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.

Longitudinal Assessment of Pancreas Volume by MRI Predicts Progression to Stage 3 Type 1 Diabetes.

OBJECTIVE: This multicenter prospective cohort study compared pancreas volume as assessed by MRI, metabolic scores derived from oral glucose tolerance testing (OGTT), and a combination of pancreas volume and metabolic scores for predicting progression to stage 3 type 1 diabetes (T1D) in individuals with multiple diabetes-related autoantibodies. RESEARCH DESIGN AND METHODS: Pancreas MRI was performed in 65 multiple autoantibody-positive participants enrolled in the Type 1 Diabetes TrialNet Pathway to Prevention study. Prediction of progression to stage 3 T1D was assessed using pancreas volume index (PVI), OGTT-derived Index60 score and Diabetes Prevention Trial-Type 1 Risk Score (DPTRS), and a combination of PVI and DPTRS. RESULTS: PVI, Index60, and DPTRS were all significantly different at study entry in 11 individuals who subsequently experienced progression to stage 3 T1D compared with 54 participants who did not experience progression (P < 0.005). PVI did not correlate with metabolic testing across individual study participants. PVI declined longitudinally in the 11 individuals diagnosed with stage 3 T1D, whereas Index60 and DPTRS increased. The area under the receiver operating characteristic curve for predicting progression to stage 3 from measurements at study entry was 0.76 for PVI, 0.79 for Index60, 0.79 for DPTRS, and 0.91 for PVI plus DPTRS. CONCLUSIONS: These findings suggest that measures of pancreas volume and metabolism reflect distinct components of risk for developing stage 3 type 1 diabetes and that a combination of these measures may provide superior prediction than either alone.

Identification of an anergic BND cell-derived activated B cell population (BND2) in young-onset type 1 diabetes patients.

Recent evidence suggests a role for B cells in the pathogenesis of young-onset type 1 diabetes (T1D), wherein rapid progression occurs. However, little is known regarding the specificity, phenotype, and function of B cells in young-onset T1D. We performed a cross-sectional analysis comparing insulin-reactive to tetanus-reactive B cells in the blood of T1D and controls using mass cytometry. Unsupervised clustering revealed the existence of a highly activated B cell subset we term BND2 that falls within the previously defined anergic BND subset. We found a specific increase in the frequency of insulin-reactive BND2 cells in the blood of young-onset T1D donors, which was further enriched in the pancreatic lymph nodes of T1D donors. The frequency of insulin-binding BND2 cells correlated with anti-insulin autoantibody levels. We demonstrate BND2 cells are pre-plasma cells and can likely act as APCs to T cells. These findings identify an antigen-specific B cell subset that may play a role in the rapid progression of young-onset T1D.

Association of High-Affinity Autoantibodies With Type 1 Diabetes High-Risk HLA Haplotypes.

OBJECTIVE: Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes. METHODS: We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least 1 RBA diabetes-related Ab [glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (IAA)] and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (z-scores) for analyses. RESULTS: Mean age at initial visit was 19.4 ± 13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA-DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (P < 0.05). CONCLUSIONS: ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

Ethanol teratogenesis in five inbred strains of mice.

BACKGROUND: Previous studies have demonstrated individual differences in susceptibility to the detrimental effects of prenatal ethanol exposure. Many factors, including genetic differences, have been shown to play a role in susceptibility and resistance, but few studies have investigated the range of genetic variation in rodent models. METHODS: We examined ethanol teratogenesis in 5 inbred strains of mice: C57BL/6J (B6), Inbred Short-Sleep, C3H/Ibg, A/Ibg, and 129S6/SvEvTac (129). Pregnant dams were intubated with either 5.8 g/kg ethanol (E) or an isocaloric amount of maltose-dextrin (MD) on day 9 of pregnancy. Dams were sacrificed on day 18 and fetuses were weighed, sexed, and examined for gross morphological malformations. Every other fetus within a litter was then either placed in Bouin's fixative for subsequent soft-tissue analyses or eviscerated and placed in ethanol for subsequent skeletal analyses. RESULTS: B6 mice exposed to ethanol in utero had fetal weight deficits and digit, kidney, brain ventricle, and vertebral malformations. In contrast, 129 mice showed no teratogenesis. The remaining strains showed varying degrees of teratogenesis. CONCLUSIONS: Differences among inbred strains demonstrate genetic variation in the teratogenic effects of ethanol. Identifying susceptible and resistant strains allows future studies to elucidate the genetic architecture underlying prenatal alcohol phenotypes.