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Imaging of β-Cell Mass and Insulitis in Insulin-Dependent (Type 1) Diabetes Mellitus

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Imaging of β-Cell Mass and Insulitis in Insulin-Dependent (Type 1) Diabetes Mellitus
  Imaging of  -Cell Mass and Insulitis inInsulin-Dependent (Type 1) Diabetes Mellitus Valentina Di Gialleonardo, Erik F. J. de Vries, Marco Di Girolamo, Ana M. Quintero, Rudi A. J. O. Dierckx, and Alberto Signore Department of Nuclear Medicine and Molecular Imaging (V.D.G., E.F.J.d.V., R.A.J.O.D., A.S.), University MedicalCenter Groningen, University of Groningen, 9700 AB, Groningen, The Netherlands; Nuclear Medicine Unit (V.D.G.,A.S.) and Radiology (M.D.G.), Faculty of Medicine and Psychology, University “Sapienza,” 00189 Rome, Italy; andDepartment of Radiology (A.M.Q.), Clinica Colsanitas SA 110010000, Bogotà, Colombia Insulin-dependent (type 1) diabetes mellitus is a metabolic disease with a complex multifactorial etiology and apoorly understood pathogenesis. Genetic and environmental factors cause an autoimmune reaction against pan-creatic  -cells,calledinsulitis,confirmedinpancreaticsamplesobtainedatautopsy.Thepossibilitytononinvasivelyquantify   -cell mass  in vivo  would provide important biological insights and facilitate aspects of diagnosis andtherapy,includingfollow-upofisletcelltransplantation.Moreover,theavailabilityofanoninvasivetooltoquantifythe extent and severity of pancreatic insulitis could be useful for understanding the natural history of humaninsulin-dependent(type1)diabetesmellitus,toearlydiagnosechildrenatrisktodevelopovertdiabetes,andtoselectpatients to be treated with immunotherapies aimed at blocking the insulitis and monitoring the efficacy of thesetherapies.Inthisreview,weoutlinetheimagingtechniquescurrentlyavailablefor invivo ,noninvasivedetectionof  -cellmassandinsulitis.Theseimagingtechniquesincludemagneticresonanceimaging,ultrasound,computedtomography,bioluminescence and fluorescence imaging, and the nuclear medicine techniques positron emission tomography andsingle-photon emission computed tomography. Several approaches and radiopharmaceuticals for imaging  -cells andlymphocyticinsulitisarereviewedindetail. ( EndocrineReviews 33:892–919,2012) I.  IntroductionII. RadiologicalTechniquesforImagingBCMandInsulitisA. Magnetic resonance imagingB. UltrasonographyC. Computed tomographyD. Concluding remarks on radiological techniquesfor imaging BCM and insulitisIII. Optical Imaging Techniques for Imaging BCM andInsulitisA. BioluminescenceB. Fluorescence imagingC. Concluding remarks on optical imaging tech-niques for imaging BCM and insulitisIV. Nuclear Medicine Techniques for BCM ImagingA. Imaging  -cellsecretorygranules(Zn 2  -mediatedsecretory vesicle formationB. Imaging ATP-sensitive potassium channelsC. Imaging neurotransmitter targets on   -cellsD. Imaging vesicular monoamine transporters type 2(VMAT)E. Imaging presynaptic vesicular acetylcholinetransportersF. Imaging   -cell metabolic pathwaysG. Imaging GLP-1 receptor (GLP-1R)H. Imaging   -cells with islet cell-specific antibodiesI. Imaging   -cells using radiolabeled peptides J. Concluding remarks on nuclear medicine tech-niques for   -cell imagingV. Nuclear Medicine Techniques for Imaging InsulitisA. Labeled lymphocytesB. Interleukin-2C. Labeled antibodiesD. [ 18 F]FluorodeoxyglucoseE. Concluding remarks on nuclear medicine tech-niques for insulitis imagingVI. General Conclusions I. Introduction T he pancreas is a small elongated organ nestled deeplyin the retroperitoneum between the duodenum,stomach,andspleen.Themajorityofthepancreasismade ISSN Print 0163-769X ISSN Online 1945-7189Printed in U.S.A.Copyright © 2012 by The Endocrine Societydoi: 10.1210/er.2011-1041 Received September 25, 2011. Accepted June 18, 2012.First Published Online August 10, 2012Abbreviations:AADC,Aminoaciddecarboxylase;BCM,  -cellmass;BLI,bioluminescenceimaging; cMORF, complementary MORF; CNS, central nervous system; CT, computedtomography;  L -DOPA,  L -3,4-dihydroxyphenylalanine; DTBZ, dihydrotetrabenazine; DTZ,dithizone;FDG,fluorodeoxyglucose;GFP,greenfluorescentprotein;GLP-1,glucagon-likepeptide receptor subtype 1; GLP-1R, GLP-1 receptor; 5-HTP, 5-hydroxytryptophan; ID,injected dose; MHC, major histocompatibility complex; MIP, mouse insulin promoter; MNP,magnetic nanoparticles; MORF, morpholino oligomer; MRI, magnetic resonance imaging;NOD,nonobesediabetic;PET,positronemissiontomography;SPECT,single-photonemissionCT; SPIO, superparamagnetic iron oxide; sstr2, somatostatin receptor type 2; STZ, streptozo-tocin;SUR,sulfonylureareceptor;T1D,insulin-dependent(type1)diabetesmellitus;THI,tissueharmonic imaging; US, ultrasound; VMAT, vesicular monoamine transporters type 2. R E V I E W 892  edrv.endojournals.org Endocrine Reviews, December 2012, 33(6):892–919 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 June 2014. at 04:40 For personal use only. No other uses without permission. . All rights reserved.  up of exocrine cells. Dispersed within the normal adulthuman exocrine pancreatic tissue, there are approxi-mately 1 million distinct microanatomical structureswith proper portal-like vasculature and innervation.These structures are known as islets of Langerhans andaccount for less than 0.005% of the adult body weight.Endocrine   -,   -,   -, and PP cells are situated withinthese islets. The   -cells are the insulin-producing cellsand account for approximately 70–80% of the cells inthe islets of Langerhans.In addition, a nonexocrine and nonendocrine compo-nent is present that is made up of endothelial cells, para-sympathetic, sympathetic, and sensory nerve cells, andcellsofhematopoieticorigin( e.g. monocytesanddendriticcells).Insulin-dependent (type 1) diabetes mellitus (T1D) is ametabolic disease with complex multifactorial etiologyand a poorly understood pathogenesis. Genetic and envi-ronmental factors may cause an autoimmune reactionagainst pancreatic   -cells. Indirect evidence for autoim-munityinhumanT1Dreliesonthedetectionofinsulitisinautopsy samples (Table 1), on the presence of anti-islet-cellantibodies,onT-cellresponseto  -cellantigens,ontheassociationofdiabeteswitharestrictedsetofclassIImajorhistocompatibilitycomplex(MHC)alleles,andonthefre-quent association with other autoimmune disorders suchas celiac disease, thyroiditis, vitiligo, and rheumatoid ar-thritis (1–3).Examination of islet tissue obtained from pancreaticbiopsies of patients with recent onset T1D confirmedthe presence of insulitis in most, but not all, patients.The presence of infiltrating CD4  and CD8  T lym-phocytes, B lymphocytes, and macrophages suggeststhat an inflammatory process has a role in the destruc-tion of the   -cells (4).The generally accepted model of the natural history of T1Dsuggestsseveraldistinctstagesstartingwithageneticsusceptibility,thenautoimmunitywithoutclinicaldisease,and finally clinical diabetes (1). Nevertheless, other sub-types of T1D have been hypothesized, including the ful-minant T1D, which is accompanied by rapid massive de-struction of    -cells probably as a consequence of a viralinfection (5, 6).Most of the pathogenetic hypotheses rely on studiesperformedintwoanimalmodelsofspontaneousdiabetes:BB/W rats (7–10) and nonobese diabetic (NOD) mice(11–14).In the autoimmune type of T1D, the appearance of autoantibodies is the first sign and precedes severalmonthsoryearsof   -celldestruction,followedbythelossof the first-phase insulin response to the iv glucose toler-ance test. The progression to overt diabetes resulting insignificant   -cell destruction is triggered by the develop-mentofamoreaggressiveT-cellinfiltrationandachangein the T-helper lymphocyte 1, T-helper lymphocyte-2(Th1/Th2)balancetowardamoreproinflammatorystate(Table 1) (4). When clinical symptoms start, the autoim-mune process is already markedly advanced. The   -celldestruction rate, however, is variable, being generallymore rapid in children than in adults (15). The exactamount of living and functional   -cells at the onset of clinical symptoms is still unknown because of the lack of an accurate method to quantify functional   -cell mass(BCM) in humans (16). However, some reports suggestthat at the time of diagnosis, as much as 60–80% of theBCM can already be dead or dysfunctional.It therefore emerges that: 1) the availability of a non-invasive tool to quantify the extent and the severity of pancreatic insulitis could be useful to understand the re-lationship between the autoimmune phenomena and theprogressiontowarddiseaseonset(17),forearlydiagnosisof children at risk to develop overt T1D and to select pa-tientstobetreatedwithimmunetherapiesaimedatblock-ingtheinsulitisprocess,andfinally,tomonitortheefficacyof these therapies; and 2) the possibility to quantify BCMchanges during the early progression of diabetes wouldalso provide important biological insights and facilitateaspectsofdiagnosisandtherapy,includingisletcelltrans-plantation (18).Because of the high clinical relevance of studying insu-litisandBCM in vivo ,alotofefforthasbeenputintothisresearchfield.Despitethat,theidealimagingtoolhasnotbeendevelopedyet,whichismainlyduetothreeproblems:1) the pancreas is not easily accessible by biopsy, thushampering histological approaches; 2) the islets of Lang-erhans represent only 2–3% of pancreatic tissue and arespread throughout the pancreatic parenchyma, althoughmore abundant in the pancreatic tail (19, 20); and 3) in- sulitis is a chronic asymptomatic process of unknown ex-tent in the prediabetes stage in humans.Whensuitablenoninvasiveimagingtechniquesbecomeavailable,high-riskindividualscouldbemonitoredbeforeonset of diabetes and over the course of their disease todetermine the natural history of the disease and the re-sponse to therapy (18).Structural (anatomical) imaging techniques [magneticresonance imaging (MRI) and computed tomography(CT)] using specific contrast agents could theoreticallyachievetheresolutionneededtoimageBCMandinsulitis(21). However, until now, it has not been possible to pre-cisely quantify BCM and insulitis with these diagnosticimagingtechniques.Themajorproblemsare:1)thesmallsize of the islet and the scattered location in the wholepancreas; 2) the small inflammatory lesion during the in- Endocrine Reviews, December 2012, 33(6):892–919 edrv.endojournals.org  893 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 June 2014. at 04:40 For personal use only. No other uses without permission. . All rights reserved.  TABLE 1.  Presence of insulitis and   -cells at T1D onset Patients (n) Sex (n)Age atdiagnosis (yr)Durationof disease InsulitisOthermarkersRemaining  -cells Ref. 4 M (1), F (1)   1 1 wk    ? 186M (1)   10   1 wk   M (1) 17   3 wk   4/4 (100%)21 M (2), F (1)   1   15 d    ? 149M (1)   1 3 months   M (2), F (2)   3   2 months   M (2), F (1) 6–13   1 month   F (2) 15   3 months   M (1), F (3) 16 4 d   M (1) 17 1 d   M (2), F (1) 20–30   14 d   11/21 (52%)11 M (2), F (1)   3   4 wk     187F (1)   10   8 wk    DegranulatedF (1) 11   8 wk   F (1)   15 1 wk   F (1) 17   3 wk   M (3) 25–30 1 wk   M (1) 31 1 wk   6/11 (54%)9 M (2) 2   8 wk   (1),  (1)    188M (2) 3   4 wk    F (1) 4 6 wk    F (1) 5 12 wk    M (1) 8 8 wk    M (1) 11 2 wk    F (1) 12 3 wk    8/9 (89%) 9/9 (100%)1 F (1) 12 1 month    HLA–I hyper, CD8    1471/1 (100%)47 M (11), F (15)   10   9 months    HLA–I hyper, HLA–DR    147, 148M (5), F (8)   10–15   6 months    M (4), F (4) 16–19   6 months    47/47 (100%) 47/47 (100%)18 M (3), F (3)   3   3 months    ? 147, 189 a M (1) 5   M (2), F (1) 6–8   M (2) 10–11   F (2) 12–14   M (1) 16   M (3) 17–21   19/19 (100%)1 M (1) 22 2 d    Increase of small lymphocytesand decrease of eosinophils   /    1901/1 (50%)7 M (4) F (3)   24   4 months    HLA–DR hyper 4/7 (57%) 191 a 88 ? 1–37   2 wk     19288/88 (100%) 84/88 (95%)18 M (11) F (7)   18   7 wk    CD8  ,  CD4  , HLA–I hyper    /    193 a 8/18 (44%)1 M (1) 19   1 wk    HLA–I hyper,  CD8  ? 1941/1 (100%)2 F (1)   1   1 month    ? 195M (1) 3   1 wk   2/2 (100%)17 M (11) F (6)   18   1 month    HLA–I hyper ? 196 a 8/17 (47%)( Continued  ) 894  Di Gialleonardo  et al.  Insulitis and   -Cell Imaging Endocrine Reviews, December 2012, 33(6):892–919 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 June 2014. at 04:40 For personal use only. No other uses without permission. . All rights reserved.  sulitisprocess;and3)thelackofinformationabout  -cellfunctionality and immune cell activity.However,recentadvancesinnoninvasiveimagingtech-niquessuchasmolecularstudiesappliedtoMRI,positronemissiontomography(PET),andopticalimagingindicatethat there could be a role for diagnostic imaging in theevaluationof   -cellnumber,mass,andfunctionandlym-phocyte infiltration/inflammatory activity in T1D (22).Withthecurrentfunctionalimagingmethodology,thesin-gle islet cannot be spatially resolved. Therefore, the isletcells or the islet-infiltrating lymphocytes must be chemi-callyresolvedwithaspecificprobethathashighspecificityfor target combined with a low background signal. Thus,the target should retain the labeled probe at least 1000-fold more avidly than the surrounding exocrine cells, re-sultinginsufficientcontrastbetweentheexocrineanden-docrine pancreas (23). In addition, the probe should bemetabolicallystableincirculationandshowsuitablephar-macokinetic properties. Combined structural and func-tional imaging might be a suitable approach to overcomethe weaknesses of each individual technique. There is avast amount of literature concerning BCM and insulitisimaging. In this review, we will outline the imaging tech-niques currently available for  in vivo , noninvasive inves-tigation of BCM and insulitis. II. Radiological Techniques for Imaging BCMand Insulitis Considering its anatomic location, the propensity for au-tolytic damage, and the distribution of islets within theexocrine tissue, pancreatic biopsies to quantify the BCMand/or detect the insulitis are not easily performed. Diag-nosticimagingoftheendocrinepancreasisalsoproblem-aticmainlyforthedifficultiestodetectisletsofLangerhansinthepancreaticparenchyma.TheradiologicalmodalitiesforpancreaticimagingincludeMRI,ultrasound(US),andCT (21). A. Magnetic resonance imaging MRI is a noninvasive approach that offers high spatialresolution, especially in comparison with nuclear medi-cine techniques and high intrinsic contrast  in vivo . It is apromisingtechniqueforisletimagingbecauseitcantargetpossible   -cell-specific components, using various mech-anisms for contrast enhancement and achieving high-res-olution images (24) with prolonged visualization of thelabeledcells.Infact,theMRIcontrastagentsdonothavetheproblemsrelatedtotheuseofradionuclides(decayandshort half-life) and may allow imaging over a long periodoftime.Althoughitremainstobedeterminedwhetherthesensitivity and applicability of MRI are sufficient for hu-man clinical applications, MRI has showed very promis-ing results in animal models in the study of insulitis, pan-creatic BCM, and islet transplantation.Early biomarkers of pancreatic insulitis that can be in-vestigatedbyMRIaretheisletmicrovasculardysfunctionand the alteration in vascular volume, flow, and permea-bility, as described in several models of T1D.Usingaparamagneticcontrastagent,gadoliniumdiethylenetriaminepentaaceticacid-fluorinated(PCG-GdDTPA-F),withhigh plasma half-life, detectable on T1-weighted MR ac-quisition, it was possible to evaluate  in vivo  vascularchangesinastreptozotocin-inducedmousemodelofT1D,demonstratingasignificantlyhigheraccumulationofgad-olinium diethylene triamine pentaacetic acid-fluorinatedinthepancreasofdiabeticanimalscomparedwithnormalanimals (25).Aspecificmagneticnanoparticle(MNP)[monocrystal-line iron oxide nanoparticles (MION-47)] for MRI hasbeen proposed to identify and quantify the vascular vol-umeandpermeabilitychangesassociatedwithinflamma-tion of the pancreas during the development of autoim- TABLE 1.  Continued Patients (n) Sex (n)Age atdiagnosis (yr)Durationof disease InsulitisOthermarkersRemaining  -cells Ref. 1 F (1) 65   1 yr    DR4,  CD4  ,  CD8  ? 197 a 1/1 (100%)29 ? Mean 28 yr 3 months    CD8  , aberrant HLA–I ? 198 a 17/29 (58%)2 ? Children Acute onset    CD45R  , CD56  , CD3  ? 1992/2 (100%)Summary277 M  F 0–37 (one of 65 yr) 0–1 yr 223/270 (82.6%) HLA–I, HLA–II, CD3, CD4,CD8, CD45, CD56144/151 (95.4%) 17 papers F, Female; M, male; HLA-I, human leukocyte antigen class I; HLA-II, human leukocyte antigen class II; HLA-DR, human leukocyte antigen class DR; CD, clusterdifferentiation antigens; hyper, hyper-expression. a Detected by biopsy. Endocrine Reviews, December 2012, 33(6):892–919 edrv.endojournals.org  895 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 June 2014. at 04:40 For personal use only. No other uses without permission. . All rights reserved.  mune diabetes in rodents (NOD/Lt, E  16/NOD, andBDC2.5/NOD mice). This method relies on the measure-mentofthemicrovascularchangesassociatedwithinflam-mation, and it is not hampered by the variations in MHCalleles or autoreactive T-cell specificities that limit otherexperimental approaches (26). The pancreatic inflamma-tion can also be detected using long-circulating phago-tropic nanoparticles that extravasate from the leaky ves-sels into the surrounding tissue and are engulfed byinfiltratinginflammatorycells,particularlymacrophages.Because MNP are superparamagnetic and thus negativeT2-weighted contrast agents, signal changes of pancre-atic parenchyma (reduction of signal intensity) on T2-weighted scans as a surrogate for vascular leak/macro-phage uptake were used. Improvement of this approachhas been done using nanoparticles with a superparamag-neticironoxide(SPIO)corecoatedwithdextran(27).Thismodification can reduce immunogenicity of the particlesand increase blood resident time. A potential applicationof this imaging technique is monitoring acute changes inpancreatic inflammation in patients who have previouslyundergoneinterventiontrialstotreatorpreventT1D(26).The second approach to monitor changes during theprogression of diabetes is to follow  ex vivo  lymphocyticaccumulationinthepancreas.Trackinglabeledautoreac-tive T lymphocytes was used to detect  in vivo  chronicmononuclearcellinfiltrationintothepancreasduringtheprediabeticphase.Thisapproachisbasedontheintracel-lular labeling of lymphocytes with superparamagneticcontrast agents (dextran magnetic particles), which aretaken up by the cells by membrane diffusion. To increasethe uptake of nanoparticles inside the cells, the nanopar-ticles can be modified to increase their hydrophobicity orcan be encapsulated into liposomes (28).Dextran-coated SPIO nanoparticles coupled withpeptides encoding for the membrane translocation sig-nal of HIV-1 (CLIO-Tat) were used to label lympho-cytes with an efficacy of internalization that was 100times higher than normal particles. After 30-min incu-bation, the nanoparticles have not only entered the cellbut were also bound to the nucleus and nucleolus (nu-clear accumulation) (29, 30).Therefore,CD8  lymphocyteslabeledwiththesenano-particles were used to track the immune cells in animalmodels of T1D. After adoptive transfer of nanoparticle-labeledTcellsintotherecipientanimal(NOD,Scidmice),it was possible to visualize the labeled T lymphocytes in-filtrating the pancreas by the signal intensity decrease inthe pancreatic parenchyma on T2-weighted images. ThedecreaseofpancreaticparenchymasignalonT2-weightedimages due to lymphocytic infiltration was not present incontrol animals without insulitis. To improve these re-sults, specific subpopulations of diabetogenic lympho-cyteswereisolatedfromtransgenicNODmiceandloadedwithCLIO-NRP-V7-coatedsuperparamagneticnanopar-ticles.TheseparticlesspecificallybindtoT-cellreceptor  on NRP-V7-reactive CD8  T cells. The labeled lympho-cytesallowedthevisualizationinrealtimeoftheprogres-sive accumulation of NRP-V7-reactive CD8  T cells intothe pancreas of NOD mice (31). The target of this lym-phocyte subpopulation is the islet glucose-6-phosphatasecatalytic subunit-related protein, and consequently, thisselectedpopulationoflymphocytesshouldselectivelymi-grate into the pancreas. Because islet glucose-6-phospha-tasecatalyticsubunit-relatedproteinisalsopresentinthehuman islets, this approach might allow translation of results to human imaging.Thereisonlyonerecentreportinhumansthatdescribesthe use of MNP as a contrast agent for MRI in T1D toimage insulitis. Gaglia  et al.  (32) evaluated 10 patientswith T1D and 12 nondiabetic controls. They used MRIMNP previously validated in mouse models, ferumox-tran-10, which has a dextran coating and size similar tothose used in animal experiments. These particles aretakenupbymacrophagesanddonotinducecellactivationor proinflammatory cytokine or superoxide anion pro-duction. MRI can detect MNP that migrate from theleakyvesselsintothesurroundingtissue(extravasation)and are phagocytized by inflammatory cells, particu-larly by macrophages. MNP are negative T2-weightedcontrastagentsbecausetheyinducechangesinT2signalof pancreatic parenchyma (reduction of signal inten-sity) as a surrogate parameter for measuring vascularleak and macrophage content. The results of the studyby Gaglia  et al.  (32) showed that T1D patients at thetimeofdiagnosisalreadyhaveareducedpancreaticvol-umecomparedwithcontrolsandshowedheterogeneityin MNP accumulation. Although not testable in thissmall study, one could speculate that such differencesreflect heterogeneity in the insulitis process itself.Therefore, this technique requires further developmentto determine its sensitivity and specificity (32).Most MRI studies have been performed for imagingBCM and transplanted islets in animal models of T1D.Gimi et al. (33)usedmanganese(Mn),acontrastagentforMRIwithT1-relaxationproperties,asatooltoimage invitro  -cellfunctionalityincellculturesofisolatedislets.Similartocalcium,extracellularMnwastakenupbyglu-cose-activated  -cells,resultingina200%increaseinMRIcontrast enhancement  vs.  nonactivated cells. This scien-tificworkcanbeconsideredthefirstmolecularMRIstudyfor   -cell imaging. After this study, several other ap-proaches were tested. 896  Di Gialleonardo  et al.  Insulitis and   -Cell Imaging Endocrine Reviews, December 2012, 33(6):892–919 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 June 2014. at 04:40 For personal use only. No other uses without permission. . All rights reserved.
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