Differences in Clinical Manifestations and Islet Autoantibodies by Age in Adult-Onset Type 1 Diabetes.

Aims/hypothesisThe reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults.MethodsWe analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants.ResultsThe T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p=0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p<0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p<0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p<0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p<0.0001) and had a lower non-HLA T1DGRS (p<0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m2) and were less likely to have other autoimmune conditions (2% vs 10%) than autoantibody-positive adults (all p<0.0001). In both adults and children, type 1 diabetes genetic risk was unaffected by the number of autoantibodies (p>0.3). These findings, along with the identification of seven misclassified adults with monogenic diabetes among autoantibody-negative adults and the results of a sensitivity analysis with and without measurement of ZnT8A, suggest that the intermediate type 1 diabetes genetic risk in autoantibody-negative adults is more likely to be explained by the inclusion of misclassified non-autoimmune diabetes (estimated to represent 67% of all antibody-negative adults, 95% CI 61%, 73%) than by the presence of unmeasured autoantibodies or by a discrete form of diabetes. When these estimated individuals with non-autoimmune diabetes were adjusted for, the prevalence of autoantibody positivity in adult-onset type 1 diabetes was similar to that in children (93% vs 91%, p=0.4).Conclusions/interpretationThe inclusion of non-autoimmune diabetes is the most likely explanation for the observed lower rate of autoantibody positivity in clinician-diagnosed adult-onset type 1 diabetes. Our data support the utility of islet autoantibody measurement in clinician-suspected adult-onset type 1 diabetes in routine clinical practice.Graphical abstract

To compare the clinical parameters, C-peptide levels, pattern of islet cell-specific autoantibodies, and prevalence of predisposing genotypes in subjects with latent autoimmune diabetes in adults (LADA) and those with adult-onset type 1 diabetes with rapid progression. We evaluated the clinical parameters, C-peptide levels, and islet cell-specific autoantibodies in 54 LADA, 57 adult-onset type 1 diabetic, and 190 type 2 diabetic patients. Islet cell autoantibodies were also compared between subgroups of newly diagnosed patients with LADA and those with newly diagnosed adult-onset and childhood-onset type 1 diabetes. The genetic study was performed in subjects with LADA and those with adult-onset type 1 diabetes in comparison with a control population. There were no differences in the clinical parameters between LADA and adult-onset type 1 diabetes. Patients with LADA had lower BMI (P < 0.0001), waist-to-hip ratio (0.0029), total cholesterol (P = 0.001), and triglycerides (P = 0.001); higher HDL cholesterol levels (P < 0.0001); and lower prevalence of hypertension (P = 0.0028) compared with patients with type 2 diabetes. C-peptide levels were similar at onset (P = 0.403) but decreased less rapidly in LADA than in adult-onset type 1 diabetes (P = 0.0253). Single-autoantibody positivity was more often seen in LADA than in type 1 diabetes (P = 0.0001). The prevalence of predisposing HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 genotypes and the DR4-DQB1*0302 haplotype were increased in both LADA and adult-onset type 1 diabetic subjects compared with the control population. There were no differences in the frequencies of these risk alleles and haplotypes between the two patient groups. Subjects with LADA had clinical characteristics similar to those with adult-onset type 1 diabetes with rapid progression. C-peptide levels did not differ at onset but decreased less rapidly in LADA. Patients with LADA rather had single islet cell-specific autoantibody positivity. The prevalence of HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 risk alleles and the DR4-DQB1*0302 high-risk haplotype did not differ in the two forms of autoimmune diabetes.

OBJECTIVEIdentifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population.RESEARCH DESIGN AND METHODSSwedish patients (n = 3,933) aged 1–18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCK, HNF1A, and HNF4A, through either routine clinical or research testing.RESULTSThe minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P = 2 × 10−44), HbA1c (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P = 1 × 10−20), plasma glucose (11.7 vs. 26.7 mmol/L; P = 3 × 10−19), parental diabetes (63% vs. 12%; P = 1 × 10−15), and diabetic ketoacidosis (0% vs. 15%; P = 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA1c <7.5% (58 mmol/mol) at diagnosis identified 36 out of 46 (78%) patients with MODY (detection rate 49%). On follow-up, the 46 patients with MODY had excellent glycemic control, with an HbA1c of 6.4% (47 mmol/mol), with 42 out of 46 (91%) patients not on insulin treatment.CONCLUSIONSAt diagnosis of pediatric diabetes, absence of all islet autoantibodies and modest hyperglycemia (HbA1c <7.5% [58 mmol/mol]) should result in testing for GCK, HNF1A, and HNF4A MODY. Testing all 12% patients negative for four islet autoantibodies is an effective strategy for not missing MODY but will result in a lower detection rate. Identifying MODY results in excellent long-term glycemic control without insulin.

Familial aggregation and heritability of childhood-onset and adult-onset type 1 diabetes: a Swedish register-based cohort study

ContextOver half of all new cases of type 1 diabetes (T1D) are diagnosed in adults, yet the natural history of adult-onset T1D, particularly in nonfamilial populations, is not fully understood.ObjectiveThis study measured the prevalence of islet autoantibodies (IA) in adults without known diabetes and irrespective of T1D family history from Colorado (USA).MethodsThe Autoimmunity Screening for Kids study screened for IAs to insulin, glutamic acid decarboxylase (GADA), islet antigen-2, and zinc transporter 8 in 1087 adults without known diabetes [mean age 40.7 years with range 19.6-63.9 years, 63% non-Hispanic White (NHW), 10% with family history of T1D in a first-degree relative, and 78% female] from Colorado. IAs were measured using radiobinding assay and electrochemiluminescence detection methods.ResultsIn total, 3.86% of adults screened positive for any IA, 0.55% screened positive for multiple IAs, and 1.75% were positive for a single IA by both detection methods. Compared to NHW, those with Hispanic race/ethnicity were more likely to screen positive for a single IA (relative risk 2.32, 95% confidence interval 1.40, 3.84, P = .001), but there was no difference in the risk of screening positive for multiple IAs when comparing across race/ethnicity. GADA was the most prevalent IA, found in 2.67% of adults.ConclusionIA prevalence was high in this sample of adults without known diabetes from Colorado. Further study is needed to fully characterize the risk of progression to clinical diabetes among adults who screen positive for IAs, particularly in nonfamilial populations.

Objective: Detection of pre-symptomatic T1D by islet autoantibody (IA) screening prevents hospitalization and diabetic ketoacidosis at clinical onset. It is unknown if presence of diabetic symptoms and random blood glucose predict islet autoantibodies. We report the efficacy of random blood glucose (RBG) measurement, among those who reported multiple symptoms for T1D, for detecting T1D autoimmunity. Methods: In 2017-18, the Autoimmunity Screening for Kids (ASK) study screened 14,418 Denver children 1-17 y old for autoantibodies to insulin, GAD, IA-2, and ZnT8. At the time of screening, the parent and/or child were asked whether or not the child had increased urination, thirst, weight loss or vomiting in the last 3 months. If two or more symptoms were reported, RBG was tested using a glucometer and IA testing was fast-tracked with results available in &amp;lt;7 days. Results: Of the children screened, 0.9% were positive for multiple IA or a single high-affinity IA conferring, respectively, a 44% and 29% 5-year risk of clinical T1D. A fast-track protocol with RBG testing was applied to 501/12,726 children screened between 6/2017-12/2018, flagged for priority testing. Ten (2%) of the 501 fast-track participants had multiple or single high-affinity IA, compared to 91/12,050 (0.8%) IA in those with one or no symptoms (p=0.002). At screening, children found later to have multiple or high-affinity IA more often reported ≥2 symptoms: 9.6% (10/104) compared with low-affinity IA, 4.3% (11/254, p=0.05), or negative, 4.9% (602/12,368, p=0.03). Among those with increased thirst and polyuria, 16/358 (4.5%) had IA. For IA positive, none reported all symptoms (12 IA neg reported all symptoms). RBG&amp;gt;140 mg/dl was detected in 1/14 (7.1%) children with multiple symptoms and IA vs. 15/440 (3.4%) children with symptoms and no IA (p=0.5). None had RBG&amp;gt;200. Conclusions: Symptoms history is helpful but RBG is not, in finding children with pre-symptomatic T1D. Disclosure K. Waugh: None. B.I. Frohnert: None. M. Rewers: None. J. Baxter: None. C.R. Geno Rasmussen: None. Funding JDRF

Autoantibodies to glutamate decarboxylase, islet antigen-2, insulin, and zinc transporter-8 are characteristic of type 1 diabetes. They are detectable before clinical onset and define the subgroup of patients with latent autoimmune diabetes in adults. Autoantibody assays are increasingly available to clinicians. This article reviews the prognostic significance of autoantibodies and considers the utility of diabetes antibody testing in routine clinical practice. The medical literature to May 2009 was reviewed for key articles and consensus statements covering use of islet autoantibody testing for prediction and classification of diabetes and implications for therapy. Sensitive and specific glutamate decarboxylase and islet antigen-2 antibody assays are widely available, although to insulin autoantibody assays remain variable. Islet autoantibodies appear early in life, and testing for multiple antibodies identifies unaffected individuals at very high risk of type 1 diabetes with high sensitivity. This is important for research, but currently no intervention prevents or delays diabetes, and evidence of benefit from awareness of risk is weak. In non-insulin-treated diabetes, patients with autoantibodies progress to insulin requirement more rapidly, but evidence that testing benefits the individual patient is limited. Antibody testing is useful in classifying diabetes of other types. Islet autoantibody testing allows prediction of type 1 diabetes and definition of the latent autoimmune diabetes in adults subgroup of non-insulin-treated patients. Although useful for research, until therapies modulating the disease process become available, the benefit to individual patients is generally questionable. With a few exceptions, diabetes antibody testing does not yet have a role in routine clinical care.

Type 1 diabetes (T1D) is an autoimmune disease characterized by loss of insulin producing beta cells and reliance on exogenous insulin for survival. T1D is one of the most common chronic diseases in childhood and the incidence is increasing, especially in children less than 5 years of age. In individuals with a genetic predisposition, an unidentified trigger initiates an abnormal immune response and the development of islet autoantibodies directed against proteins in insulin producing beta cells. There are currently four biochemical islet autoantibodies measured in the serum directed against insulin, glutamic decarboxylase, islet antigen 2, and zinc transporter 8. Development of islet autoantibodies occurs before clinical diagnosis of T1D, making T1D a predictable disease in an individual with 2 or more autoantibodies. Screening for islet autoantibodies is still predominantly done through research studies, but efforts are underway to screen the general population. The benefits of screening for islet autoantibodies include decreasing the incidence of diabetic ketoacidosis that can be life threatening, initiating insulin therapy sooner in the disease process, and evaluating safe and specific therapies in large randomized clinical intervention trials to delay or prevent progression to diabetes onset.

Objective: To describe the characteristics of youth diagnosed with T2D who have tested positive for ≥1 islet autoantibody (IA) and to examine the persistence of IA over time. Methods: Youth enrolled in the PDC T2D Registry with ≥2 years follow-up after diagnosis and ≥1 positive IA at any time were identified. T2D was determined using ADA guidelines. IAs were measured at each PDC site according to local practice and included IAA, GADA, IA-2A, ZnT8A, and ICA. Positive IAA tests were excluded if measured after insulin initiation. Clinical characteristics, clinical presentation, and treatment over time were analyzed. Results: Positive IA is an exclusion for enrollment in the PDC T2D Registry; however, on review of the ∼1,300 youth in the PDC, 38 were found to have IA. A single IA was found in 35 and &amp;gt;1 IA in 3 participants. GADA was most common (N=32); 3 were persistently positive, 13 converted to negative, 8 became positive after a negative GADA, and 8 had only 1 IA determination. Positive IAA (N=5), IA-2A (N=4) and ZnT8 (N=1) were uncommon or rare, no positive ICA were found. At diagnosis, those IA positive were more likely to be treated with insulin (95% vs. 73%) but with similar HbA1c (10.4% vs. 10.0%). At last visit, those IA positive had longer diabetes duration (5.7 years. vs. 4.8 years.) and higher insulin use (71% vs. 59%) compared to the IA negative cohort, but HbA1c levels were similar (8.7% vs. 9.0%). Age at diagnosis, race/ethnicity, percent male, and BMI were not different between those with and without IA. Conclusion: Most IA positive youth with a T2D phenotype require insulin at diagnosis and more IA positive than IA negative youth require insulin during follow-up treatment. These findings suggest the importance of IA ascertainment at diagnosis and in those failing oral therapy. In T2D youth GADA is the most common IA; yield from ZnT8 and ICA determinations is low; fluctuations in IA positivity are not uncommon. Additional study of youth with T2D phenotype and IA is needed. Disclosure G.J. Klingensmith: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Foundation. P. Cheng: None. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. M.M. Kelsey: Other Relationship; Self; Daiichi Sankyo Company, Limited, Merck Sharp &amp; Dohme Corp. C. Kollman: Research Support; Self; JDRF, Bigfoot Biomedical, Dexcom, Inc., Tandem Diabetes Care, Inc., Medtronic MiniMed, Inc., Helmsley Charitable Trust.

A-β+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved β-cell function in persons with a phenotype of obesity-associated type 2 diabetes (T2D). The prevalence of KPD has not been evaluated in children. We investigated children with DKA at "T2D" onset and determined the prevalence and characteristics of pediatric A-β+ KPD within this cohort. We reviewed the records of 716 children with T2D at a large academic hospital and compared clinical characteristics of those with and without DKA at onset. In the latter group, we identified patients with A-β+ KPD using criteria of the Rare and Atypical Diabetes Network (RADIANT) and defined its prevalence and characteristics. Mean age at diagnosis was 13.7 ± 2.4 years: 63% female; 59% Hispanic, 29% African American, 9% non-Hispanic White, and 3% other. Fifty-six (7.8%) presented with DKA at diagnosis and lacked islet autoantibodies. Children presenting with DKA were older and had lower C-peptide and higher glucose concentrations than those without DKA. Twenty-five children with DKA (45%) met RADIANT A-β+ KPD criteria. They were predominantly male (64%), African American or Hispanic (96%), with substantial C-peptide (1.3 ± 0.7 ng/mL) at presentation with DKA and excellent long-term glycemic control (HbA1c 6.6% ± 1.9% at follow-up (median 1.3 years postdiagnosis)). In children with a clinical phenotype of T2D and DKA at diagnosis, approximately half meet criteria for A-β+ KPD. They manifest the key characteristics of obesity, preserved β-cell function, male predominance, and potential to discontinue insulin therapy, similar to adults with A-β+ KPD.

To investigate the prevalence, clinical significance and antepartum to postpartum trajectory of zinc transporter 8 autoantibodies, a novel marker of islet autoimmunity, in women with gestational diabetes mellitus. A total of 302 consecutive women attending a multi-ethnic Australian gestational diabetes clinic were prospectively studied. Zinc transporter 8 autoantibodies were measured at gestational diabetes diagnosis and 3months postpartum using an enzyme-linked immunosorbent assay, and were correlated with maternal phenotype, antepartum and postpartum glucose tolerance, treatment and perinatal outcomes. Of the 302 women, 30 (9.9%) were positive for one islet autoantibody antepartum. No participant had multiple islet autoantibodies. Zinc transporter 8 autoantibodies were the most prevalent autoantibody [zinc transporter 8 autoantibodies: 13/271 women (4.8%); glutamic acid decarboxylase 7/302 women (2.3%); insulinoma-associated antigen-2: 6/302 women (2.0%); insulin: 4/302 women (1.3%)]. Zinc transporter 8 autoantibody positivity was associated with a higher fasting glucose level on the antepartum oral glucose tolerance test, but not with BMI, insulin use, perinatal outcomes or postpartum glucose intolerance. Five of the six women who tested positive for zinc transporter 8 autoantibodies antepartum were negative for zinc transporter 8 autoantibodies postpartum, which corresponded to a significant decline in titre antepartum to postpartum (26.5 to 3.8 U/ml; P=0.03). This was in contrast to the antepartum to postpartum trajectory of the other islet autoantibodies, which remained unchanged. Zinc transporter 8 autoantibodies were the most common islet autoantibody in gestational diabetes. Zinc transporter 8 autoantibody positivity was associated with slightly higher fasting glucose levels and, unlike other islet autoantibodies, titres declined postpartum. Zinc transporter 8 autoantibodies may be a marker for islet autoimmunity in a proportion of women with gestational diabetes, but the clinical relevance of zinc transporter 8 autoantibodies in pregnancy and gestational diabetes requires further investigation.

Introduction and Objective: Total pancreatectomy with islet auto transplantation (TPIAT) is a non-immune model of islet transplant. The presence of islet autoantibodies post TPIAT has been observed, but the impact on β cell function is unknown. We compared measures of β cell function between children who were islet autoantibody positive (IAP) and negative (IAN) for up to 2 years post TPIAT. Methods: Clinical data was collected from children who underwent TPIAT between 2015 and 2021. All patients were screened for islet autoantibodies and underwent Mixed Meal Tolerance Testing (MMTT) at 12 months and 18-24 months post TPIAT. IAP was defined as the detection of one or more of the following: Glutamic Acid Decarboxylase (GAD), Islet Antigen-2 (IA-2), or Zinc Transporter 8 (ZnT8). Insulin Antibody (IAA) was excluded due to the likelihood that detection was secondary to exogenous insulin exposure. At 12 months, 23 patients were identified: 7 IAP and 16 IAN. At 18-24 months, 20 patients were identified: 7 IAP and 13 IAN. Results: There were no differences in age at TPIAT, sex, or HbA1C levels between patients who were IAP or IAN. At 12 months post TPIAT, insulinogenic index, peak C peptide, C peptide secretion index and area under the curve C peptide were higher in the IAP group. BMI was significantly higher in the IAP group at 12 and 18-24 months. At 18-24 months, although not statistically significant, the median age was lower in the IAN group. Conclusion: The role of islet autoantibodies on β cell function post TPIAT remains unclear. IAP group is associated with increased insulin secretion post TPIAT. These data suggest that age and BMI influenced insulin secretion more than the presence of islet autoantibodies over this short post TPIAT duration. We suspect a longer exposure to islet antibodies is required to assess impact on β cell function. Disclosure O. Kothawala: None. L. Hornung: None. A.R. Lavik: None. S. Swauger: None. C.M.O. Lowe: None. M. Abu-El-Haija: None. S.E. Tellez: None. D.A. Elder: Research Support; Dexcom, Inc., Sanofi.

In patients with Type2 diabetes, intensive glycaemic control is associated with hypoglycaemia and possibly increased mortality. However, no blood biomarkers exist to predict these outcomes. Using participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesized that insulin deficiency and islet autoantibodies in patients with clinically diagnosed Type2 diabetes would be associated with severe hypoglycaemia and death. A nested case-control study design was used. A case (n=86) was a participant who died with at least one episode of severe hypoglycaemia, defined as hypoglycaemia requiring assistance, at any point during ACCORD follow-up. A control (n=344) was a participant who did not die and did not have severe hypoglycaemia during follow-up. Each case was matched to four controls (glycaemic intervention arm, race, age and BMI). Baseline insulin deficiency (fasting C-peptide ≤0.15 nmol/l) and islet autoantibodies [glutamic acid decarboxylase (GAD), tyrosine phosphatase-related islet antigen2 (IA2), insulin (IAA) and zinc transporter (ZnT8)] were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used. Death during ACCORD in those who experienced at least one episode of severe hypoglycaemia was associated with insulin deficiency [OR 4.8 (2.1, 11.1): P<0.0001], GAD antibodies [OR 2.3 (1.1, 5.1): P=0.04], the presence of IAA or baseline insulin use [OR 6.1 (3.5,10.7): P<0.0001], which remained significant after adjusting for age, BMI, and diabetes duration. There was no significant association with IA2 or ZnT8 antibodies. In patients with Type2 diabetes, C-peptide or GAD antibodies may serve as blood biomarkers predicting higher odds of subsequent severe hypoglycaemia and death. (Clinical Trial Registry No: NCT00000620, www.clinicaltrials.gov for original ACCORD study).

Islet autoantibodies have taught us almost all we know about the disease process leading up to type 1 diabetes (T1D). In the absence of direct access to target organ tissue prior to diagnosis, they have provided the best available window on islet autoimmunity in humans. Detection of islet cell antibodies (ICA) in unaffected relatives identified for the first time the prodrome preceding clinical onset (1), and autoantibodies to insulin (IAA), glutamate decarboxylase (GADA), islet antigen-2, and zinc transporter 8 now provide the foundations for studies of the natural history of the condition. In prospective studies from birth, such as Diabetes Autoimmunity Study of the Young (DAISY), BABYDIAB, Diabetes Prediction and Prevention (DIPP), and more recently The Environmental Determinants of Diabetes in the Young (TEDDY), appearance of islet autoantibodies has been used to define the onset of autoimmunity (2–5). This can then be related to genetic characteristics and environmental exposures of potential etiological relevance. Autoantibodies also form the basis of disease prediction, allowing the sensitive, specific, and quantified assessment of risk that has made possible intervention studies to delay or prevent clinical onset of T1D (6). Islet autoantibodies are, however, difficult to measure. Islet cell antibodies have been largely abandoned because the indirect immunofluorescence assays are complex, labor-intensive, and hard to standardize. Even for antibodies directed against the four identified islet autoantigens—and in spite of international workshop programs—assay performance varies markedly between laboratories and a relatively small number achieve high levels of sensitivity and specificity (7,8) Current assays pick up both disease-relevant and nondisease-associated (disease-irrelevant) signals. …

The HLA-A*24 allele has shown negative associations with autoantibodies to islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) in patients with established type 1 diabetes. Understanding how this HLA class I allele affects humoral islet autoimmunity gives new insights into disease pathogenesis. We therefore investigated the epitope specificity of associations between HLA-A*24 and islet autoantibodies at disease onset. HLA-A*24 genotype and autoantibody responses to insulin (IAA), glutamate decarboxylase (GADA), IA-2, IA-2β, and ZnT8 were analyzed in samples collected from patients with recent-onset type 1 diabetes. After correction for age, sex, and HLA class II genotype, HLA-A*24 was shown to be a negative determinant of IA-2A and ZnT8A. These effects were epitope specific. Antibodies targeting the protein tyrosine phosphatase domains of IA-2 and IA-2β, but not the IA-2 juxtamembrane region, were less common in patients carrying HLA-A*24 alleles. The prevalence of ZnT8A specific or cross-reactive with the ZnT8 tryptophan-325 polymorphic residue, but not those specific to arginine-325, was reduced in HLA-A*24-positive patients. No associations were found between HLA-A*24 and IAA or GADA. Association of an HLA class I susceptibility allele with altered islet autoantibody phenotype at diagnosis suggests CD8 T-cell and/or natural killer cell–mediated killing modulates humoral autoimmune responses.