Teplizumab and ß-Cell Function in Newly Diagnosed Type 1 Diabetes.

BACKGROUND: Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. METHODS: In this phase 3, randomized, placebo-controlled trial, we assessed ß-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in ß-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. RESULTS: Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. CONCLUSIONS: Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of ß-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).

Lessons and gaps in the prediction and prevention of type 1 diabetes.

Type 1 diabetes (T1D) is a serious chronic autoimmune condition. Even though the root cause of T1D development has yet to be determined, enough is known about the natural history of T1D pathogenesis to allow study of interventions that may delay or even prevent the onset of hyperglycemia and clinical T1D. Primary prevention aims to prevent the onset of beta cell autoimmunity in asymptomatic people at high genetic risk for T1D. Secondary prevention strategies aim to preserve functional beta cells once autoimmunity is present, and tertiary prevention aims to initiate and extend partial remission of beta cell destruction after the clinical onset of T1D. The approval of teplizumab in the United States to delay the onset of clinical T1D marks an impressive milestone in diabetes care. This treatment opens the door to a paradigm shift in T1D care. People with T1D risk need to be identified early by measuring T1D related islet autoantibodies. Identifying people with T1D before they have symptoms will facilitate better understanding of pre-symptomatic T1D progression and T1D prevention strategies that may be effective.

Medical management of children with type 1 diabetes on low-carbohydrate or ketogenic diets.

OBJECTIVES: Low-carbohydrate and ketogenic diets are becoming increasingly popular choices for people with type 1 diabetes (T1D) aiming to achieve optimal glycemic control. A carbohydrate-restricted diet in children has been associated with negative health effects including poor linear growth and inadequate bone mineralization. Guidelines for monitoring children and adolescents choosing to follow a carbohydrate-restricted diet do not exist. We aimed to create a clinical protocol outlining how to clinically and biochemically follow patients choosing a carbohydrate-restricted diet with the goal of medical safety. METHODS: An interdisciplinary committee was formed and reviewed current consensus guidelines for pediatric patients on carbohydrate-restricted diets for epilepsy and metabolic disorders. A literature search was done to determine management strategies for children with T1D on a low-carbohydrate or ketogenic diet. Key health parameters that require monitoring were identified: growth, glycemic control, bone health, cardiometabolic health, and nutritional status. These health outcomes were used to develop a protocol for monitoring children on carbohydrate-restricted diets. RESULTS: A one-page protocol for medical providers and educational materials for families interested in following a low-carbohydrate or ketogenic diet were developed and successfully implemented into clinical care. CONCLUSION: Implementing a protocol for children on carbohydrate-restricted diets in clinic allows medical providers to ensure medical safety while being open to discussing a family's dietary preferences. Following children in the protocol over time will lead to informed clinical guidelines for patients with T1D who choose to follow a carbohydrate-restricted diet.

Screening children for type 1 diabetes-associated antibodies at community health fairs.

OBJECTIVE: The incidence of type 1 diabetes (T1D) is increasing, most notably in young children and in racial and ethnic minorities. Historically, screening for risk with T1D-associated antibodies has been limited to those with a family history, while up to 90% of newly diagnosed patients lack such a family history. To address the needs to screen diverse ethnic groups in the general population, we screened children for T1D-associated antibodies in the Denver, Colorado metro area at community health fairs. METHODS: Children attending health fairs from 2015 to 2018 were offered free T1D screening by measuring the four prototypical T1D-associated antibodies. A finger stick capillary puncture was performed to collect blood spots on filter paper. Dried blood spots (DBSs) were eluted and antibodies were measured using fluid-phase radio-binding assays. RESULTS: At 39 health fairs, children were educated on the signs and symptoms of diabetes, and screened for T1D-associated antibodies (n = 478), which represented 90% of those that attended. Median age was 9.0 years (range of 1-18) with diverse ethnic backgrounds: 37% Hispanic, 31% Caucasian, 20% African American, and 12% other. Nine children screened positive for antibodies, single n = 8 and multiple n = 1, and confirmation with serum samples showed excellent correlation to the measurements from DBSs for antibodies directed against GAD, IA-2, and ZnT8 (P < .01 for each). CONCLUSIONS: Screening for T1D risk at community health fairs using DBSs on filter paper is feasible and provides an avenue to screen children from ethnically diverse backgrounds.

Unmethylated Insulin as an Adjunctive Marker of Beta Cell Death and Progression to Type 1 Diabetes in Participants at Risk for Diabetes.

Islet autoantibody (iAb)-positive individuals have a high risk of progression to type 1 diabetes (T1D), although the rate of progression is highly variable and factors involved in the rate of progression are largely unknown. The ratio of unmethylated/methylated insulin DNA levels (unmethylated INS ratio) has been shown to be higher in participants at high risk of T1D compared to healthy controls. We aimed to evaluate whether an unmethylated INS ratio may be a useful biomarker of beta cell death and rate of progression to T1D. In TrialNet participants who were followed in the Pathway to Prevention Study and progressed to diabetes (n = 57, median age of onset 15.3 years), we measured unmethylated INS ratio and autoantibodies by electrochemiluminescence (ECL) assays (ECL-IAA, ECL-GADA, and ECL-IA2) and radioimmunoassays (RIA) (mIAA, GADA, IA2A, and ZnT8A) longitudinally for 24 months prior to diagnosis. Linear models were used to test the association between unmethylated INS ratio and the age at T1D diagnosis and unmethylated INS ratio and iAb over time. Close to diabetes onset, the unmethylated INS ratio was associated with mIAA (p = 0.003), ECL-IAA (p = 0.002), and IA2A (p = 0.01) levels, but not with GADA, ECL-GADA, ECL-IA2, or ZnT8A levels. No significant associations were found at baseline (24 months prior to T1D diagnosis). Only mIAA levels were significantly associated with an unmethylated INS ratio over time, with a 0.24 change in the ratio for each 0.1 change in mIAA z-score (p = 0.02). Adjusting for a baseline unmethylated INS ratio, an increased rate of change in unmethylated INS ratio from baseline to diabetes onset was associated with a five-year decrease in age at T1D diagnosis (p = 0.04).

Reduced Bone Mineral Density Is Associated with Celiac Disease Autoimmunity in Children with Type 1 Diabetes.

OBJECTIVE: To evaluate the association between bone mineral density (BMD), glycemic control (hemoglobin A1c [HbA1c]), and celiac autoimmunity in children with type 1 diabetes mellitus (T1D) and in an appropriate control population. STUDY DESIGN: BMD was assessed cross-sectionally in 252 children with T1D (123 positive for anti-tissue transglutaminase antibody [tTGA] and 129 matched children who were negative for tTGA). In addition, BMD was assessed in 141 children without diabetes who carried T1D-associated HLD-DR, DQ genotypes (71 positive for tTGA and 70 negative). RESULTS: Children with T1D who were positive for tTGA had significantly worse BMD L1-L4 z-score compared with children with T1D who were negative for tTGA (-0.45 ± 1.22 vs 0.09 ± 1.10, P = .0003). No differences in growth measures, urine N-telopeptides, 25-hydroxyvitamin D, ferritin, thyroid stimulating hormone, or HbA1c were found. However, both higher HbA1c (ß = -1.25 ± 0.85, P = .0016) and tTGA (ß = -0.13 ± 0.05, P = .0056) were significant and independent predictors of lower BMD in multivariate analyses. No differences in BMD or other variables measured were found between children without diabetes who were positive vs negative for tTGA. CONCLUSIONS: The results suggest a synergistic effect of hyperglycemia and celiac autoimmunity on low BMD.

Immune Intervention and Preservation of Pancreatic Beta Cell Function in Type 1 Diabetes.

Type 1 diabetes (T1D) results from the immune-mediated destruction of insulin-producing ß cells located within the pancreatic islets of Langerhans. The autoimmune process leads to a deficiency in insulin production and resultant hyperglycemia requiring lifelong treatment with insulin administration. T1D continues to dramatically increase in incidence, especially in young children. Substantial knowledge surrounding human disease pathogenesis exists, such that T1D is now predictable with the measurement of antibodies in the peripheral blood directed against insulin and other ß cell proteins. With the ability to predict, it naturally follows that T1D should be preventable. As such, over the last two decades, numerous well-controlled clinical trials have been completed attempting to prevent diabetes onset or maintain residual ß cell function after clinical onset, all providing relatively disappointing results. Here, we review the T1D prevention efforts, the current landscape of clinical therapies, and end with a discussion regarding the future outlook for preventing T1D.

Clinical Features and HLA Genetics Differ in Children at Type 1 Diabetes Onset by Hispanic Ethnicity.

CONTEXT: Type 1 diabetes incidence continues to increase in children, especially among Hispanic Whites (HW). OBJECTIVE: We investigated the clinical, immunologic, and genetic characteristics of HW and Non-Hispanic White (NHW) children that presented at type 1 diabetes diagnosis. METHODS: In this single-center, observational study, children who were diagnosed with type 1 diabetes (<20 years old) and tested for islet autoantibodies within 1 year of diagnosis were included in the study and divided into two groups by Hispanic ethnicity. RESULTS: Of 1297 children, 398 HW children presented with a younger age at diabetes onset (10.2 ± 3.9 vs. 11.1 ± 4.1 years, p<0.001) and more diabetic ketoacidosis (62.4% vs. 51.9%, p<0.001) compared to NHW children (n=899). There was no difference in sex, A1c levels, or the number and prevalence of islet autoantibodies between the two cohorts. A subset of our cohort was HLA typed as specific alleles confer strong genetic risk for type 1 diabetes (e.g., HLA-DR4 and DQ8). Among 637 HLA-typed children, HW children had a significantly higher prevalence of the DR4-DQ8 haplotype compared to NHW children (79.1% vs. 60.1%, p<0.001), and this frequency was much higher than a reference Hispanic population (OR = 6.5, 95% CI 4.6-9.3). CONCLUSIONS: Hispanic White children developing type 1 diabetes have a high prevalence of HLA DR4-DQ8, which can be utilized to select individuals for immune monitoring with islet autoantibodies to lessen diabetic ketoacidosis and potentially prevent diabetes onset.

Pediatric Endocrine Society Statement on Considerations for Use of Teplizumab (Tzield™) in Clinical Practice.

Teplizumab (TzieldTM, Provention Bio), a monoclonal antibody directed at T-cell marker CD3, is the first medication approved by the FDA to delay progression from stage 2 to stage 3 type 1 diabetes. To date, the overwhelming majority of pediatric endocrinologists do not have experience using immunotherapeutics and seek guidance on the use of teplizumab in clinical practice. To address this need, the Pediatric Endocrine Society (PES) Diabetes Special Interest Group (Diabetes SIG) and Drug and Therapeutics Committee assembled a task force to review clinical trial data and solicit expert recommendations on the approach to teplizumab infusions. We present considerations on all aspects of teplizumab administration, utilizing evidence where possible and providing a spectrum of expert opinions on unknown aspects. We discuss patient selection and prescreening, highlighting the safety and considerations for monitoring and treatment of side effects. We propose a schedule of events, a protocol for administration, and discuss practice management aspects. We advocate for the need for further long-term systematic surveillance studies to continue evaluating the efficacy and safety of teplizumab.

Lower Prevalence of Diabetic Ketoacidosis at Diagnosis in Research Participants Monitored for Hyperglycemia.

CONTEXT: In Colorado children, the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) has been increasing over time. OBJECTIVE: Evaluate the prevalence of and factors involved in DKA at T1D diagnosis among participants followed in monitoring research studies before diagnosis compared to patients from the community. SETTING AND PARTICIPANTS: Patients < 18 years diagnosed with T1D between 2005 and 2021 at the Barbara Davis Center for Diabetes. OUTCOME: Prevalence of and factors associated with DKA at diagnosis among participants in preclinical monitoring studies compared to those diagnosed in the community. RESULTS: Of 5049 subjects, 164 were active study participants, 42 inactive study participants, and 4843 were community patients. Active study participants, compared to community patients, had lower HbA1c (7.3% vs 11.9%]; P < 0.001) and less frequently experienced DKA (4.9% vs 48.5%; P < 0.001), including severe DKA (1.2% vs 16.2%; P < 0.001). Inactive study participants had intermediate levels for both prevalence and severity of DKA. DKA prevalence increased in community patients, from 44.0% to 55%, with less evidence for a temporal trend in study participants. DKA prevalence was highest in children <2 years (13% in active study participants vs 83% in community patients). In community patients, younger age (P = 0.0038), public insurance (P < 0.0001), rural residence (P < 0.0076), higher HbA1c (P < 0.0001), and ethnicity minority status (P < 0.0001) were associated with DKA at diagnosis. CONCLUSIONS: While DKA prevalence increases in community patients over time, it stayed <5% in active research participants, who have a 10 times lower prevalence of DKA at diagnosis, including in minorities.

Screening and Prevention of Type 1 Diabetes: Where Are We?

A diagnosis of type 1 diabetes (T1D) and the subsequent requirement for exogenous insulin treatment is associated with considerable acute and chronic morbidity and a substantial effect on patient quality of life. Importantly, a large body of work suggests that early identification of presymptomatic T1D can accurately predict clinical disease, and when paired with education and monitoring, can yield improved health outcomes. Furthermore, a growing cadre of effective disease-modifying therapies provides the potential to alter the natural history of early stages of T1D. In this mini review, we highlight prior work that has led to the current landscape of T1D screening and prevention, as well as challenges and next steps moving into the future of these rapidly evolving areas of patient care.

Historical Insights and Current Perspectives on the Diagnosis and Management of Presymptomatic Type 1 Diabetes.

Objective: The article provides practical guidance for (1) interpreting and confirming islet autoantibody screening results for type 1 diabetes (T1D) and (2) follow-up of individuals with early stages of T1D with the goal of ensuring medical safety and providing patients and their families with an assessment of risk for progression to a clinical diagnosis of T1D. Research Design and Methods: We used an explicit a priori methodology to identify areas of agreement and disagreement in how to manage patients with early T1D. We used a modified Delphi method, which is a systematic, iterative approach to identifying consensus. We developed a list of topic questions, ranked them by importance, and developed consensus statements based on available evidence and expert opinion around each of the 30 topic questions consistently ranked as being most important. Results: Consensus statements for screening and monitoring are supported with figures proposing an algorithm for confirmation of T1D diagnosis and management of early T1D until clinical diagnosis. Conclusions: Disseminating and increasing knowledge related to how to interpret T1D screening tests, confirm early T1D diagnosis and monitor for medical safety and clinical disease risk prediction is critically important as there are currently no clinical recommendations. Published guidance will promote better management of T1D screening-detected individuals.

Anxiety and Risk Perception in Parents of Children Identified by Population Screening as High Risk for Type 1 Diabetes.

OBJECTIVE: To assess anxiety and risk perception among parents whose children screened positive for islet autoantibodies, indicating elevated risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: The Autoimmunity Screening for Kids (ASK) study identified 319 children age 1 to 17 years at risk for T1D via screening for islet autoantibodies; 280 children with confirmed islet autoantibodies and their caregivers enrolled in a follow-up education and monitoring program to prevent diabetic ketoacidosis at diagnosis. Parents completed questionnaires at each monitoring visit, including a 6-item version of the State Anxiety Inventory (SAI), to assess anxiety about their child developing T1D, and a single question to assess risk perception. RESULTS: At the first ASK follow-up monitoring visit, mean parental anxiety was elevated above the clinical cutoff of 40 (SAI 46.1 ± 11.2). At the second follow-up monitoring visit (i.e., visit 2), mean anxiety remained elevated but started to trend down. Approximately half (48.9%) of parents reported their child was at increased risk for T1D at the initial follow-up monitoring visit (visit 1). Parents of children with more than one islet autoantibody and a first-degree relative with T1D were more likely to report their child was at increased risk. CONCLUSIONS: Most parents of autoantibody-positive children have high anxiety about their child developing T1D. Information about the risk of developing T1D is difficult to convey, as evidenced by the wide range of risk perception reported in this sample.

Temporal development of T cell receptor repertoires during childhood in health and disease.

T cell receptor (TCR) sequences are exceptionally diverse and can now be comprehensively measured with next-generation sequencing technologies. However, a thorough investigation of longitudinal TCR repertoires throughout childhood in health and during development of a common childhood disease, type 1 diabetes (T1D), has not been undertaken. Here, we deep sequenced the TCR-ß chain repertoires from longitudinal peripheral blood DNA samples at 4 time points beginning early in life (median age of 1.4 years) from children who progressed to T1D (n = 29) and age/sex-matched islet autoantibody-negative controls (n = 25). From 53 million TCR-ß sequences, we show that the repertoire is extraordinarily diverse early in life and narrows with age independently of disease. We demonstrate the ability to identify specific TCR sequences, including those known to recognize influenza A and, separately, those specific for insulin and its precursor, preproinsulin. Insulin-reactive TCR-ß sequences were more common and frequent in number as the disease progressed in those who developed T1D compared with genetically at risk nondiabetic children, and this was not the case for influenza-reactive sequences. As an independent validation, we sequenced and analyzed TCR-ß repertoires from a cohort of new-onset T1D patients (n = 143), identifying the same preproinsulin-reactive TCRs. These results demonstrate an enrichment of preproinsulin-reactive TCR sequences during the progression to T1D, highlighting the importance of using disease-relevant TCR sequences as powerful biomarkers in autoimmune disorders.

High-Throughput Multiplex Electrochemiluminescence Assay Applicable to General Population Screening for Type 1 Diabetes and Celiac Disease.

Objective: Large-scale screening of the general population for islet autoantibodies (IAbs) to detect type 1 diabetes (T1D) has started worldwide. The standard screening method of separate radio-binding assay (RBA) for each IAb is an inefficient bottleneck. Furthermore, most positive results by RBA in screening of general population individuals without a clinical diagnosis of T1D are low-affinity and not predictive of future diabetes. Research Design and Methods: We have developed and validated a novel 6-Plex assay based on electrochemiluminescence (ECL) technology that combines in a single well high-affinity IAbs (to insulin, GAD, IA-2, and ZnT8), transglutaminase autoantibodies for celiac disease, and severe acute respiratory syndrome coronavirus 2 antibodies. The Autoimmunity Screening for Kids (ASK) provided 880 serum samples, from 828 children aged 1-17 years without diabetes who were previously tested for IAbs using single ECL assays and RBA assays. Results: Levels of all six antibodies in the 6-Plex ECL assay correlated well with respective single ECL assay levels. Similar to single ECL assays, the 6-Plex ECL assay positivity was congruent with the RBA in 95% (35/37) of children who later developed T1D and in 88% (105/119) high-risk children with multiple IAbs. In contrast, only 56% (86/154, P < 0.0001) of children with persistent single IAb by RBA were found to be positive by 6-Plex ECL assay. Of 555 samples negative for all IAbs by RBA, few (0.2%-0.5%) were positive at low levels in the 6-Plex ECL assay. Conclusions: The study demonstrated that the 6-Plex ECL assay compares favorably to the standard RBAs in terms of disease specificity for general population screening in children. The 6-Plex ECL assay was therefore adopted as the primary screening tool in the general population screening ASK program with advantages of high efficiency, low cost, and low serum volume.

Peripheral immunophenotyping of AITD subjects reveals alterations in immune cells in pediatric vs adult-onset AITD.

Autoimmune thyroid disease (AITD) is caused by aberrant activation of the immune system allowing autoreactive B and T cells to target the thyroid gland leading to disease. Although AITD is more frequently diagnosed in adults, children are also affected but rarely studied. Here, we performed phenotypic and functional characterization of peripheral blood immune cells from pediatric and adult-onset AITD patients and age-matched controls using mass cytometry. Major findings indicate that unlike adult-onset AITD patients, pediatric AITD patients exhibit a decrease in anergic B cells (BND) and DN2 B cells and an increase in immature B cells compared to age-matched controls. These results indicate alterations in peripheral blood immune cells seen in pediatric-onset AITD could lead to rapid progression of disease. Hence, this study demonstrates diversity of AITD by showing differences in immune cell phenotypes and function based on age of onset, and may inform future therapies.

Weight Management in Youth with Type 1 Diabetes and Obesity: Challenges and Possible Solutions.

PURPOSE OF REVIEW: This review highlights challenges associated with weight management in children and adolescents with type 1 diabetes (T1D). Our purpose is to propose potential solutions to improve weight outcomes in youth with T1D. RECENT FINDINGS: A common barrier to weight management in T1D is reluctance to engage in exercise for fear of hypoglycemia. Healthcare practitioners generally provide limited guidance for insulin dosing and carbohydrate modifications to maintain stable glycemia during exercise. Adherence to dietary guidelines is associated with improved glycemia; however, youth struggle to meet recommendations. When psychosocial factors are addressed in combination with glucose trends, this often leads to successful T1D management. Newer medications also hold promise to potentially aid in glycemia and weight management, but further research is necessary. Properly addressing physical activity, nutrition, pharmacotherapy, and psychosocial factors while emphasizing weight management may reduce the likelihood of obesity development and its perpetuation in this population.

One-Hour Oral Glucose Tolerance Tests for the Prediction and Diagnostic Surveillance of Type 1 Diabetes.

CONTEXT: Once islet autoantibody-positive individuals are identified, predicting which individuals are at highest risk for type 1 diabetes (T1D) is important. A metabolic risk score derived from 2-hour oral glucose tolerance test (OGTT) data, the Diabetes Prevention Trial-Type 1 risk score (DPTRS), can accurately predict T1D. However, 2-hour OGTTs are time-consuming and costly. OBJECTIVE: We aimed to determine whether a risk score derived from 1-hour OGTT data can predict T1D as accurately as the DPTRS. Secondarily, we evaluated whether a 1-hour glucose value can be used for diagnostic surveillance. METHODS: The DPTRS was modified to derive a 1-hour OGTT risk score (DPTRS60) using fasting C-peptide, 1-hour glucose and C-peptide, age, and body mass index. Areas under receiver operating curves (ROCAUCs) were used to compare prediction accuracies of DPTRS60 with DPTRS in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 654) and TrialNet Pathway to Prevention (TNPTP) (n = 4610) participants. Negative predictive values (NPV) for T1D diagnosis were derived for 1-hour glucose thresholds. RESULTS: ROCAUCs for T1D prediction 5 years from baseline were similar between DPTRS60 and DPTRS (DPT-1: 0.805 and 0.794; TNPTP: 0.832 and 0.847, respectively). DPTRS60 predicted T1D significantly better than 2-hour glucose (P < .001 in both cohorts). A 1-hour glucose of less than 180 mg/dL had a similar NPV, positive predictive value, and specificity for T1D development before the next 6-month visit as the standard 2-hour threshold of less than 140 mg/dL (both ≥ 98.5%). CONCLUSION: A 1-hour OGTT can predict T1D as accurately as a 2-hour OGTT with minimal risk of missing a T1D diagnosis before the next visit.

Failed Genetic Protection: Type 1 Diabetes in the Presence of HLA-DQB1*06:02.

Certain HLA class II genes increase the risk for type 1 diabetes (T1D) development while others provide protection from disease development. HLA class II alleles encode MHC proteins on antigen-presenting cells, which function to present peptides and activate CD4 T cells. The DRB1*15:01 (DR15)-DQA1*01:02-DQB1*06:02 (DQ6) haplotype provides dominant protection across all stages of T1D and is a common haplotype found in Caucasians. However, it is present in <1% of people with T1D. Knowing which metabolic, immunologic, and genetic features are unique to individuals who fail genetic protection and develop T1D is important for defining the underlying mechanisms of DQB1*06:02-mediated protection. We describe a T1D cohort with DQB1*06:02 (n = 50) and compare them to individuals with T1D and without DQB1*06:02 (n = 2,759) who were identified over the last 26 years at the Barbara Davis Center for Diabetes. The age at diagnosis was similar between the cohorts and normally distributed throughout childhood and early adulthood. The average hemoglobin A1c was 10.8 ± 2.8% (95 ± 7 mmol/mol) at diagnosis in those DQB1*06:02 positive. The majority of T1D DQB1*06:02 + individuals were positive for one or more islet autoantibodies; however, there was a greater proportion who were islet autoantibody negative compared with those T1D DQB1*06:02 - individuals. Interestingly, DQB1*03:02, which confers significant T1D risk, was present in only those DQB1*06:02 + individuals with islet autoantibodies. This is one of the largest studies examining patients presenting with clinical T1D in the presence of DQB1*06:02, which provides a population to study the mechanisms of failed genetic protection against T1D.

B cells in type 1 diabetes mellitus and diabetic kidney disease.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder that affects an estimated 30 million people worldwide. It is characterized by the destruction of pancreatic ß cells by the immune system, which leads to lifelong dependency on exogenous insulin and imposes an enormous burden on patients and health-care resources. T1DM is also associated with an increased risk of comorbidities, such as cardiovascular disease, retinopathy, and diabetic kidney disease (DKD), further contributing to the burden of this disease. Although T cells are largely considered to be responsible for ß-cell destruction in T1DM, increasing evidence points towards a role for B cells in disease pathogenesis. B cell-depletion, for example, delays disease progression in patients with newly diagnosed T1DM. Loss of tolerance of islet antigen-reactive B cells occurs early in disease and numbers of pancreatic CD20+ B cells correlate with ß-cell loss. Although the importance of B cells in T1DM is increasingly apparent, exactly how these cells contribute to disease and its comorbidities, such as DKD, is not well understood. Here we discuss the role of B cells in the pathogenesis of T1DM and how these cells are activated during disease development. Finally, we speculate on how B cells might contribute to the development of DKD.