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The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

ObjectiveThe 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.Research design and methodsWe 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.ResultsDuring 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.ConclusionsThe type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.

ObjectiveThe phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogenesis. We investigated the relationship of type 2 diabetes-associated transcription factor 7 like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) with immunologic and metabolic characteristics at type 1 diabetes diagnosis.Research design and methodsWe studied TrialNet participants with newly diagnosed autoimmune type 1 diabetes with available TCF7L2 rs4506565 and rs7901695 SNP data (n = 810; median age 13.6 years; range 3.3-58.6). We modeled the influence of carrying a TCF7L2 variant (i.e., having 1 or 2 minor alleles) on the number of islet autoantibodies and oral glucose tolerance test (OGTT)-stimulated C-peptide and glucose measures at diabetes diagnosis. All analyses were adjusted for known confounders.ResultsThe rs4506565 variant was a significant independent factor of expressing a single autoantibody, instead of multiple autoantibodies, at diagnosis (odds ratio [OR] 1.66 [95% CI 1.07, 2.57], P = 0.024). Interaction analysis demonstrated that this association was only significant in participants ≥12 years old (n = 504; OR 2.12 [1.29, 3.47], P = 0.003) but not younger ones (n = 306, P = 0.73). The rs4506565 variant was independently associated with higher C-peptide area under the curve (AUC) (P = 0.008) and lower mean glucose AUC (P = 0.0127). The results were similar for the rs7901695 SNP.ConclusionsIn this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes-linked TCF7L2 variants were associated with single autoantibody (among those ≥12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT. Thus, carriers of the TCF7L2 variant had a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis, which could be partly driven by type 2 diabetes-like pathogenic mechanisms.

ObjectiveWe aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth.Research design and methodsWe studied 1,117 children in the TrialNet Pathway to Prevention cohort (autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index. Recursive partitioning and multivariate analyses yielded sex- and age-specific ceBMI thresholds for greatest type 1 diabetes risk.ResultsHigher ceBMI conferred significantly greater risk of progressing to type 1 diabetes. The increased diabetes risk occurred at lower ceBMI values in children

ObjectiveTo compare characteristics of autoantibody (aAb)-positive and -negative cases of type 1 diabetes (T1D)

Despite major advances over the past decade, prevention and treatment of type 1 diabetes mellitus (T1DM) remain suboptimal, with large and unexplained variations in individual responses to interventions. The current classification schema for diabetes mellitus does not capture the complexity of this disease or guide clinical management effectively. One of the approaches to achieve the goal of applying precision medicine in diabetes mellitus is to identify endotypes (that is, well-defined subtypes) of the disease each of which has a distinct aetiopathogenesis that might be amenable to specific interventions. Here, we describe epidemiological, clinical, genetic, immunological, histological and metabolic differences within T1DM that, together, suggest heterogeneity in its aetiology and pathogenesis. We then present the emerging endotypes and their impact on T1DM prediction, prevention and treatment. There is a growing awareness that type 1 diabetes mellitus (T1DM) is a heterogeneous disease that can be characterized into distinct endotypes. This Review discusses the evidence for endotypes in T1DM and explores the implications for clinical practice. Key points: Type 1 diabetes mellitus (T1DM) is heterogeneous; defining endotypes, or disease subtypes each of which has a unique aetiopathogenesis that is amenable to a particular intervention, will help apply precision medicine to T1DM. T1DM endotype 1 (T1DE1) includes T1DM diagnosed in early childhood and is characterized by extensive, early, β-cell destruction, aggressive insulitis with abundant CD8+ T and CD20+ B cells, aberrant proinsulin processing and an elevated circulating proinsulin to C-peptide ratio. T1DM endotype 2 (T1DE2) includes T1DM diagnosed in adolescence or adulthood and is characterized by retention of many residual insulin-containing islets and without insulitis, fewer infiltrating CD8+ T cells, few CD20+ B cells, normal proinsulin processing and lower proinsulin to C-peptide ratio than T1DE2. Evidence is emerging that T1DE1 might respond better than T1DE2 to interventional immunotherapy with agents targeted to specific immune cell subsets, such as rituximab or teplizumab, while GAD–alum therapy might be effective for treating T1DE2. The T1DE2 endotype could underlie a spectrum of phenotypes with different degrees of severity of the autoimmune attack and thus, different rates of progression to insulin dependence, ranging from classic T1DM to latent autoimmune diabetes mellitus in adults or slowly progressive insulin-dependent diabetes mellitus. Whether T1DM endotypes exist is still a matter of debate, but data are accumulating that support this framework, which will benefit from further research, including testing interventions directed to their underlying aetiopathogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Maturity‐onset diabetes of the young (MODY) is often misdiagnosed as type 1/type 2 diabetes. We aimed to define patient characteristics to guide the decision to test for MODY in youth with diabetes. Research Design and Methods: Of 4750 patients enrolled in the Diabetes Registry at Texas Children's Hospital between July 2016 and July 2019, we selected ("Study Cohort", n = 350) those with: (1) diabetes diagnosis <25 years, (2) family history of diabetes in three consecutive generations, and (3) absent islet autoantibodies except for GAD65. We retrospectively studied their clinical and biochemical characteristics and available MODY testing results. Cluster analysis was then performed to identify the cluster with highest rate of MODY diagnosis. Results: Patients in the Study Cohort were 3.5 times more likely to have been diagnosed with MODY than in the overall Diabetes Registry (4.6% vs. 1.3%, p < 0.001). The cluster (n = 16) with the highest rate of clinician‐diagnosed MODY (25%, n = 4/16) had the lowest age (10.9 ± 2.5 year), BMI‐z score (0.5 ± 0.9), C‐peptide level (1.5 ± 1.2 ng/ml) and acanthosis nigricans frequency (12.5%) at diabetes diagnosis (all p < 0.05). In this cluster, three out of five patients who underwent MODY genetic testing had a pathogenic variant. Conclusions: Using a stepwise approach, we identified that younger age, lower BMI, lower C‐peptide, and absence of acanthosis nigricans increase likelihood of MODY in racially/ethnically diverse children with diabetes who have a multigenerational family history of diabetes and negative islet autoantibodies, and can be used by clinicians to select patients for MODY testing. [ABSTRACT FROM AUTHOR]

Objective: Commercial gene panels identify pathogenic variants in as low as 27% of patients suspected to have MODY, suggesting the role of yet unidentified pathogenic variants. We sought to identify novel gene variants associated with MODY. Research Design and Methods: We recruited 10 children with a clinical suspicion of MODY but non‐diagnostic commercial MODY gene panels. We performed exome sequencing (ES) in them and their parents. Results: Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non‐Hispanic white, 5 Hispanic, and 1 Asian. Our variant prioritization analysis identified a pathogenic, de novo variant in INS (c.94G > A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with "autoantibody‐negative type 1 diabetes (T1D)" at 3 y/o. This rare variant, absent in the general population (gnomAD database), has been reported previously in neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 in a child with a previous diagnosis of "autoantibody‐negative T1D" at 12 y/o. The variant was inherited from the mother, who was diagnosed with "thin type 2 diabetes" at 25 y/o. Heterozygous protein‐truncating variants in RFX6 gene have been recently reported in individuals with MODY. Conclusions: We diagnosed two patients with MODY using ES in children initially classified as "T1D". One has a likely pathogenic novel gene variant not previously associated with MODY. We demonstrate the clinical utility of ES in patients with clinical suspicion of MODY. [ABSTRACT FROM AUTHOR]

The incidence of diabetes, both type 1 and type 2, is increasing. Health outcomes in pediatric diabetes are currently poor, with trends indicating that they are worsening. Minority racial/ethnic groups are disproportionately affected by suboptimal glucose control and have a higher risk of acute and chronic complications of diabetes. Correct clinical management starts with timely and accurate classification of diabetes, but in children this is becoming increasingly challenging due to high prevalence of obesity and shifting demographic composition. The growing obesity epidemic complicates classification by obesity's effects on diabetes. Since the prevalence and clinical characteristics of diabetes vary among racial/ethnic groups, migration between countries leads to changes in the distribution of diabetes types in a certain geographical area, challenging the clinician's ability to classify diabetes. These challenges must be addressed to correctly classify diabetes and establish an appropriate treatment strategy early in the course of disease for all. This may be the first step in improving diabetes outcomes across racial/ethnic groups. This review will discuss the pitfalls in the current diabetes classification scheme that is leading to increasing overlap between diabetes types and heterogeneity within each type. It will also present proposed alternative classification schemes and approaches to understanding diabetes type that may improve the timely and accurate classification of pediatric diabetes type. [ABSTRACT FROM AUTHOR]

Background Osteocalcin ( OC), a hormone secreted by osteoblasts, improves beta-cell function in vitro and in vivo. We aimed to understand the relationship between OC and hemoglobin A1c ( HbA1c) in pediatric diabetes. Methods Children ( n = 70; mean [ SD] age = 11.8 years [3.1]; 34.3% non-Hispanic white, 46.3% Hispanic, 14.9% African-American, 4.5% other) newly diagnosed with diabetes (69.1% type 1 diabetes [ T1D], 30.9% type 2 diabetes [ T2D]) were studied. We collected clinical data at diagnosis and first clinical visit ( V1) 9 weeks later (interquartile range [ IQR] = 7.9-12.0). Serum undercarboxylated OC ( uOC) and carboxylated OC ( cOC) were measured 7.0 weeks ( IQR 4.3-8.9) after diagnosis. Results Mean [ SD] uOC was 20.3 (19.6) ng/mL, cOC 29.7 [13.7] ng/mL and u/ cOC 0.68 [0.81]. uOC, cOC, or u/ cOC were not different by gender, race/ethnicity, age, diabetes type, BMI percentile, or random C-peptide, glucose or HbA1c at diagnosis. However, among 61 children with V1 within 4 months of diagnosis, uOC was higher in those with V1 HbA1c < 7.5% ( HbA1c < 58 mmol/mol) ( uOC=33.1 [22.0]) compared with children with HbA1c ≥ 7.5% ( uOC=17.4 [2.3], P = .0004). The difference was larger among patients with T2D (34.6 and 4.7 ng/mL, respectively, P = .0001) than T1D (32.2 and 19.3, P = .0169), and in males (36.1 and 17.4, P = .018) than females (27.6 and 17.3, P = .072). Analysis for u/ cOC were similar while there were no differences in cOC. uOC was inversely correlated with HbA1c at V1 (Spearman's rho = −0.29, P = .02). Conclusion Our findings suggest that serum uOC is inversely related to HbA1c shortly after diagnosis of pediatric diabetes. This potentially modifiable factor of glucose metabolism warrants further studies. [ABSTRACT FROM AUTHOR]

Objective Current data are limited on the course of type 1 diabetes ( T1D) in children and adolescents through the first few years of diabetes. The Pediatric Diabetes Consortium T1D new onset ( NeOn) Study was undertaken to prospectively assess natural history and clinical outcomes in children treated at 7 US diabetes centers from the time of diagnosis. This paper describes clinical outcomes in the T1D NeOn cohort during the first 3 years postdiagnosis. Results A total of 1048 participants (mean age 9.2 years, 49% female, 65% non-Hispanic White) were enrolled between July 2009 and April 2011. Mean glycated hemoglobin ( HbA1c) (± SD) was 7.2% (55 mmol/mol) at 3 months, followed by a progressive rise to 8.4% (68 mmol/mol) at 36 months postdiagnosis, with only 30% of participants achieving target HbA1c<7.5% (58 mmol/mol). The percentage of participants in partial remission estimated by insulin dose adjusted HbA1c [ HbA1c % + (4×insulin dose unit/kg/24 h)] ≤9 sharply declined from 23% at 12 months to 7% at 36 months. The percentage of participants developing diabetic ketoacidosis ( DKA) was 1% in the first year after diagnosis, increasing to 6% in years 2 and 3. Conclusions These results demonstrate the gradual decline in glycemic control due to waning residual endogenous insulin secretion with increasing duration of T1D in children and adolescents. These data indicate the need to translate recent advances in automated insulin delivery, new insulin analogs, and adjunctive pharmacologic agents into novel treatment strategies to maintain optimal glycemic control even early in the course of T1D. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus ( T1DM) is the archetypal example of a T cell-mediated autoimmune disease characterized by selective destruction of pancreatic β cells. The pathogenic equation for T1DM presents a complex interrelation of genetic and environmental factors, most of which have yet to be identified. On the basis of observed familial aggregation of T1DM, it is certain that there is a decided heritable genetic susceptibility for developing T1DM. The well-known association of T1DM with certain human histocompatibility leukocyte antigen ( HLA) alleles of the major histocompatibility complex ( MHC) was a major step toward understanding the role of inheritance in T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (e.g., HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/ DQ alleles [e.g., DRB1*03- DQB1*0201 ( DR3/ DQ2) or DRB1*04- DQB1*0302 ( DR4/ DQ8)]. In addition, the HLA allele DQB1*0602 is associated with dominant protection from T1DM in multiple populations. A concordance rate lower than 100% between monozygotic twins indicates a potential involvement of environmental factors on disease development. The detection of at least two islet autoantibodies in the blood is virtually pre-diagnostic for T1DM. The majority of children who carry these biomarkers, regardless of whether they have an a priori family history of the disease, will develop insulin-requiring diabetes. Facilitating pre-diagnosis is the timing of seroconversion which is most pronounced in the first 2 yr of life. Unfortunately the significant progress in improving prediction of T1DM has not yet been paralleled by safe and efficacious intervention strategies aimed at preventing the disease. Herein we summarize the chequered history of prediction and prevention of T1DM, describing successes and failures alike, and thereafter examine future trends in the exciting, partially explored field of T1DM prevention. [ABSTRACT FROM AUTHOR]

Objective To test the hypothesis that anti-islet autoantibody expression and random serum C-peptide obtained at diagnosis define phenotypes of pediatric diabetes with distinct clinical features. Subjects We analyzed 607 children aged <19 yr consecutively diagnosed with diabetes after exclusion of 13% of cases with secondary diabetes (e.g., cystic fibrosis related, steroid induced) and 7.3% of cases lacking measurement of C-peptide and/or autoantibodies. Methods Autoantibody positivity (A+) was defined as ≥1 positive out of GAD65, insulin, and ICA512 antibodies. Preserved beta-cell function (β+) was defined as random serum C-peptide at diagnosis ≥ 0.6 ng/mL. Body mass index ( BMI) was measured at median 1.2 months after diagnosis. Characteristics at diagnosis and 2 yr (range 18-30 months) after diagnosis were compared among groups. Results Autoantibody expression and C-peptide at diagnosis defined the following groups: A+β− (52.1% of the children), A+β+ (32.8%), A−β+ (12.5%), and A−β− (2.6%). These four groups differed in gender, race/ethnicity, and clinical characteristics at diagnosis [i.e., age, pubertal development, obesity/overweight, diabetic ketoacidosis, glycemia, and hemoglobin A1c ( HbA1c)] and at 2 yr (i.e., clinical diagnosis, treatment, and HbA1c) (all p < 0.0001). Among all β+ children, C-peptide >2 ng/mL was associated with lower HbA1c at onset (p = 0.0001) and, in the A+β+ subgroup, with higher frequency of achieving HbA1c < 7% at 2 yr (p = 0.03). All three patients (0.7% of total) with monogenic diabetes (maturity onset diabetes of the young, MODY) were A−β+ with C-peptide between 0.6 and 2 ng/mL. Conclusions Anti-islet autoantibodies status and serum random C-peptide at diagnosis define four distinct phenotypes of pediatric diabetes with prognostic value. [ABSTRACT FROM AUTHOR]

Objective To examine the relationship between BMI and beta-cell function at diagnosis of autoimmune type 1 diabetes ( T1D) in a large group of ethnically diverse children. Methods Cross-sectional analysis of 524 children (60.8% White, 19.5% Hispanic, 14.5% African-American, 5.2% other non-Hispanic; mean age = 9.8 yr [ SD = 2.5]) with newly diagnosed autoimmune T1D. Results As much as 22.2% of children were overweight or obese. Median random serum C-peptide was 0.40 ng/mL (25th-75th percentiles = 0.3-0.8), with median glycemia of 366 mg/dL (25th-75th percentiles = 271-505). Median C-peptide was 0.3, 0.5, 0.7, and 0.85 ng/mL, respectively, in underweight, normal weight, overweight, and obese children (p < 0.0001, Kruskal-Wallis). In the final model (p < 0.0001), the odds of having preserved C-peptide (≥0.6 ng/mL) were increased by 2.4-fold (95% CI = 1.2-4.9, p < 0.015) and 4.1-fold (1.9-8.5, p < 0.0001), respectively, in overweight and obese compared to lean children; 1.3-fold per each year of age; 2.5-fold in girls compared to boys; 4-fold in children who presented without, compared to with, diabetes ketoacidosis ( DKA); and decreased by 21% for each point increase in HbA1c. Tanner stage, race/ethnicity, glycemia, and number of anti-islet antibodies expressed were not independently associated with preserved C-peptide. The association between BMI and C-peptide levels was significant in children with and without preserved C-peptide. Excluding patients who presented with DKA and/or using BMI obtained 5 wk after diagnosis did not alter the results. Conclusion Obese and overweight children compared to lean children have greater beta-cell function at the onset of autoimmune T1D. Prospective studies on the relationships among BMI, beta-cell function, and progression to clinical T1D are warranted. [ABSTRACT FROM AUTHOR]

Approximately 50% of the genetic risk for type 1 diabetes is attributable to the HLA region. We evaluated associations between candidate genes outside the HLA region-INS, cytotoxic T-lymphocyte-associated antigen (CTLA)-4, interleukin (IL)-4, IL-4R, and IL-13 and islet autoimmunity among children participating in the Diabetes Autoimmunity Study in the Young (DAISY). Children with persistent islet autoantibody positivity (n = 102, 38 of whom have already developed diabetes) and control subjects (n = 198) were genotyped for single nucleotide polymorphisms (SNPs) in the candidate genes. The INS-23Hph1 polymorphism was significantly associated with both type I diabetes (OR = 0.30; 95% CI 0.13-0.69) and persistent islet autoimmunity but in the latter, only in children with the HLA-DR3/4 genotype (0.40; 0.18-0.89). CTLA-4 promoter SNP was significantly associated with type 1 diabetes (3.52; 1.2210.17) but not with persistent islet autoimmunity. Several SNPs in the IL-4 regulatory pathway appeared to have a predisposing effect for type 1 diabetes. Associations were found between both IL-4R haplotypes and IL-4-IL-13 haplotypes and persistent islet autoimmunity and type 1 diabetes. This study confirms the association between the INS and CTLA-4 loci and type 1 diabetes. Genes involved in the IL-4 regulatory pathway (IL-4, IL-4R, IL-13) may confer susceptibility or protection to type 1 diabetes depending on individual SNPs or specific haplotypes. Diabetes 54:2482-2486, 2005 [ABSTRACT FROM AUTHOR]

Twin studies help to elucidate the contribution of genes and environment to type 1 diabetes (T1DM). The Diabetes Prevention Trial-1 (DPT-1) tested for anti-islet autoantibodies: 34,765 non-diabetic non-twin siblings of patients with T1DM, and 896 non-diabetic potential twins of patients with T1DM. Zygosity (being monozygotic [MZ] or dizygotic [DZ]) was unknown except for 357 non-diabetic subjects with opposite gender to their diabetic twin, who must be DZ. Expression of cytoplasmic islet cell (ICA), GAD65, ICA512 and insulin autoantibodies in 357 different-sex (DZ) potential non-diabetic twins of T1DM patients was, respectively, 4.5%, 4.7%, 3.0% and 2.4%, which was lower than in 539 same-sex potential non-diabetic twins (including MZ and DZ) of T1DM patients for ICA (7.8%, p<0.05), GAD65 (13.4%, p<0.0001) and ICA512 (6.5%, p<0.03). In contrast, expression of ICA, GAD65, ICA512 and insulin autoantibodies was not significantly different in different-sex (DZ) potential twins versus all siblings (respectively, 4.2%, 4.8%, 2.2%, 2.5%), different-sex siblings (3.9%, 4.9%, 2.2%, 2.5%) or same-sex siblings (4.4%, 4.7%, 2.2%, 2.5%) of T1DM patients. In conclusion, anti-islet autoimmunity is not increased in non-diabetic DZ twins of T1DM patients compared to non-diabetic siblings of T1DM patients, suggesting that the greater environmental sharing by twins does not increase risk of anti-islet autoimmunity. [Copyright &y& Elsevier]

Wilson and coworkers (Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP, Strominger JL, Hafler DA: Extreme Th1 bias of invariant V alpha24J alpha Q T-cells in type 1 diabetes. Nature 391:177-181, 1998) have recently reported raised serum levels of interleukin-4 (IL-4) in anti-islet autoantibody-positive first-degree relatives of patients with type 1A diabetes who did not progress to diabetes. Protection from diabetes has been noted for several human lymphocyte antigen (HLA) alleles, such as HLA DR2-DQA1*0102-DQB1*0602. We, therefore, wanted to determine whether this cytokine phenotype was associated with HLA genes protective for type 1A diabetes. We used a two-site fluoroimmunoassay with the same monoclonal antibodies as those reported by Wilson et al. Using this assay, we have found evidence for human heterophile antibodies mimicking serum IL-4: all serum IL-4 reactivity was lost if mouse serum or mouse immunoglobulin were added to the assay; serum IL-4 activity was bound and then eluted by protein A/G chromatography; and levels of anti-mouse antibodies correlated with apparent serum IL-4. This pseudo-IL-4 activity was found in a subset of control subjects, patients with type 1A diabetes, and their relatives and was primarily associated with specific HLA alleles protective for type 1A diabetes (e.g., DQB1*0602). After adjustment for HLA, positive levels of heterophile antibodies were not associated with protection from diabetes. The confounding effect of protective HLA alleles associated with heterophile antibodies could explain the previously reported association between raised serum IL-4 and protection from type 1A diabetes. The mechanism by which specific DQ alleles protect from diabetes and are associated with increased heterophile antibodies is currently unknown. [ABSTRACT FROM AUTHOR]

Background: We explored the association of C‐peptide (marker of secreted insulin), proinsulin and proinsulin ⁄C‐peptide ratio (PI/C) (markers of beta‐cell endoplasmic reticulum [ER] stress) with undercarboxylated (uOC) and carboxylated osteocalcin (cOC) and their ratio (uOC/cOC) in children with recently diagnosed type 1 (T1D) or type 2 diabetes (T2D), and the correlation of these variables with partial remission (PR) in children with T1D. Methods: Demographic and clinical data of children with new‐onset diabetes (n = 68; median age = 12.2 years; 33.8% non‐Hispanic White, 45.6% Hispanic/Latino, 16.2% African American and 4.4% other) were collected at diagnosis and during the first (V1), second (V2) and third clinical visits at 9.0, 32.0 and 175.7 weeks, respectively. Serum proinsulin, C‐peptide, uOC and cOC values were measured 7.0 weeks after diagnosis. PR was defined as insulin dose–adjusted HbA1c (IDAA1c) ≤9. Results: In children with new‐onset T1D with DKA (33.3%) or T2D (29.4%), Spearman's correlation coefficient revealed a positive association between the C‐peptide levels and both uOC and uOC/cOC ratio. In T1D (n = 48), both higher serum C‐peptide levels and low PI:C ratio were associated with higher BMI percentile (β = 0.02, P =.001; β = −0.01, P =.02, respectively) and older age at diagnosis (β = 0.13, P =.001; β = −0.12, P =.001, respectively). Furthermore, in children with T1D, C‐peptide levels at V1 correlated with IDAA1c ≤ 9 at V1 (P =.04). Conclusion: C‐peptide levels are associated with a higher uOC and uOC/cOC ratio in paediatric diabetes. In new‐onset T1D children, older age and higher BMI were associated with lower beta‐cell stress and higher preserved function, which was predictive of PR on follow‐up. [ABSTRACT FROM AUTHOR]

A corrections to the article "Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs" that was published in a previous issue of the Journal of Clinical Investigation is presented.