Positive Islet Autoantibodies Research Articles

74-OR: Islet Autoantibodies in Youth with Diabetes from South Asia

The prevalence of diabetes in many South Asian countries is above 10%, but type 1 diabetes (T1D) is not fully characterized due to a lack of widespread access to islet autoantibody (IA) testing. Determining the prevalence of IA positivity in new and recent onset cases of childhood diabetes in these countries will allow for improved classification of diabetes and may impact treatment. We measured IA directed against glutamic acid decarboxylase 65 (GADA), insulinoma antigen-2 (IA-2A), insulin (IAA) and zinc transporter 8 (ZnT8A) using fluid-phase radiobinding assays from dried blood spot eluents in children with diabetes from the Republic of Maldives (n=64), Bangladesh (n=103) and Pakistan (n=54). We compared the results to youth from our large diabetes Center in Colorado (n=132). South Asian children with clinically diagnosed T1D have a lower rate of positivity for each IA when compared to youth with T1D from Colorado (p<0.0001) (Figure). The majority of youth with T1D in each country were diagnosed at a young age, not overweight, and required insulin treatment. Interestingly, 52% of Bangladeshi youth are antibody negative (p<0.0001 compared to Colorado), yet 92% require insulin treatment, thus highlighting the need to investigate other forms of diabetes such as monogenic causes. Studying the phenotype of diabetes in youth across the globe provides an opportunity to dissect the heterogeneity within childhood onset diabetes.View largeDownload slideView largeDownload slide DisclosureK. Simmons: Other Relationship; Self; Provention Bio, Inc. E. M. Youngkin: None. A. Condie: None. A. Alkanani: None. K. Mcdaniel: None. L. Yu: None. G. D. Ogle: None. A. W. Michels: Stock/Shareholder; Self; IM Therapeutics.FundingNational Institutes of Health (K12DK094712-08)

Islet autoantibody types mark differential clinical characteristics at diagnosis of pediatric type 1 diabetes.

We aimed to study whether islet autoantibody type marks differential characteristics at the time of type 1 diabetes (T1D) diagnosis. We studied 711 children with newly diagnosed autoimmune T1D. We compared demographic (sex, age, race/ethnicity), clinical (pubertal development, BMI percentile, diabetic ketoacidosis [DKA]) and laboratory (glucose, hemoglobin A1c [HbA1c], C-peptide, tissue transglutaminase antibodies [tTGA], thyroglobulin antibodies, and thyroid peroxidase antibodies [TPOA]) characteristics by presence/absence of autoantibodies to insulin (IAA), GAD65 (GADA), or IA-2/ICA512 (IA-2A). Islet autoantibody titers were evaluated among the children positive for the relevant autoantibody type. We used multivariable analysis to adjust for potential confounders. IAA+ was statistically associated with younger age (p< 0.0001) and lower HbA1c (p= 0.049) while Tanner stage, GADA status and number of positive islet autoantibodies were not significant in the multivariable model. GADA+ was associated with female sex (OR=4.0, p= 0.002) and negatively with elevated tTGA titers (>50 U/mL) (OR=0.21, p =0.026) but not with age, IAA status, IA-2A status, islet autoantibody number, or thyroid autoimmunity. None of the associations with IA-2A positivity was statistically significant in the multivariable analysis. In multivariable models, IAA titer was significantly associated with younger age (p =0.006), DKA (p =0.017) and higher tTGA levels (p =0.002); GADA titer with female sex (p =0.028), racial minority (p =0.046) and TPOA positivity (p =0.021); and IA-2A titer with older age (p =0.001) and not being African American (p =0.024). Islet autoantibody type is associated with differential characteristics at diagnosis of pediatric T1D. Longitudinal and mechanistic studies are needed to evaluate T1D endotypes by autoantibody type.

Insulin Receptor-Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice.

Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic β cells occurs. In previous work, when purified IR+ and IR- T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.

Adult-onset autoimmune diabetes: comparative analysis of classical and latent presentation

IntroductionAdult-onset autoimmune diabetes (AID) has two different phenotypes: classic type 1 diabetes mellitus (T1DM), with insulin requirement just after diagnosis, and latent autoimmune diabetes in adults (LADA). The purpose of this study is to characterize patients with AID followed on a tertiary centre, comparing classic T1DM and LADA.MethodsWe collected data from patients with diabetes and positive islet autoantibodies, aged 30 years old and over at diagnosis. Patients who started insulin in the first 6 months were classified as T1DM and patients with no insulin requirements in the first 6 months were classified as LADA. Data regarding clinical presentation, autoantibodies, A1C and C-peptide at diagnosis, pharmacologic treatment and complications were analysed.ResultsWe included 92 patients, 46 with classic T1DM and 46 with LADA. The percentage of females was 50% in T1DM group and 52.1% in LADA group. The median age at diagnosis was 38 years (IQR–15) for T1DM and 42 years (IQR–15) for LADA (p = 0.057). The median time between diagnosis of diabetes and diagnosis of autoimmune aetiology was 0 months in T1DM group and 60 months in LADA group (p < 0.001). The mean BMI at diagnosis was 24.1 kg/m2 in T1DM group and 26.1 kg/m2 in LADA group (p = 0.042). In T1DM group, 67.4% of the patients had more than one positive autoantibody, comparing to 41.3% of LADA patients (p = 0.012). There was no statistical difference in what concerns to title of GAD autoantibodies, A1C and C-peptide at diagnosis of autoimmune aetiology. The presence of symptoms at diagnosis was associated with T1DM group (p < 0.001). The median daily insulin dose was 40 IU for T1DM (0.58 IU/kg) and 33.5 IU for LADA (0.57 IU/kg), with no statistical difference. LADA patients were more often under non-insulin antidiabetic drugs (p = 0.001). At 10 years follow up, 21.1% of T1DM patients and 63.3% of LADA patients had microvascular complications (p = 0.004). Diabetic nephropathy was present in 23.5% of T1DM patients and 53.3% of LADA patients (p = 0.047). At the last evaluation, 55.6% of T1DM and 82.6% of LADA patients had metabolic syndrome and this difference was independent of diabetes duration.ConclusionPatients with classic T1DM presented more often with symptoms, lower BMI and higher number of autoantibodies, which may be related to a more aggressive autoimmune process. Patients with LADA developed more frequently microvascular complications for the same disease duration, namely diabetic nephropathy, and had more often metabolic syndrome.

Older age of childhood type 1 diabetes onset is associated with islet autoantibody positivity >30 years later: the Pittsburgh Epidemiology of Diabetes Complications Study.

To examine the association between islet autoantibody positivity and clinical characteristics, residual β-cell function (C-peptide) and prevalence of complications in a childhood-onset (age <17 years), long-duration (≥32 years) type 1 diabetes cohort. Islet autoantibodies (glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter-8 antibodies) were measured in the serum of participants who attended the 2011-2013 Pittsburgh Epidemiology of Diabetes Complications study follow-up examination (n=177, mean age 51 years, diabetes duration 43 years). Prevalences of islet autoantibodies were: glutamic acid decarboxylase, 32%; insulinoma-associated protein 2, 22%; and zinc transporter-8, 4%. Positivity for each islet autoantibody was associated with older age at diabetes onset (glutamic acid decarboxylase antibodies, P=0.03; insulinoma-associated protein 2 antibodies, P=0.001; zinc transporter-8 antibodies, P<0.0001). Older age at onset was also associated with an increasing number of autoantibodies (P = 0.001). Glutamic acid decarboxylase antibody positivity was also associated with lower HbA1c (P = 0.02), insulinoma-associated protein 2 antibody positivity was associated with lower prevalence of severe hypoglycaemic episodes (P=0.02) and both distal and autonomic neuropathy (P=0.04 for both), and zinc transporter-8 antibody positivity was associated with higher total and LDL cholesterol (P=0.01). No association between autoantibody positivity and C-peptide was observed. The strong association between islet autoantibody positivity and older age at type 1 diabetes onset supports the hypothesis of a less aggressive, and thus more persistent, immune process in those with older age at onset. This observation suggests that there may be long-term persistence of heterogeneity in the underlying autoimmune process.

Single Islet Autoantibody at Diagnosis of Clinical Type 1 Diabetes is Associated With Older Age and Insulin Resistance.

Multiple islet autoantibody positivity usually precedes clinical (stage 3) type 1 diabetes (T1D). To test the hypothesis that individuals who develop stage 3 T1D with only a single autoantibody have unique metabolic differences. Cross-sectional analysis of participants in the T1D TrialNet study. Autoantibody-positive relatives of individuals with stage 3 T1D. Autoantibody-positive relatives who developed stage 3 T1D (at median age 12.4 years, range = 1.4-58.6) and had autoantibody data close to clinical diagnosis (n = 786, 47.4% male, 79.9% non-Hispanic white). Logistic regression modeling was used to assess relationships between autoantibody status and demographic, clinical, and metabolic characteristics, adjusting for potential confounders and correcting for multiple comparisons. At diagnosis of stage 3 T1D, single autoantibody positivity, observed in 119 (15.1%) participants (72% GAD65, 13% microinsulin antibody assay, 11% insulinoma-associated antigen 2, 1% islet cell antibody, 3% autoantibodies to zinc transporter 8 [ZnT8]), was significantly associated with older age, higher C-peptide measures (fasting, area under the curve, 2-hour, and early response in oral glucose tolerance test), higher homeostatic model assessment of insulin resistance, and lower T1D Index60 (all P < 0.03). While with adjustment for age, 2-hour C-peptide remained statistically different, controlling for body mass index (BMI) attenuated the differences. Sex, race, ethnicity, human leukocyte antigen DR3-DQ2, and/or DR4-DQ8, BMI category, and glucose measures were not significantly associated with single autoantibody positivity. Compared with multiple autoantibody positivity, single autoantibody at diagnosis of stage 3 T1D was associated with older age and insulin resistance possibly mediated by elevated BMI, suggesting heterogeneous disease pathogenesis. These differences are potentially relevant for T1D prevention and treatment.

Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies.

A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies, irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39 and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change in FPIR over time was significantly different between those with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932), and IKZF4 (rs1701704) genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR.

Circulating CXCR5\u2212PD-1hi peripheral T helper cells are associated with progression to type 1 diabetes

Aims/hypothesisType 1 diabetes is preceded by a period of asymptomatic autoimmunity characterised by positivity for islet autoantibodies. Therefore, T helper cell responses that induce B cell activation are likely to play a critical role in the disease process. Here, we aimed to evaluate the role of a recently described subset, C-X-C motif chemokine receptor type 5-negative, programmed cell death protein 1-positive (CXCR5−PD-1hi) peripheral T helper (Tph) cells, in human type 1 diabetes.MethodsThe phenotype of blood CXCR5−PD-1hi CD4+ T cells was analysed by multicolour flow cytometry. The frequencies of circulating CXCR5−PD-1hi T cells were analysed in a cohort of 44 children with newly diagnosed type 1 diabetes, 40 autoantibody-positive (AAb+) at-risk children and 84 autoantibody-negative healthy control children, and the findings were replicated in a separate cohort of 15 children with newly diagnosed type 1 diabetes and 15 healthy control children.ResultsCirculating CXCR5−PD-1hi Tph cells share several features associated with B cell helper function with circulating CXCR5+PD-1hi follicular T helper (Tfh) cells. Moreover, the frequency of circulating Tph cells was increased in children with newly diagnosed type 1 diabetes, especially in those who are positive for multiple autoantibodies. Importantly, circulating Tph cells were also increased in autoantibody-positive at-risk children who later progressed to type 1 diabetes.Conclusions/interpretationOur results demonstrate that circulating CXCR5−PD-1hi Tph cells are associated with progression to clinical type 1 diabetes. Consequently, Tph cells could have potential both as a biomarker of disease progression and as a target for immunotherapy in type 1 diabetes.

1344-P: Persistent ß-Cell Responsiveness in Children at High Risk for Type 1 Diabetes (T1D) Is Associated with Decreased Progression to T1D in the Diabetes Prevention Trial-Type 1 (DPT-1)

High-risk individuals with islet autoantibody positivity (Ab+) vary in their rates of progression to T1D. We hypothesized that changes in C-peptide over time account for some of this variation. Among Ab+ children (&amp;lt;18.0 years) followed with 2-hour OGTTs for development of T1D in DPT-1, we compared Progressors to T1D with Non-Progressors for the change in AUC C-peptide from the baseline OGTT to the last available OGTT (last before diagnosis in Progressors). Results were stratified by low or high baseline DPT-1 Risk Score (DPTRS: fasting C-peptide, sum C-peptide and sum glucose values from 30-120 minutes, age and BMI; DPTRS &amp;lt;7.00= lower risk and ≥7.00= higher risk). As shown in the Table, Non-Progressors from each group exhibited increases in AUC C-peptide over time, while Progressors showed no significant changes in AUC C-peptide. A logistic regression model with adjustment for age indicated an inverse association of T1D development with increasing AUC-C-peptide/year [Odds ratio: 0.587 (0.430, 0.802), p&amp;lt;0.001]. In conclusion, even in individuals with high baseline risk assessments, increasing AUC C-peptide over time is associated with decreased progression to T1D. This persistent C-peptide responsiveness could result from increased β-cell reserve (either functional or mass) or β-cell regeneration. Disclosure E.K. Sims: None. H.M. Ismail: None. B.M. Nathan: None. J.M. Sosenko: None. Funding National Institutes of Health

No Association Between Ljungan Virus Seropositivity and the Beta-cell Damaging Process in the Finnish Type 1 Diabetes Prediction and Prevention Study Cohort.

Ljungan virus (LV) has not confirmed to associate with any human disease, but a possible connection with type 1 diabetes has been suggested. LV is a rodent-borne picornavirus that induces a diabetes-like condition in rodents. Approximately 30% of adults and 60% of children are seropositive in Finland. The Finnish Type 1 Diabetes Prediction and Prevention study enabled the use of very well characterized sample panels from children seroconverted to positivity for multiple islet autoantibodies during their prospective observation from birth; in addition, samples from age, sex, human leukocyte antigen (HLA), and residence area matched control children. We analyzed LV IgG seroprevalence in 102 case children (65 had also developed type 1 diabetes), in addition to nondiabetic control children. LV and human parechovirus (HPeV) immunofluorescence assays were used to analyze LV and HPeV-specific IgG from 102 plasma samples taken at the time of islet autoantibody appearance and from 204 samples from the matched control children. Altogether 46.1% of the case and 50.7% of the control children were positive for LV IgG (odds ratio 0.8; 95% confidence interval, 0.47-1.36; P = 0.416) and 67.6% versus 79.8% were positive for HPeV IgG, respectively (odds ratio 0.49, 0.27-0.9, P = 0.023). Thus, no risk associations between LV or HPeV-specific IgG and islet autoimmunity were observed. However, a trend for significantly higher prevalence of HPeV antibodies in control children (P = 0.023) suggests a possible protective association of this virus with islet autoimmunity.

Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies.

Antibodies to posttranslationally modified insulin (oxPTM-INS-Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM-INS-Ab can improve T1D prediction in children with positive standard islet autoantibodies (AAB). We evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM-INS-Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA-2A) in a cohort of islet AAB-positive (AAB+ ) children from the general population (median follow-up 8.8years). oxPTM-INS-Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA-2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM-INS-Ab was higher than GADA and IAA (P=0.003 and P=0.017, respectively), and similar to IA-2A (P=0.896). oxPTM-INS-Ab and IA-2A were more effective than IAA for detecting progr-T1D when used as second-line biomarker in GADA+ children. Risk for diabetes was higher (P=0.03) among multiple AAB+ who were also oxPTM-INS-Ab+ compared with those who were oxPTM-INS-Ab- . Importantly, when replacing IAA with oxPTM-INS-Ab, diabetes risk increased to 100% in children with oxPTM-INS-Ab+ in combination with GADA+ and IA-2A+ , compared with 84.37% in those with IAA+ , GADA+ , and IA-2A+ (P=0.04). Antibodies to oxidized insulin (oxPTM-INS-Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB+ children.

Serum 25-Hydroxyvitamin D Concentrations at Birth in Children Screened for HLA-DQB1 Conferred Risk for Type 1 Diabetes.

ContextVitamin D has several effects on the immune system that might be of relevance for the pathogenesis of type 1 diabetes (T1D).ObjectiveTo evaluate whether umbilical cord serum concentrations of 25-hydroxy-vitamin D (25[OH]D) differ in children developing either islet autoimmunity (IA) or overt T1D during childhood and adolescence.DesignUmbilical cord serum samples from 764 children born from 1994 to 2004 with HLA-DQB1 conferred risk for T1D participating in the Type 1 Diabetes Prediction and Prevention Study were analyzed for 25(OH)D using an enzyme immunoassay.SettingDIPP clinics in Turku, Oulu, and Tampere University Hospitals, Finland.ParticipantsTwo hundred fifty children who developed T1D diabetes at a median age of 6.7 years (interquartile range [IQR] 4.0 to 10.1 years) and 132 additional case children who developed IA, i.e., positivity for multiple islet autoantibodies. Cases were matched for date of birth, gender, and area of birth with 382 control children who remained autoantibody negative. The median duration of follow up was 9.8 years (IQR 5.7 to 13.1 years).Main Outcome MeasureThe median 25(OH)D concentrations.ResultsThe median 25(OH)D concentration in cord serum was low [31.1 nmol/L (IQR 24.0 to 41.8); 88% <50 nmol/L], but not statistically different between children who developed T1D or IA and their control groups (P = 0.70). The levels were associated mainly with geographical location, year and month of birth, age of the mother, and maternal intake of vitamin D during pregnancy.ConclusionsThe 25(OH)D concentrations at birth are not associated with the development of T1D during childhood.

Islet autoantibody positivity in overweight and obese adults with type 2 diabetes

Islet autoantibodies are typically associated with type 1 diabetes, but have been found in patients diagnosed with type 2 diabetes in whom they are associated with lower adiposity. The significance of autoantibody positivity in overweight and obese patients is not well understood. The aim of this study was to determine the prevalence and clinical significance of islet autoantibodies in overweight/obese adults diagnosed with type 2 diabetes. This study includes 204 participants at one site of the multicenter Look AHEAD (Action for Health in Diabetes) trial (ClinicalTrials.gov identifier: NCT00017953) which randomized overweight/obese adults diagnosed with type 2 diabetes to an intensive lifestyle intervention or diabetes support and education. We measured antibodies to glutamic acid decarboxylase, insulinoma antigen-2, and zinc transporter 8. Participants with and without autoantibodies were compared with respect to baseline clinical features, and longitudinal changes in weight, hemoglobin A1c, and antihyperglycemic medications. We found that 13 participants (6.4%) were autoantibody positive, including six of 47 participants (12.8%) with BMI ≥40 kg/m2. At baseline, autoantibody positive participants had higher HDL cholesterol (1.27 vs. 1.09 mmol/L, p = .034) and lower fasting C-peptide (0.32 vs. 0.57 nmol/L, p = .049). Over four years, autoantibody positive participants lost 5.1 kg more weight than autoantibody negative participants (p = .056). Longitudinal changes in hemoglobin A1c did not differ by autoantibody status, though autoantibody positive participants were more likely to increase the number of antihyperglycemic medications or initiate insulin (p = .011). In conclusion, islet autoantibodies were present in 6.4% of overweight/obese adults with type 2 diabetes including those with severe obesity, and were associated with distinct clinical features. The effect of autoantibody positivity on weight loss interventions requires further study.

Transcription Factor 7-Like 2 (TCF7L2) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes.

The type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes. We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used. During follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age. The type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.

Identification of a distinct phenotype of elderly latent autoimmune diabetes in adults: LADA China Study 8.

Latent autoimmune diabetes in adults (LADA) exhibits significant clinical heterogeneity, but the underlying causes remain unclear. The aim of this study was to investigate whether age of onset of LADA contributes to the observed clinical heterogeneity by comparing the clinical, metabolic, and immunogenetic characteristics between elderly and young LADA patients. The cross-sectional study included a total of 579 patients with LADA which was further divided into elderly LADA (E-LADA) group (n=135, age of onset ≥60years) and young LADA (Y-LADA) group (n=444, age of onset <60years). Age-matched subjects with type 2 diabetes were served as control (E-T2D group, n=622). Clinical characteristics, serum autoantibodies, and HLA-DQ haplotypes were compared among these groups. Compared with patients with Y-LADA, patients with E-LADA have better residual beta-cell function and higher level of insulin resistance (both P<.01), more metabolic syndrome characteristics, similar proportion of islet autoantibody positivity, and strikingly different HLA-DQ genetic background. In comparison with E-T2D patients, E-LADA patients tend to have similar metabolic syndrome prevalence, comparable C-peptide levels, and insulin resistance levels and share similar HLA-DQ genetic characteristics. Elderly LADA differs phenotypically and genetically from Y-LADA but has a clinical and genetic profile more similar to that of E-T2D. These distinct phenotypes could potentially help physicians better manage patients with E-LADA.

Reduction in White Blood Cell, Neutrophil, and Red Blood Cell Counts Related to Sex, HLA, and Islet Autoantibodies in Swedish TEDDY Children at Increased Risk for Type 1 Diabetes.

Islet autoantibodies (IAs) precede the clinical onset of type 1 diabetes (T1D); however, the knowledge is limited about whether the prodrome affects complete blood counts (CBCs) in 4- to 12-year-old children with increased genetic risk for T1D. This study tested whether CBCs were altered in 4- to 12-year-old children without (n = 376) or with one or several IAs against insulin, GAD65, or IA-2 (n = 72). CBC was analyzed during longitudinal follow-up in 448 Swedish children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A linear mixed-effects model was used to assess potential association between IA and CBC measurements over time. The white blood cell and neutrophil counts were reduced in children with IAs, primarily in boys. In contrast, girls had lower levels of hemoglobin and hematocrit. Positivity for multiple IAs showed the lowest counts in white blood cells and neutrophils in boys and red blood cells, hemoglobin, and hematocrit in girls. These associations were primarily observed in children with the HLA-DR3-DQ2/DR4-DQ8 genotype. We conclude that the reduction in neutrophils and red blood cells in children with multiple IAs and HLA-DR3-DQ2/DR4-DQ8 genotype may signal a sex-dependent islet autoimmunity detected in longitudinal CBCs.

Clinical Characteristics and Antibody Persistence over Time in Youth in the Pediatric Diabetes Consortium (PDC) Type 2 Diabetes (T2D) Cohort

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.

The MultiPepT1De Study—Examining the Safety of Peptide Immunotherapy Using Multiple Islet Antigens in Recent-Onset Type 1 Diabetes

Background: Peptide immunotherapy (PIT) aims to modulate immune responses to specific antigens in order to restore immune tolerance. Recently, we reported outcomes of a phase 1b study of PIT at type 1 diabetes onset, showing safety, tolerability and changes in immune regulation pathways, following up to 12 doses of 10μg of a single proinsulin peptide that is naturally processed and presented by HLA-DR4 (DRB1*0401). Preclinical PIT studies show that multiple peptides in combination enhance tolerance induction. Aims: To evaluate the safety and clinical effects of PIT using a mix of multiple islet autoantigen peptides in adults with recent-onset type 1 diabetes. Methods: The MultiPepT1De study was a single centre, double-blind placebo-controlled, ascending dose, randomized trial recruiting adults aged 18-45 years within 4 years of diagnosis with HLA-DRB1*0401 genotype, positive islet autoantibodies and stimulated C-peptide &amp;gt;0.2pmol/mL. Study drug comprised of 6 naturally processed and presented, islet-derived peptides (MultiPepT1De). Participants were enrolled into 3 cohorts for monthly intradermal injections for 6 months. In each cohort, subjects were randomized to receive placebo (n=2) or MultiPepT1De (n=6) at 10µg (Cohort 1), 100µg (Cohort 2) or 500µg (Cohort 3) doses. Results: Twenty-seven participants were randomized; 3 participants withdrew for non-clinical reasons and were replaced. There were no episodes of systemic hypersensitivity, anaphylaxis or serious adverse reactions linked to MultiPepT1De administration. Analysis of changes in stimulated C-peptide, HbA1c and insulin dose per kg showed no evidence of disease acceleration following dosing compared with placebo. Mild transient injection site erythema was observed in all cohorts, with no increase on repeated dosing. Conclusions: Intradermal administration of multiple islet-derived peptides up to a cumulative dose of 3000µg, is well tolerated with no safety concerns. Disclosure Y. Liu: Other Relationship; Self; Novo Nordisk Limited. Research Support; Self; Bristol-Myers Squibb Company. J.K. Powrie: None. S. Arif: None. N. Fountoulakis: None. M. Joshi: None. E.L. Smith: Employee; Self; UCB, Inc. F. Strimenopoulou: Employee; Self; UCB, Inc. M. Thomson: Employee; Self; UCB, Inc. M. Peakman: Research Support; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Bristol-Myers Squibb Company. Consultant; Self; UCB, Inc.. Research Support; Self; UCB, Inc.. Advisory Panel; Self; T1D Exchange.

Islet Autoantibody Patterns in Patients With Type 2 Diabetes Aged 60 and Higher: A Cross-Sectional Study in a Chinese Hospital.

Some elderly citizens with a clinical diagnosis of type 2 diabetes had evidence of positive islet autoantibodies. We aimed to discover their islet autoantibody patterns and independent correlative factors that might lead to a better understanding of significance of islet autoimmunity in the progression of elderly diabetes. A total of 541 inpatients of clinically diagnosed type 2 diabetes aged 60 and over were recruited. Three islet autoantibodies including insulin autoantibody (IAA), islet cell antibody (ICA), and glutamic acid decarboxylase antibody (GADA) as well as clinical and biochemical characteristics were tested and collected in Huashan Hospital. Associations between these antibodies and clinical features were analyzed by Spearman correlation and binary logistic analyses. In our current study, total positive rate of islet autoantibodies (IAA, ICA, and GADA) was 35.67% with 26.62% for individual IAA, 5.55% for ICA, and 5.91% for GADA, in elderly with type 2 diabetes. None of combinations of such autoantibodies were observed, with the exception of IAA + ICA (0.74%, n = 4), IAA + GADA (1.48%, n = 8), and ICA + GADA (0.18%, n = 1). Compared with GADA negative group, patients in positive group tended to have lower level of fasting and postprandial C peptide, fasting blood glucose (FBG), and body mass index (BMI). After adjusted for the BMI, FBG, and postprandial C peptide, fasting C peptide seemed to be an independent factor related to GADA positivity (OR = 0.52, p = 0.02). As for patients with positive IAA, they were more likely to have insulin treatment with longer duration of diabetes, higher level of BMI, and lower level of postprandial C peptide. After adjusted for the duration of diabetes, BMI, and postprandial C peptide, insulin treatment was a significant predictor for IAA positivity (OR = 5.20, p < 0.0001). Furthermore, hs-CRP was positively related to ICA positivity, and hs-CRP appeared to be an independent indicator for ICA (OR = 3.43, p = 0.008). In elderly with type 2 diabetes, high prevalence rate of IAA was frequently accompanied with insulin treatment, while ICA and GADA were more closely associated with the systemic inflammation and beta-cell failure, respectively.

Heterogeneity of Type 1 Diabetes: The Effect of Ethnicity.

Most of the current understanding of type 1 diabetes (T1D) etiology and pathogenesis stemmed from studies conducted in majoritarily Non-Hispanic White (NHW) populations. However, evidence is emerging that unique mechanisms of disease may contribute to the development of T1D in individuals of Hispanic ethnicity. We reviewed the currently available literature on genetic, immunologic, metabolic and clinical characteristics of T1D in Hispanic as compared with NHW individuals. We searched PubMed, Google Scholar, and authors' bibliographies to collect information from relevant articles on the influence of ethnicity on T1D etiology and pathogenesis. There are significant epidemiological variation based on ethnicity, with consistently higher T1D incidence and prevalence rate in NHWs than Hispanics. The frequencies of T1D high-risk HLA haplotypes and genotypes, as well as their susceptibility or protective effects show considerable ethnic differences. There are conflicting data on immunologic factors (e.g. islet autoantibody positivity) and markers of beta-cell function (e.g., C-peptide levels), as well as in some clinical characteristics (e.g. frequencies of diabetic ketoacidosis and severe hypoglycemia), while age of onset is consistently similar between both groups. Higher prevalence of obesity, less intensive diabetes management, and poorer glycemic control were reported in Hispanics. Accordingly, ethnic disparities in clinical outcomes have been demonstrated as well. There are considerable differences in T1D characteristics between NHWs and Hispanics. Better insight into these ethnic differences would not only affect patient care of patients with T1D, but may also inform the design of future prediction and prevention trials.