Adult-Onset Autoimmune Diabetes inEurope Is PrevalentWith aBroad ClinicalPhenotypeAction LADA 7

MOHAMMED I. HAWA, PHD1

HUBERT KOLB, MD2

NANETTE SCHLOOT, MD2

HURIYA BEYAN, PHD1

STAVROULA A. PASCHOU, PHD, MD1

RAFFAELLA BUZZETTI, MD3

DIDAC MAURICIO, MD4

ALBERTO DE LEIVA, MD4

KNUD YDERSTRAEDE, MD5

HENNING BECK-NEILSEN, MD5

JAAKKO TUOMILEHTO, MD6

CINZIA SARTI, MD6

CHARLES THIVOLET, MD7

DAVID HADDEN, MD8

STEVEN HUNTER, MD8

GUNTRAM SCHERNTHANER, MD9

WERNER A. SCHERBAUM, MD2

RHYS WILLIAMS, MD10

SINEAD BROPHY, MD10

PAOLO POZZILLI, MD1,11

RICHARD DAVID LESLIE, MD1

ON BEHALF OF THE ACTION LADACONSORTIUM*

OBJECTIVEdSpecific autoantibodies characterize type 1 diabetes in childhood but are alsofound in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent auto-immune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes.

RESEARCH DESIGN AND METHODSdWe consecutively studied 6,156 Europeandiabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) exam-ined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A).

RESULTSdOf 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8Aalone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, oninsulin (49.5 vs. 13.2%), and female (P, 0.0001 for each), though LADA patients (9.7% of total)did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes.Similarly, more GADA patients with high (.200 World Health Organization IU) (n = 403)compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%)(P , 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%)and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3).

CONCLUSIONSdAdult-onset autoimmune diabetes emerges as a prevalent form of autoim-mune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompassestype 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. Atdiagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring andclinically indistinguishable from patients with type 2 diabetes, though they tend to be younger andleaner.Onlywith screening for autoantibodies, especiallyGADA, can they be identifiedwith certainty.

Diabetes Care 36:908–913, 2013

Type 1 diabetes is an autoimmunedisease in which insulin deficiencyresults from immune-mediated de-

struction of insulin-secreting islet cells(1). Type 1 diabetes was formerly calledinsulin-dependent diabetes, reflecting theseverity of the destructive process and therequirement for insulin therapy in all ca-ses. The majority of patients with type 1diabetes have autoantibodies in their pe-ripheral blood, and these autoantibodiescan predict the future onset of the disease(1). Autoimmune diabetes is character-ized by specific autoantibodies such asGAD autoantibodies (GADA), insuli-noma-associated antigen-2 autoanti-bodies (IA-2A) or zinc-transporter 8autoantibodies (ZnT8A). Type 1 diabetesis the most prevalent form of diabetes inchildren but also occurs in adults (1). Aproportion of patients with adult-onsetinitially non–insulin-requiring diabeteshave diabetes-associated autoantibodiesand are thought to have a form of auto-immune diabetes called latent autoim-mune diabetes of adult onset (LADA)(2,3). Descriptions of the proportions ofLADA patients in clinical case series vary,in part through selection biases such asascertainment of nonobese cases (4), in-sulin-naïve cases (5), or treatment-naïvecases (6) or the inclusion of impaired glu-cose tolerance (7). These studies have es-tablished that patients with autoimmunediabetes, as characterized by the presenceof GADAs, have a clinical phenotype dis-tinct from initially non–insulin-requiringdiabetic patients without GADAs whoare mostly designated as type 2 diabetic(1–9). There are no studies of the relativefrequency of type 1 diabetes and LADA inadults.

The key uncertainty regarding adult-onset diabetic patients is whether LADA isdistinct from type 1 diabetes or morecommon (10,11). Furthermore, it is as yetunclear which factors are associated withprogression toward insulin therapy inadult-onset autoimmune diabetes. ActionLADA is a European study that seeks toaddress these questions by ascertaining

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From the 1Blizard Institute, QueenMary University of London, London, U.K.; the 2Heinrich-Heine UniversityD€usseldorf, D€usseldorf, Germany; the 3University “La Sapienza,” Rome, Italy; the 4Hospital de Sant Pau,Barcelona, Spain; the 5Odense University Hospital, Odense, Denmark; the 6National Institute for Health andWelfare, Helsinki, Finland; the 7Hospital EdouardHerriot, Lyon, France; the 8Royal Victoria Hospital, Belfast,U.K.; the 9RudolfstiftungHospital, Vienna, Austria; 10SwanseaUniversity, Swansea, U.K.; and the 11UniversityCampus Bio-Medico, Rome, Italy.

Corresponding author: Richard David Leslie, r.d.g.leslie@qmul.ac.uk.Received 14 May 2012 and accepted 18 September 2012.DOI: 10.2337/dc12-0931This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10

.2337/dc12-0931/-/DC1.A slide set summarizing this article is available online.*A full list of the members of the Action LADA consortium can be found in the APPENDIX.© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and thework is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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E p i d e m i o l o g y / H e a l t h S e r v i c e s R e s e a r c hO R I G I N A L A R T I C L E

adult-onset diabetic patients presentingto nine European hospital-based clinics(some recruiting from a community ofprimary care settings; see below)within a defined period.We hypothesizedthat autoimmune diabetes would be prev-alent in Europe, that LADA would bemore prevalent than type 1 diabetes,and that these two would show pheno-typic differences. Furthermore, we pre-dicted that GADA could detect mostcases of autoimmune diabetes.

RESEARCH DESIGN ANDMETHODSdThe study design iscross-sectional and includes adult-onsetdiabetic patients, recruited between 2004and 2007, from nine European countries:Finland, Odense (Denmark), Vienna(Austria), Belfast (Northern Ireland),D€usseldorf (Germany), London (U.K.),Lyon (France), Rome (Italy), and Barcelona(Spain). Each center is involved in ActionLADA, a European Union–funded multi-center European study with the aim ofidentifying risk factors for adult-onset au-toimmune diabetes (www.actionlada.org). All centers recruited patients (aged30–70 years, with primary diabetes, anddiagnosed within the past 5 years). Fourrecruited from a community or primarycare setting (Helsinki, D€usseldorf, Rome,and Odense). The remaining five centers(Vienna, London, Belfast, Rome, Barce-lona, and Lyon) recruited patients in ahospital setting.

Patients were designated with diabe-tes according to standard criteria, andLADA was defined as follows: patients1) aged 30–70 years, 2) with diabetes-associated autoantibodies, and 3) whodid not require insulin treatment for atleast 6 months postdiagnosis (12). Type1 autoimmune diabetic patients were de-fined as case subjects with diabetes andwith diabetes-associated autoantibodiesin whom insulin was started at diagnosisor within 1 month of diagnosis. Inclusioncriteria for all patients were that patientshave diabetes (with at least two recordedfasting blood glucose measurements $7mmol/L) (12), that time from diagnosiswas,5 years for all patients, and that pa-tients were aged 30–70 years at the time ofrecruitment. Exclusion criteria were insuf-ficient dataset, current pregnancy, renaldisease with raised creatinine or protein-uria, or acute illness at the time of testing.Data on medication and risk factors wereregistered by the attending physicianbased upon the medical files. Serum andplasma samples were collected according

to standard procedures and stored at2208C.

Waist and hip circumferences weremeasured in a standardized procedure,and blood pressure was recorded locallyfor each subject. Blood pressure wasmeasured at least twice in the sittingpositions. Lipids and lipoproteins (serumtotal and HDL cholesterol and triglycer-ides) were determined by standardizedassays at each center.

All patients were tested in a centrallaboratory (London) for serum GADA,IA-2A, and ZnT8A using established ra-dioimmunoprecipitation assays (13,14).Positive results were duplicated, reducingfalse positives to ,0.2%. In the 2003 Di-abetes Antibody Standardization Program(DASP 2003) (London), assay character-istics were GADA sensitivity 72%, speci-ficity 95%, and IA-2A sensitivity 68%,specificity 98% (15). In the latest DASPprogram (DASP 2010), GADA sensitivitywas 90% and specificity 93%, IA-2A sen-sitivity 68% and specificity 95%, andZnT8A sensitivity 60% and specificity88% (M.I.H. and R.D.L., unpublisheddata). The pJH4z1 probe for ZnT8A wasprovided by Dr. J. Hutton (University ofColorado, Denver, CO) and is a syntheticmolecule that combines cytoplasmicZnT8 COOH-terminal domains with animmunoglobulin Cg3 hinge sequencein a single-chain construct. It accountsfor a ZnT8 dimer containing the proteinepitopes 325Trp and 325Arg.

Each assay included serially dilutedsera from a prediabetic individual; thesein-house standards were diluted to an endpoint. A separate positive serum sample(equivalent to the World Health Organi-zation [WHO] standard of 250 WHOunits) was used as an in-house control tostandardize each assay for unit calcula-tion. The cutoff for positivity was selectedarbitrarily based on the end point of thestandard curve and further confirmedwith Quantile-Quantile (Q-Q) probabil-ity plots.

Statistical analysisData are presented, where appropriate, asmeans SD, interquartile range, or oddsratios (ORs) (95% CI). The differencesbetween groups were tested with x2 testor Fisher exact test when appropriate. Alogistic regression analysis was performedto evaluate confounding by covariables,with adjustment for sex, age of onset, dis-ease duration, and ethnicity to calculateORs. All analyses were performed usingSPSS statistical software for Windows.

AP value,0.05was considered statisticallysignificant. Q-Q probability plots wereused to analyze the distribution of auto-antibody measurements for normality.Observed antibody values were plottedalong the horizontal axis against expectednormal values under normality on thevertical axis using Blom proportion esti-mation formula. The study protocol is inaccordance with the Declaration of Hel-sinki and was approved by local ethicscommittees in each study area. Informedwritten consent was obtained from allsubjects before blood sampling. Thestudy was approved by the U.K. NationalResearch Ethics Committee (reference no.P/02/240).

RESULTS

Diabetes autoantibody prevalenceand demographicsA total of 6,810 patients were screened fordiabetes-associated autoantibodies fromthe samples received from the ActionLADA cohort. Of these, 654 subjectswere misclassified, owing to inappropri-ate age or disease duration, and wereexcluded. Of 6,156 subjects fulfilling theinclusion criteria, 84.6% were Caucasian,2.5% Asian, 1.2% African, 4.5% of theMiddle East, and 7.2% of other origins.Overall mean (SD) age was 54.4 (9.6)years, mean duration of diabetes was 2.2(1.6) years, and 58.5% were male. Ofthese 6,156 patients, 598 (9.7%) werepositive for at least one autoantibody(Table 1). Of these, 68.6% were positivefor GADA only, 5.0% positive for IA-2Aonly, and 2.3% positive for ZnT8A only(Fig. 1). At least two autoantibody typeswere found in 144 (24.1%) patients. Thedetermination of IA-2A and ZnT8A, inaddition to GADA, modestly improvedthe recognition of autoimmune diabetesfrom 8.8 to 9.7% of the total study group.Within the entire cohort of patients withautoimmune diabetes, 541 of 598(90.5%) were positive for GADA.

The demographics of the autoanti-body-positive and -negative patients areshown in Table 1. GADA-positive pa-tients in hospital-based clinics (10.0%)were more prevalent than among thecommunity-based patients (7.8%) (P ,0.0001) (Supplementary Table 1). Auto-antibody-positive patients comparedwith autoantibody-negative patientshad a significantly lower mean age of on-set (P , 0.001) (Table 1). Analysis of BMIwas corrected for age of onset, sex, and du-ration of disease, and other analyses were

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corrected for age of onset, sex, duration ofdisease, and BMI.Of autoantibody-positivecompared with autoantibody-negative pa-tients after this correction, mean age, ageof onset, BMI, waist-to-hip ratio (WHR),waist circumference, and systolic blood

pressure were significantly lower (P ,0.001), while HDL cholesterol was higher(P, 0.001) (Table 1). No differences wereseen in LDL cholesterol values (Table 1).More autoantibody-positive patientswere receiving insulin at the time of

examination (49.5% compared with13.2% autoantibody-negative patients;P , 0.001); the proportion was similarin hospital-based and community-basedclinics (45.5 and 51.4%, respectively)(Supplementary Table 1).

Diabetes phenotype by number ofautoantibodiesPatients positive for at least two autoanti-bodies compared with those positive for asingle antibody did not show relevantdifferences in any demographic or clinicalparameters (data not shown). Moreover,patients with an autoantibody other thanGADA or with low-titer GADA wereleaner and more likely to be insulintreated than autoantibody-negative pa-tients (Supplementary Table 2 and Sup-plementary Table 3).

Diabetes phenotypes by GADA titerTo further define autoantibody positivity,for autoantibody titers on the whole co-hort we used the Q-Q plot analysis, and alaboratory cutoff set at 70 WHO unitsfrom the standard curves was confirmed,with a further inflection at 200 WHOunits indicating high-titer GADA (Sup-plementary Fig. 1). Patients with high-titer GADA (n = 403), in contrast tolow-titer GADA (n = 138), were morelikely to be female and younger, havelower BMI (P, 0.01 for all comparisons),and lower serum triglycerides (P ,0.001), andmore often be on insulin treat-ment (54.6 vs. 39.7%; P = 0.005) (Table2). Compared with GADA-negative pa-tients, high–GADA titer patients hadlower waist circumference and WHR aswell as higher HDL cholesterol, and morepatients were insulin treated (P, 0.001 forall comparisons) (Tables 1 and 2). Com-pared with GADA-negative patients, thelow–GADA titer group also had lowerwaist circumference, WHR, and BMI(P , 0.01 for all comparisons), as well ashigher LDL cholesterol (P = 0.02), andmore patients were insulin treated (P ,0.001) (Supplementary Table 3). Amongall GADA-positive patients, GADA titerwas directly correlated with age at diagno-sis (r = 0.129, P = 0.010) and inverselycorrelated with WHR (r = 20.103, P =0.047) but not BMI (r =20.054, P = 0.24).

Comparative features of adult-onsettype 1 diabetes and LADAOf 598 patients positive for at least oneautoantibody (GADA, IA-2A, or ZnT8A),279 were on insulin; of these 279 insulin-treated autoantibody-positive patients,

Figure 1dVenn diagram of numbers of patients with GADA, IA-2A, or ZnT8A; n = 598 of 6,156(9.8%). Of the autoantibody-positive samples, GADA was identified in 90% of the samples whenan autoantibody was detected, with IA-2A and ZnT8A accounting for the remaining 10% of theautoantibodies detected. GADA, n = 541 (8.8%); IA-2A, n = 144 (2.3%); and ZnT8A, n = 110 (1.8%).

Table 1dFeatures of any autoantibody-positive (GADA, IA-2A, or ZnT8A) versusautoantibody-negative patients

Autoantibody positive Autoantibody negative P

Cases 598 5,558Females, n (%)* 299 (50.0) 2,260 (40.7)

,0.001Males, n (%) 294 (49.0) 3,298 (59.3)Age (years) 49.6 (10.7) 54.9 (9.4) ,0.001Age at onset (years) 47.4 (11.7) 52.5 (10.6) ,0.001Duration of disease (years) 2.2 (1.6) 2.3 (1.6) .0.50BMI (kg/m2) 27.2 (6.2) 30.9 (6.5) ,0.001Subjects on insulin 279/564 (49.5) 728/5,508 (13.2) ,0.001Time to insulin (years) 0.61 (1.03) 0.87 (1.4) 0.180WHR 0.90 (0.1) 0.95 (0.09) ,0.001Waist circumference (cm) 93.7 (16.1) 103.8 (14.6) ,0.001HDL cholesterol (mmol/L) 1.44 (0.4) 1.29 (0. 39) ,0.001LDL cholesterol (mmol/L) 2.05 (0.95) 1.60 (0.82) .0.50Systolic BP (mmHg) 116.6 (29.1) 122 (31.0) ,0.001TGL (mmol/L) 1.5 (1.4) 1.97 (1.5) ,0.001

Data are n,means (SD), or n/n (%) unless otherwise indicated.More autoantibody-positive patientswere receivinginsulin (49.5 vs. 13.2% autoantibody-negative patients; P, 0.001), younger (49.6 vs. 54.9 years old), and leaner(27.2 vs. 30.9 kg/m2). BP, blood pressure; TGL, triglyceride. *Information for sex was missing in five auto-antibody cases.

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information on precise time to insulintherapy was available for 203, of whom114 (56.2%) were designated as type 1diabetic (started insulin at diagnosis andall autoantibody positive), 65 (32.0%)were classified as LADA (free of insulinfor .6 months from diagnosis and auto-antibody positive), and 24 (11.8%) wereintermediate (started insulin within 6months but after 1 month from diagnosisand autoantibody positive).

LADA was more prevalent than clas-sic autoimmune type 1 diabetes (OR 3.3).Of autoantibody-positive patients, thoseclassified as type 1 diabetic comparedwith LADA were younger and had a lowerage of onset, BMI, waist circumference,andWHR (P, 0.001 for all comparisons)but higher LDL cholesterol (P = 0.013),whereas the number of patients with highGADA titer did not differ between thegroups (80 vs. 79%) (Table 3).

CONCLUSIONSdThese observa-tions show that adult-onset autoimmunediabetes is not rare, as it was reported in9.7% of this large cohort of adult-onsetdiabetic patients diagnosed between 30and 70 years of age attending primary andsecondary care European centers. Similarstudies have been much smaller withmarked selection bias, usually ascer-taining only patients with non–insulin-requiring diabetes (2–9). Nevertheless,several of these studies also found that~10% (range 5–15) of patients with adult-onset diabetes have diabetes-associatedautoantibodies, notably GADA (2–9).This present study is the largest to dateand benefits from an analysis of all case

subjects attending these clinics, irrespectiveof clinical features, as well as screening forthree major diabetes-associated autoanti-bodies. Insulin autoantibodies, a featureof childhood-onset diabetes, were not in-cluded in our screening program, as wewere studying adults. The proportion ofcase subjects classified with type 1 diabetesis probably exaggerated, as clinicians whohad access to a local GADA assay result areknown to start insulin if the patient isGADA positive (16). GADA were by farthe most prevalent diabetes-associated au-toantibodies, with only a small additionalfraction of patients having other autoanti-bodies. Thus, the projected shortfall ofascertainment of adult-onset autoimmunediabetes using GADA alone would besmall.

We show for the first time that inadult-onset diabetes, LADA is more fre-quent than adult-onset autoimmune type1 diabetes, but the two together do notaccount for all cases of adult-onset auto-immune diabetes, as some patients prog-ress to insulin therapy between diagnosisand 6 months postdiagnosis. Other stud-ies, unlike this present analysis, failed toeliminate the potential error resultingfrom limited autoantibody specificity,which we did by testing for all autoanti-bodies twice to limit false positive results.A potential bias in our study is the use ofhospital-based clinics in five of nine set-tings, since patients with autoimmunediabetes are more likely to be ascertainedin such clinics given their greater risk ofinsulin treatment. Such a bias wouldincrease the relative proportion of caseswith autoantibodies and, specifically, the

proportion with type 1 diabetes com-pared with LADAda bias evident for theformer but not the latter. That former biaswould not influence the characteristics ofautoantibody-positive versus autoantibody-negative patients butmight further exagger-ate the number of apparent cases of type 1diabetes (16,17). The inclusion of patientsup to 4 years postdiagnosis might have ledto an underestimation of LADA cases be-cause autoantibodies might become nega-tive with time. Variation in ascertainmentthrough hospital-based or primary care–based clinics around Europe precludesanalysis of differential frequencies of auto-immune diabetes within Europe. Despitethese potential biases, there was a strikingexcess of LADA compared with type 1 di-abetes, implying that the typical presenta-tion of adult-onset autoimmune diabetesis as non–insulin-requiring diabetes, withneither LADA nor type 1 diabetes, as de-fined, capturing all adult-onset autoim-mune diabetes cases.

Patients with autoimmune diabetes inthis large cohort, compared with the re-maining autoantibody-negative diabeticpatients, tended to more often be female,younger at diagnosis, leaner, and subse-quently more likely to be on insulintreatment with metabolic changes includ-ing higher HDL cholesterol and lowertriglycerides. These differences werenoted irrespective of the number of au-toantibodies or presence or absence ofGADAs. Importantly, patients with auto-antibodies other than GADA were alsoleaner and more likely to be on insulintreatment, consistent with them having adisease process similar to that of theGADA-positive patients. Among patientswith autoimmune diabetes, those withtype 1 diabetes, compared with the re-mainder, also tended to be female, youn-ger at diagnosis, leaner, and by definition,on insulin treatment, with lower trigly-cerides. Moreover, there was a strikingmale excess in autoantibody-negativetype 2 diabetes cases, which was less ap-parent here in adult-onset autoimmunetype 1 diabetes cases (51.8% male) butstill in line with the known male excess inthat group (18). Apart from detection ofdiabetes-associated autoantibodies, therewere no categorical features that couldclinically distinguish adult-onset autoim-mune diabetes from type 2 diabetes. Weidentified at least two modes within theGADA-positive patientsdone modewith a cutoff of 70 WHO IU (low GADAtiter) and another at 200 WHO IU (highGADA titer)dthough it should be noted

Table 2dFeatures of GADA high- versus GADA low-titer patients

GADA high GADA low P

Cases 403 138Females, n (%) 220 (54.4) 59 (42.8)Males, n (%) 180 (44.6) 78 (56.5) 0.02Age (years) 49.3 (10.7) 50.2 (10.9) 0.09Age at onset (years) 47.0 (14.0) 47.6 (10.8) 0.08Duration of disease (years) 2.14 (1.6) 2.46 (1.7) 0.07BMI (kg/m2) 26.7 (6.1) 28.5 (6.6) 0.008Subjects on insulin 207/379 (54.6) 52/131 (39.7) 0.005Time to insulin (years) 0.67 (1.0) 0.86 (1.4) 0.81WHR 0.90 (0.1) 0.89 (0.1) 0.10Waist circumference (cm) 92.0 (15.7) 96.7 (16.6) 0.013HDL cholesterol (mmol/L) 1.49 (0.5) 1.44 (0.5) 0.6LDL cholesterol (mmol/L) 2.36 (0.98) 2.16 (1.08) 0.33Systolic BP (mmHg) 116.3 (28.8) 116.0 (31.1) 0.96TGL (mmol/L) 1.23 (0.9) 1.81 (1.7) 0.002

Data are n, means (SD), or n/n (%) unless otherwise indicated. BP, blood pressure; TGL, triglyceride.

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that it may not be possible to relate ourcutoff values to other GADA assay levels.Patients with high-titer compared withlow-titer GADAs were more likely to befemale, younger at onset, leaner, and oninsulin treatment, with lower HDL cho-lesterol and higher triglycerides; in thesefeatures, they resemble patients with type1 diabetes. However, each form of auto-immune diabetes could be found acrossthe range of GADA titers, though type 1diabetic patients tended to have hightiters and LADA patients tended to havelow titers. Moreover, patients with lowGADA titer, compared with those whowere GADA negative, were also youngerat diagnosis and leaner with higher HDLcholesterol, and a higher proportion wastreated with insulin. Thus, there is a gra-dation of clinical and biochemical fea-tures in patients, in which GADA titeris a continuous variable, ranging fromhigh through low titer to GADA negativity,without any clear distinction apart fromthe presence or absence of GADA. Othersmaller studies have shown that high-titer GADA-positive patients had a ten-dency to greater genetic (HLA) diseaseassociations compared with low–GADAtiter patients and that these genetic asso-ciations for autoimmune diabetes arebroadly similar even over awide age range,as are components of the metabolic syn-drome (5,19,20).

As a result, we recommend that type 1diabetes and LADA be viewed as part of abroad clinical spectrum that more truly

represents autoimmune diabetes. Themost prevalent form of diabetes is adult-onset type 2 diabetes, which affects ~4–7% of the adult European population.Childhood-onset type 1 diabetes, on theother hand, affects only some 0.25% ofEuropean children and adolescents,though a lifetime disease-risk analysissuggested that up to 1% develop classictype 1 diabetes, with a proportion doingso after age 30 years (21). Since we nowshow that nearly 10% of adult-onset di-abetic patients have autoimmune di-abetes, it follows that adult-onsetautoimmune diabetes is probably moreprevalent than childhood-onset type 1 di-abetes, while in adult-onset autoimmunediabetes, LADA is more prevalent thanclassic type 1 diabetes (OR 3.3). Clini-cally, knowledge that adult-onset diabeticpatients have GADA should alert physi-cians to the increased likelihood of morerapid progression to insulin therapy; i.e.,there is value in measuring GADA in alladult-onset diabetes cases because a sig-nificant proportion of them with GADA,unidentifiable by clinical phenotype, po-tentially have a different therapeutic tra-jectory than in classic type 2 diabetes. Insummary, this present study now showsthat the majority of adult-onset autoim-mune diabetic patients are non–insulinrequiring at diagnosis and can be identi-fied through GADA screening. In the ten-dency to be adult onset, with variabledestruction of the target organ, leadingto a broad clinical spectrum, autoimmune

diabetes can now be seen to resembleother autoimmune diseases.

AcknowledgmentsdThis study was partiallyfunded by the 5th Framework Programme ofthe European Union. D.M. was supported by agrant from Instituto Carlos III, Madrid, Spain(project no. FIS 061104). This study was alsofunded by DeveloGen. No other potentialconflicts of interest relevant to this article werereported.M.I.H. coordinated the study, analyzed

samples, researched data, and contributed tothe final manuscript. H.K. and N.S. providedsamples and contributed to the final manu-script. H.B. analyzed samples and contributedto the final manuscript. S.A.P. researched dataand contributed to the final manuscript. R.B.,D.M., A.D.L., K.Y., H.B.-N., J.T., C.S., C.T.,D.H., S.H., G.S., andW.A.S. provided samplesand contributed to the final manuscript. R.W.and S.B. collated data from centers and con-tributed to the final manuscript. P.P. providedsamples and contributed to the final manu-script. R.D.L. coordinated the study, researcheddata, and contributed to the final manuscript.R.D.L. is the guarantor of this work and, as such,had full access to all the data in the study andtakes responsibility for the integrity of the dataand the accuracy of the data analysis.Parts of this studywere presented in abstract

form at the 72nd Scientific Sessions of theAmerican Diabetes Association, Philadelphia,Pennsylvania, 8–12 June 2012.

APPENDIXdMembers of the ActionLADA group are as follows: R.D.L., M.I.H.,H.B., and S.A.P., Blizard Institute; P.P.,University Campus Bio-Medico; R.W.and S.B., Swansea University; H.B.-N. andK.Y., Odense University Hospital; S.H. andD.H., Royal Victoria Hospital; R.B., Uni-versity “La Sapienza”; W.A.S. and H.K.,University of D€usseldorf; N.S., GermanDiabetes Centre, University of D€usseldorf,and Clinic for Metabolic Diseases at Uni-versity Hospital D€usseldorf (on leave ofabsence from the German Diabetes Centreandcurrently employedbyLillyDeutschland,Bad Homburg); J. Seissler, Ludwig-Maximilians-University;G.S., RudolfstiftungHospital; J.T. and C.S., National InstituteforHealth andWelfare;A.D.L. andE.Brugue,Universitat Autonoma de Barcelona; D.M.,Hospital Universitari Arna de Vilanova; andC.T., Hospital Edouard Herriot.

References1. Bluestone JA, Herold K, Eisenbarth G.

Genetics, pathogenesis and clinical inter-ventions in type 1 diabetes. Nature 2010;464:1293–1300

Table 3dFeatures of type 1 diabetic versus LADA patients

Type 1 diabetes LADA P

Cases 114 377Females, n (%) 55 (48.2) 187(49.6)Males, n (%) 59 (51.8) 190(50.4) .0.5Mean age (years) 44.1 (9.9) 51.9 (10.5) ,0.001Age at onset (years) 41.8 (15.2) 49.7 (12.3) ,0.001Duration of disease (years) 1.93 (1.7) 2.37 (1.6) 0.005Subjects on insulin 114/114 (100) 152/377 (40.3) ,0.001Time to insulin (years) 0.04 (0.08) 1.85 (1.1) ,0.001Multiple autoantibodies(GADA/IA-2A and ZnT8A) 15/114 (13.2) 34/377 (9.0) 0.17

GADA high titer 91/114 (79.8) 296/377 (78.5) 0.43BMI (kg/m2) 25.6 (5.0) 28.6 (6.6) ,0.001WHR 0.87 (0.08) 0.90 (0.1) ,0.001Waist circumference (cm) 88.3 (12.7) 96.8 (16.6) ,0.001HDL cholesterol (mmol/L) 1.4 (0.4) 1.5 (0.5) .0.5LDL cholesterol (mmol/L) 2.8 (1.0) 2.2 (1.0) 0.013Systolic BP (mmHg) 120 (25) 119 (26) .0.5TGL (mmol/L) 1.2 (0.5) 1.6 (1.5) 0.16

Data are n, means (SD), or n/n (%) unless otherwise indicated. BP, blood pressure; TGL, triglyceride.

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