service (doi:10.1210/jc.2007-0918) of ClinicalEndocrinologyandMetabolism responsestoamixedmeal. incretin andinsulinsecretory haveexaggerated neuroglycopenia aftergastricbypasssurgery Jones DB,SchneiderBE,HolstJJ&PattiME.Patientswith Goldfine AB,MunEC,DevineE,BernierR,Baz-HechtM, 1 after bariatricsurgery. Hormonal mechanismsofweightlossanddiabetesresolution Cummings DE,OverduinJ,ShannonMH&Foster-SchubertKE. (doi:10.1097/00000658-199509000-00011) Annals ofSurgery be themosteffectivetherapyforadult-onsetdiabetesmellitus. JM PG, BrownBM,BarakatHA,deRamonRA,IsraelG,Dolezal Pories WJ,SwansonMS,MacDonaldKG,LongSB,Morris 2765559891) mellitus? Pories WJ.Whydoesthegastricbypasscontroltype2diabetes 2006 by islethyperplasiaorincreasedbeta-cellturnover. isnotaccompanied hypoglycemia aftergastricbypasssurgery Meier JJ,ButlerAE,GalassoR&PC.Hyperinsulinemic Diabetologia inappropriate insulinsecretionandpancreaticislethyperplasia. post-gastric bypassrequiringpartialpancreatectomy:evidencefor Hanto DW, M,ArkyR,NoseV Callery Patti ME,McMahonG,MunEC,BittonA,HolstJJ,GoldsmithJ, of Medicine nesidioblastosis aftergastric-bypasssurgery. Clavell ML&LloydRV. Hyperinsulinemichypoglycemiawith FJ,AndrewsJC,Collazo- GJ,ThompsonGB,Service Service Diabetologia forobesityin1986–2006Sweden. patients undergoingsurgery study ofpost-gastricbypasshypoglycaemiaincluding5040 Marsk R,JonasE,RasmussenF&NaslundE.Nationwidecohort (doi:10.1016/j.gie.2011.09.019) treatment option. & Vella A.US-guidedethanolablationofinsulinomas:anew Levy MJ,ThompsonGB,Topazian MD,CallstromMR,GrantCS Surgery pancreatectomy forinsulinoma(withvideo). Villacreses D,StaufferJ,HoracioJ&AsbunJ.Laparoscopiccentral 135–139. of Laparoendoscopic andAdvancedSurgicalTechniques 358–368. et al 29 2016 . Whowouldhavethoughtit?Anoperationprovesto 1554–1559. Obesity Surgery (doi:10.1089/lap.2009.0296) (doi:10.2337/db13-0954) 2005 (doi:10.1016/j.soard.2005.03.208) 2010 2005 (doi:10.2337/dc12-1535) 153 1995 353 473–474. 48 53 Gastrointestinal Endoscopy Gastroenterology 2236–2240. 2307–2311. 249–254. (doi:10.2337/dc06-0392) Surgery forObesityandRelatedDiseases Surgery 222 1992 339–350;discussion350–332. (doi:10.1016/j.jviscsurg.2016.06.004) 2 (doi:10.1056/NEJMoa043690) 303–313. 2014 (doi:10.1007/s00125-005-1933-x) (doi:10.1007/s00125-010-1798-5) N EKittahandAVella 2014 et al 15 2007 2007 171–179. 146 (doi:10.1381/09608929 . Severe hypoglycaemia . Severehypoglycaemia Diabetes Care Diabetes 2012 New England Journal New EnglandJournal 92 92 Journal ofVisceralJournal 669–680e662. 4678–4685. 4563–4565. 75 Reviews in Diabetes Care 2010 (doi:10.1007/ 2014 200–206. 2013 Journal Journal 20 63 Journal Journal 2005

36

of hypoglycemia Pathogenesis andmanagement 44 49 48 47 46 45 57 56 55 54 53 52 51 50 modified diet. hypoglycemia syndrome:characterizationandresponsetoa Buchwald H&IkramuddinS.Postgastricbypasshyperinsulinemic Kellogg TA, BantleJP, LeslieDB,RedmondJB,SlusarekB,SwanT, patients. hypoglycemia syndrome:anupdatein10surgicallytreated Heerden JA&GrantCS.Noninsulinomapancreatogenous FJ,AndrewsJC,LloydRV,Thompson GB,Service NattN,van Surgery treatment fornesidioblastosisaftergastricbypasssurgery. distalpancreatectomyas Laparoscopic spleen-preserving Alvarez GC,FariaEN,BeckM,GirardonDT&MachadoAC. 2547–2555. pancreatogenous hypoglycemia. Meacham J.Managementofpostgastricbypassnoninsulinoma Mathavan VK,ArreguiM,DavisC,SinghK,PatelA& soard.2011.05.010) for ObesityandRelatedDiseases hypoglycemia inpatientafterRoux-en-Ygastricbypass. Use ofdiazoxideinmanagementseverepostprandial Gonzalez-Gonzalez A,DelgadoM&Fraga-FuentesMD. (doi:10.1097/01.med.0000244222.91280.71) in Endocrinology, DiabetesandObesity forobesity.following gastricbypasssurgery Goldfine AB,MunE&PattiME.Hyperinsulinemichypoglycemia 492–499. noninsulinoma pancreatogenoushypoglycaemia syndrome and morphologicalcharacterization of10patientswith HD, Burcus N,PittengerG&Vinik A.Clinicalfeatures Won JG,Tseng HS,Yang AH,Tang KT, JapTS,LeeCH,Lin (SICI)1096-9136(199711)14:11<985::AID-DIA483>3.0.CO;2-L) of theBritishDiabeticAssociation adult nesidioblastosis:acasereport. Selective intra-arterialcalciuminjectionintheinvestigationof Lee WL,Won JG,ChiangJH,HwangJI,LeeCH&Tsay SH. jc.84.5.1582) Endocrinology andMetabolism of mutationsinKir6.2andSUR1genes. hyperinsulinemic hypoglycemiainadultsindependent pancreatogenous hypoglycemia:anovelsyndromeof Andrews JC,LorenzE,Terzic A&LloydRV. Noninsulinoma FJ,NattN,ThompsonGB,GrantCS,vanHeerden JA, Service soard.2013.05.012) for ObesityandRelatedDiseases and utilityfortreatmentofendocrinecomplications. Laparoscopic reversalofRoux-en-Ygastricbypass:technique Campos GM,ZiemelisM,PaparodisR,AhmedM&DavisDB. 908–912. the gastricbypassintoanormalanatomy. Himpens J,DapriG&CadiereGB.Laparoscopicconversionof jc.2009-1628) Endocrinology andMetabolism consequence ofalterednutrientdelivery. hyperinsulinemic hypoglycemiaaftergastricbypass:a McLaughlin T, PeckM,HolstJ&DeaconC.Reversible surg.2010.09.027) 148 hypoglycemia fromdiffuseisletcelldisease. after partialpancreatectomyfornoninsulinomapancreatogenous ML, Vella A,Vollrath FJ. Outcomesandqualityoflife B&Service Vanderveen KA,GrantCS,ThompsonGB,FarleyDR,Richards (doi:10.1001/archsurg.1981.01380170055010) adults. Asurgicaldilemma. Fajans SS,KraftRO,HowardDR&ClarkKA.Nesidioblastosisin Harness JK,GeelhoedGW, ThompsonNW, NishiyamaRH, (doi:10.1067/msy.2000.110243) 1237–1245;discussion1245–1236. 2007 Surgery (doi:10.1016/j.soard.2008.05.005) (doi:10.1381/096089206777822179) (doi:10.1007/s00464-010-1001-6) 17 Surgery forObesityandRelatedDiseases Surgery 550–552. 2000 128 Downloaded fromBioscientifica.com at09/26/202106:38:39AM (doi:10.1007/s11695-007-9096-0) 937–944;discussion944–935. Archives ofSurgery 1999 2010 2013 2014 1997 Surgical Endoscopy 84 95 2006 9 10 Diabetic Medicine: A Journal Diabetic Medicine:AJournal 1582–1589. 1851–1855. e18–e19. 14 36–43. Journal of Clinical ofClinical Journal (doi:10.1016/j. 177 985–988. Journal of Clinical ofClinical Journal 13 Obesity Surgery www.eje-online.org Current Opinion :1 Surgery 419–424. 1981 (doi:10.1016/j. (doi:10.1016/j. (doi:10.1210/ (doi:10.1210/ 2010 (doi:10.1002/ 2010 116 2008 Surgery Surgery 575–580. Surgery Surgery 24 2006 Obesity 4 R45

16 via freeaccess

European Journal of Endocrinology www.eje-online.org 74 73 72 71 70 69 68 67 66 65 64 63 62 61 60 59 58 Review jc.2008-1416) Endocrinology andMetabolism induced hypoglycemia:asystematic review. PJ &MontoriVM.Clinicalreview:drug- Elamin MB,Erwin Murad MH,Coto-YglesiasF, Wang AT, SheidaeeN,Mullan RJ, 31802004000400010) Medical Journal M. Insulinautoimmunesyndrome:casereport. Moreira RO,LimaGA,PeixotoPC,FariasML&Vaisman (doi:10.2337/db11-0674) suppresses specificisletantibodies. Pugliese A,KrischerJ&EisenbarthGS.Rituximabselectively Yu L,Herold K,Krause-SteinraufH,McGeePL,BundyB, Metabolism glucose monitoring. insulin autoimmunesyndromewithrituximabandcontinuous Saxon DR,McDermottMT&MichelsAW. Novelmanagementof (doi:10.1530/endoabs.32.p289) Hirata disease). Uchigata Y&HirataY. Insulinautoimmunesyndrome(IAS, (doi:10.1172/JCI109374) hypoglycemia. insulin andproinsulin-bindingantibodiesinautoimmune Fisher LK,RoeTF&SchnureJJ.Characterizationofcirculating Goldman J,BaldwinD,RubensteinAH,KlinkDD,BlackardWG, 86 MedicalAssociation oftheFormosan Xue HuiZaZhi:Journal polyclonal anti-insulinautoantibodies:reportofacase. syndrome inamethimazole-treatedGraves’patientwith Lee YJ,ShinSJ,Torng JK,LiuWJ&Tsai JH.Insulinautoimmune Metabolism autoimmune syndromeingraves’disease. Kim SY&KwakSH.Two casesofmethimazole-inducedinsulin Roh E,KimYA, KuEJ,BaeJH,KimHM,ChoYM,ParkYJ,KS, 2009 autoimmune syndrome. Uchigata Y, HirataY&IwamotoY. Drug-inducedinsulin lupus erythematosus. Guillevin L.Insulinautoimmunesyndromerevealingsystemic Rouabhia S,RamanoelinaJ,GodmerP, ReachG,DutelJL& 393–394. insulin autoimmunesyndromewithHLA-DR4. S, MiyamotoM,OmoriY, JujiT&HirataY. Strongassociationof Uchigata Y, KuwataS,Tokunaga K,EguchiY, Takayama-Hasumi 603–618, vii. America Endocrinology andMetabolismClinicsofNorth Redmon JB&NuttallFQ.Autoimmunehypoglycemia. (doi:10.1080/003655101753352013) Investigation:Supplementum Laboratory diseases inhealthcare. R.Theepidemiologyandsignificanceofautoimmune Cervera nte.1974.00320200146022) Medicine of Internal cases diagnosedonthebasisofinsulinantibodies. FJ&PalumboPJ.Factitialhypoglycemia.Three Service Endocrine Practice Insulin autoimmunityandhypoglycemiainsevenwhitepatients. FJ,YuBasu A,Service L,HeserD,FerriesLM&EisenbarthG. Metabolism Virally M&GuillausseauP. Hypoglycemiainadults. Medicine diabetes nottreatedwithinsulin. proteins inacasewithspontaneoushypoglycemiaandmild Hirata Y&IshizuH.Elevatedinsulin-bindingcapacityofserum j.1365-2265.2006.02629.x) (NIPHS). 164–170. 83 e19–e20. 1972 Clinical Endocrinology (doi:10.1016/0140-6736(92)90080-M) 2013 1999 2016 (doi:10.1016/0168-8227(87)90074-x) (doi:10.1016/S0889-8529(05)70090-6) 107 2004 Journal ofClinicalInvestigation Journal Annales deMedecineInterne 1011931–1934. 2005 28 25 (doi:10.1016/j.diabres.2008.10.015) 277–286. 1974 55–60. 477–490. Journal ofClinicalEndocrinologyand Journal 122 Annales deMedecineInterne 11 Scandinavian Journal ofClinicaland Scandinavian Journal Diabetes Research andClinical Practice 134 178–180. 97–103. (doi:10.3803/EnM.2013.28.1.55) 2009 (doi:10.1620/tjem.107.277) 336–340. 2006 Tohoku ofExperimental Journal (doi:10.1210/jc.2016-1097) N EKittahandAVella 94 (doi:10.4158/EP.11.2.97) (doi:10.1590/S1516- Diabetes 65 741–745. 2001 566–578. (doi:10.1001/archi 1999 Endocrinology and 2011 235 Journal ofClinical Journal 1979 Lancet Sao Paulo 27–30. (doi:10.1210/ 150 2003 (doi:10.1111/ 60 Archives 63 2560–2565. 245–253. 1999 Diabetes and 1992 1050–1059. 154

Taiwan Yi 1987 28 59–60. 339

of hypoglycemia Pathogenesis andmanagement 75 82 81 80 79 78 77 76 90 89 88 87 86 85 84 83 cases. Seltzer HS.Drug-inducedhypoglycemia.Areviewbasedon473 binding ofinsulin-likegrowthfactorIIinthedevelopment Daughaday WH&KapadiaM.Significanceofabnormalserum NEJM198812013192202) ofMedicine England Journal factor IIbyaleiomyosarcoma withassociatedhypoglycemia. M &RotweinP. Synthesisandsecretionofinsulin-likegrowth Daughaday WH,EmanueleMA,BrooksMH,BarbatoAL,Kapadia 211–216. tumor hypoglycemia. features ofinsulin-likegrowthfactor-IIproducingnon-islet-cell Sata A,MoritaJ,KurimotoM,OkuboY&Takano K.Clinical Fukuda I,HizukaN,IshikawaY, Yasumoto K,MurakamiY, 1989 tumors. Daughaday WH.Hypoglycemiainpatientswithnon-isletcell 6736(77)91321-6) hypoglycaemia. O’Keefe SJ&MarksV. Lunchtimeginandtonicacauseofreactive 1986 patients. Causesandoutcomes. Fischer KF, LeesJA&NewmanJH.Hypoglycemiainhospitalized 163–183. America Endocrinology andMetabolismClinicsofNorth Seltzer HS.Drug-inducedhypoglycemia.Areviewof1418cases. (doi:10.1186/1471-2407-7-13) with anexon9mutation:acasereport. hypoglycemia inapatientwithgastrointestinal stromaltumor Buckley L,GonzalezR&McCarterMD. Severeparaneoplastic Escobar GA,RobinsonWA, NydamTL,HeipleDC, Weiss GJ, 0606-1) of ClinicalOncology fibrous tumorinahypoglycemicpatient. The therapeuticchallengeofanonresectablesolitary Hoogenberg K,SleijferDT, SuurmeijerAJ&vanderGraafWT. de BoerJ,JagerPL,Wiggers T, NieboerP, Wymenga AM,PrasE, 1999 review oftheliterature. associated withalargemesenchymaltumor:casereportand Rose MG,Tallini G,Pollak J&MurrenJ.Malignanthypoglycemia jc.2013-3382) Endocrinology andMetabolism islet-cell tumorhypoglycemia:aclinicalreview. Bodnar TW, Acevedo MJ&PietropaoloM.Managementofnon- CNCR22>3.0.CO;2-#) (doi:10.1002/(SICI)1097-0142(19980415)82:8<1585::AID- with tumorhypoglycemia. administration inthediagnosisandtreatmentofpatients Hoff AO&Vassilopoulou-Sellin R.Theroleofglucagon 2013 literature. hypoglycemia: areportoffivecasesandbriefreviewthe Khandelwal N&BhansaliA.Non-isletcelltumor-induced Dutta P, A,GogateY, Aggarwal NaharU,ShahVN,SinglaM, 13-1012) ofEndocrinology Journal clinical updateontumor-inducedhypoglycemia. Iglesias P&DiezJJ.Managementofendocrinedisease:a (doi:10.1111/j.1365-2265.1990.tb00469.x) hypoglycaemia. growth factorIinthediagnosisofnon-isletcelltumour like growthfactorIIinrelationtosuppressedinsulin-like Teale JD&MarksV. Inappropriatelyelevatedplasmainsulin- 86 hypoglycemia inpatientswithnon-islet-celltumors. 6778–6782. 130046. 18 315 5 Diabetes 48–51. 91–101. Endocrinology and Metabolism Clinics of North America Endocrinology andMetabolismClinicsofNorth 1245–1250. (doi:10.1016/j.ghir.2006.05.003) (doi:10.2337/diab.21.9.955) Endocrinology, DiabetesandMetabolismCaseReports 1972 (doi:10.1530/edm-13-0046) (doi:10.1073/pnas.86.17.6778) Lancet Clinical Endocrinology 2006 21 Growth Hormone andIGFResearchGrowth Hormone (doi:10.1056/NEJM198611133152002) 1977 955–966. Downloaded fromBioscientifica.com at09/26/202106:38:39AM 2014 Cancer Journal from Scientific American Cancer Journal 11 1988 Cancer 478–481. 2014 1 1286–1288. 170 New England Journal ofMedicine New EnglandJournal 319 (doi:10.2337/diab.21.9.955) R147–R157. 1998 99 1434–1440. 1990 713–722. (doi:10.1007/s10147-006- BMC Cancer 177 82 (doi:10.1016/s0140- International Journal International 1585–1592. 33 :1 87–98. (doi:10.1210/ (doi:10.1530/EJE- Journal ofClinical Journal (doi:10.1056/ European 2007 1989 PNAS 2006

7 1989 18 R46 13. 2013

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New via freeaccess

European Journal of Endocrinology 104 103 102 101 100 99 98 97 96 95 94 93 92 91 Review TA.0b013e31818255e8) study. for rapidsequenceinduction:aprospectiverandomized DE. Adrenalsuppressionfollowingasingledoseofetomidate NEJMra0804635) ofMedicine England Journal Metabolism sensitivity inhealthyhumans. Early endotoxemiaincreasesperipheralandhepaticinsulin Endert E,Tanck MW, HP. SerlieMJ,vanderPollT&Sauerwein 75–84. a reviewoftheliterature. JCO.2005.02.4828) ofClinicalOncology Journal advanced gastrointestinalstromaltumors:areportoftwocases. caused byparaneoplasticproductionofIGF-IIinpatientswith A, KnippH,Vanhoefer U&ReichardtP. Severehypoglycemia Hildreth AN,MejiaVA, MaxwellRA,SmithPW, DartBW&Barker Bornstein SR.Predisposingfactorsforadrenalinsufficiency. van derCrabbenSN,BlumerRM,StegengaME,AckermansMT, Mizock BA.Alterationsincarbohydratemetabolismduringstress: Pink D,SchoelerLindnerT, Thuss-PatiencePC,Kretzschmar 1996 hypoglycemia. like growthfactoraxisinachildwithnonisletcelltumor P. Theeffectofgrowthhormonetreatmentontheinsulin- Katz LE,LiuF, BakerB,AgusMS,NunnSE,HintzRL&Cohen 3476(95)70071-4) ofPediatrics Journal in achild:successfullong-termtherapywithgrowthhormone. Cohen P. Non-islet-celltumorassociatedwithhypoglycemia Agus MS,KatzLE,Satin-SmithM,MeadowsAT, HintzRL& Metabolism cell tumorhypoglycemia. proteins byglucocorticoidandgrowthhormoneinnonislet Regulation oftheinsulin-likegrowthfactorsandtheirbinding Baxter RC,HolmanSR,CorbouldA,StranksS,HoPJ&BraundW. 1992 changes inIGFbindingprotein-3. hypoglycaemia bygrowthhormonetherapyisassociatedwith Teale JD,BlumWF&MarksV. Alleviationofnon-isletcelltumour hormone. Treatment oftumour-inducedhypoglycaemiawithhumangrowth Khaleeli A,PerumainarM,SpeddingAV, Teale JD&MarksV. (doi:10.1046/j.1365-2265.1996.721542.x) glucocorticosteroids. imaging andefficacyofoctreotide,growthhormone islet celltumour-associatedhypoglycaemia:111In-octreotide Perros P, SimpsonJ,InnesJA,Teale JD&McKnightJA.Non- 359–361. hypoglycemia. old womanwithrecurrenthypoglycemia:non-isletcelltumour Ma RC,Tong PC,ChanJC,CockramCS&MH.A67-year- Metabolism Reviews Marks V&Teale JD.Tumours producinghypoglycaemia. dia351>3.3.co;2-e) 324–326. disseminated pancreaticcarcinoma. in anoninsulin-dependentdiabetesmellituspatientwith Sturrock ND,SelbyC&HoskingDJ.Spontaneoushypoglycaemia 81 29 Journal ofTraumaJournal (doi:10.1016/S0002-9343(99)80083-7) 1141–1146. 314–323. (doi:10.1503/cmaj.050422) (doi:10.1002/(sici)1096-9136(199704)14:4<324::aid- Journal oftheRoyalSocietyMedicine Journal 2009 1995 Journal ofClinicalEndocrinologyandMetabolism Journal Canadian MedicalAssociationJournal 94 80 (doi:10.1177/000456329202900312) 1995 1991 463–468. 2700–2708. (doi:10.1210/jc.81.3.1141) Clinical Endocrinology 2008 127 7 American Journal ofMedicine American Journal 2005 2009 Journal ofClinicalEndocrinologyand Journal 79–91. 403–407. (doi:10.1210/jc.2008-0761) 65 Journal ofClinicalEndocrinologyand Journal 23 360 (doi:10.1210/jc.80.9.2700) 573–579. (doi:10.1002/dmr.5610070202) Annals ofClinicalBiochemistry N EKittahandAVella 6809–6811. 2328–2339. Diabetic Medicine (doi:10.1016/S0022- 1996 (doi:10.1097/ 1992 (doi:10.1200/ 44 (doi:10.1056/ 727–731. 2005 85 1995 1997 303. Diabetes/ 173 98 14 New

105 Accepted 5April2017 Revised versionreceived15March2017 Received 23December2016 111 110 109 108 107 106 119 118 117 116 115 114 113 112 of hypoglycemia Pathogenesis andmanagement Proceedings a 25-yearexperienceattheMayoClinic. (doi:10.7326/0003-4819-45-1-56) of Addison’s disease. Addison’s diseaseandactivetuberculosis: areviewof125cases (doi:10.1111/j.1365-2265.1994.tb02790.x) disease. (doi:10.1186/cc11674) study.retrospective observational with increasedriskofmortalityinpatientssepsis:a3-year SW &JungKS.Mildhypoglycemiaisindependentlyassociated CCM.0b013e3181de562c) Critical Care Medicine Hypoglycemia isassociatedwithintensivecareunitmortality. Rosendaal FR,ZandstraDF, HoekstraJB&DeVries JH. 0000282073.98414.4B) 2007 patients: riskfactorsandoutcomes. S0025-6196(11)63123-6) 4819-137-2-200207160-00009) Medicine Annals ofInternal 2-252) Medicine Internal insulin. Diagnosis,treatment,andlong-termfollow-up. Factitious hypoglycemiaduetosurreptitiousadministrationof peds.2009-1830) therapy. hypoglycemia: factitioushypoglycemiaduringinsulin-pump 2008 insulin analoguesinfactitioushypoglycemia. 839. child withfactitioushyperglycemia. (doi:10.1530/EJE-14-0824) crisis. 94 insufficiency. (doi:10.1089/dia.2011.0158) Disease). adrenalinsufficiency(Addison’ssystem inpatientswithprimary hypoglycemia identifiedbyacontinuousglucosemonitoring 3553–3559. ofClinicalEndocrinologyandMetabolism Journal studies ofacutecortisolwithdrawalinadrenocorticalfailure. Effects ofcortisoloncarbohydrate,lipid,andproteinmetabolism: Christiansen JS,SchmitzO,Weeke J,JorgensenJO&Moller N. Vella A,NippoldtTB&MorrisJC3rd.Adrenalhemorrhage: Christiansen JJ,DjurhuusCB,GravholtCH,IversenP, Sanford JP&FavourCB.Theinterrelationshipsbetween Kong MF&JeffcoateW. Eighty-sixcasesofAddison’s Park S,KimDG,SuhGY, KangJG,JuYS,LeeYJ,ParkJY, Lee Hermanides J,BosmanRJ,Vriesendorp TM,DotschR, Krinsley JS&GroverA.Severehypoglycemiaincriticallyill Bates DW. Unexpected hypoglycemiainacriticallyillpatient. Grunberger G,Weiner JL,SilvermanR,Taylor S&GordenP. Osipoff JN,SattarN,Garcia M&Wilson TA. Prime-time Neal JM&HanW. Insulinimmunoassaysinthedetectionof Vanelli M.Munchausen’s syndromebyproxyweb-mediated ina Allolio B.Extensiveexpertiseinendocrinology. Adrenal Arlt W. Theapproachtotheadultwithnewlydiagnosedadrenal Meyer G,HackemannA,ReuschJ&BadenhoopK.Nocturnal 1059–1067. (doi:10.1067/mpd.2002.129976) 35 14 European Journal ofEndocrinology European Journal Clinical Endocrinology 2262–2267. 1006–1010. Pediatrics Diabetes Technology andTherapeutics 2001 (doi:10.1210/jc.2007-0445) Journal ofClinicalEndocrinologyandMetabolism Journal (doi:10.1210/jc.2009-0032) 1988 76 2010 161–168. (doi:10.1097/01.CCM. (doi:10.4158/EP.14.8.1006) Annals of Internal Medicine Annals ofInternal 2010 108 125 Downloaded fromBioscientifica.com at09/26/202106:38:39AM 2002 252–257. 38 e1246–e1248. 1994 (doi:10.1016/ 1430–1434. 137 Critical Care 41 Critical Care Medicine 110–116. Journal ofPediatrics Journal (doi:10.7326/0003-4819-108- 757–761. 2015 177 Mayo Clinic (doi:10.1542/

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