Objectives: The goal was to implement a risk profile that would prospectively identify youth with T1D at risk of severe hypoglycemia (SH) over the course of 1 year. We hypothesized that subjects with ...specific risk factors such as prior SH, a high frequency of nocturnal hypoglycemia (NH), and impaired hypoglycemia awareness would have a high rate of SH within the following year. If confirmed, an accurate assessment can lead to efficient application of interventions to reduce future risk of SH.
Methods: 404 subjects were followed for 14 months for SH, defined as a seizure, coma or loss of consciousness in the setting of presumed hypoglycemia (ISPAD guidelines). Subjects completed a survey that queried about SH, NH, and hypoglycemia unawareness. Comparisons were made using Chi-squared or Fisher’s exact tests for categorical variables and Wilcoxon Rank-Sum tests for continuous variables.
Results: Of the 404 enrolled, 18 subjects had SH in 14 months (4.46%). In the univariate analysis, those who had SH had indicated SH on the enrollment questionnaire (p-value 0.0015) and hypoglycemia unawareness as always or often (p-value 0.0259). Subjects with SH were more likely to wear CGMs (p-value 0.0369). Subject characteristics, T1D management, insurance, and NH were not statistically significant. In addition, we evaluated the 13 subjects who indicated on their initial questionnaire SH in the prior three months. In the univariate analysis, those subjects had more NH defined as ≥2 nights in a 3 month period (P=0.006) and less hypoglycemia awareness (P=0.030). With regards to insulin management, they had a lower insulin sensitivity factor (P=0.012) and higher proportion of basal insulin (P=0.003).
Conclusions: In a diverse cohort of T1D, this study shows the ability to identify pediatric subjects at risk for SH with hypoglycemia unawareness and prior SH. As SH is a rare event, as this study is expanded, there is the opportunity for a scored risk questionnaire to capture T1D youth at risk for SH.
Disclosure
K. Cossen: None. J. Figueroa: None. A.B. Muir: None.
Background: Depression in teens with type 1 diabetes (T1DM) is associated with poor disease management. Multiple depression screening questionnaires are validated in teens with chronic disease; no ...ideal instrument has been identified.
Methods: Subjects aged 11 - 17 years with T1DM, completed the PROMIS and PHQ-9 on the same day (n=20), within 3 months (n=17), or within 6 months (n=11). PHQ-9 was completed by the subject and PROMIS was completed by the subject (PROMIS-Ch) and a parent (PROMIS-P). 1-way ANOVA determined statistical significance.
Results:
1. Subjects with no or mild risk of depression on PHQ-9 had a PROMIS-Ch or PROMIS-P score >1.5 SD.
2. Clinical evaluation confirmed risk for depression in 5/6 subjects with moderate/severe risk on PHQ-9. PROMIS-Ch >1.5 SD in 2/5 subjects and PROMIS-P score >2 SD in 1/5 subjects.
3. Mean PHQ-9 score of 4 subjects with documented suicidal ideation (SI) was 18.4 (±6.7). The PROMIS-Ch was >1.5 SD in 2 of 4; PROMIS-P was >1.5 SD in 1 of 4.
Conclusions: Both surveys distinguished children at moderate/severe risk of depression from those with no/mild risk. Neither PROMIS survey distinguished between children who were at mild or no risk on PHQ-9. Those with SI had mean high risk PHQ-9 score, but did not have consistently high risk PROMIS scores. When screening for depression in adolescents, PHQ-9 had a higher sensitivity when compared to PROMIS.
Disclosure
S. Nadella: None. S.P. Fritz: None. A.B. Muir: None.
Thyroid hormones are essential for proper neurodevelopment in early life. There is evidence that exposure to polybrominated diphenyl ethers (PBDEs) affects thyroid function, but previous studies have ...been inconsistent, and no studies among children have been conducted in the United States where PBDE levels are particularly high. Serum levels of seven PBDE congeners and thyroid hormones and other thyroid parameters were measured in 80 children aged 1–5 years from the southeastern United States between 2011 and 2012. Parents of the children completed questionnaires with details on demographics and behaviors. Multivariate linear regression models were used to estimate the associations between serum PBDE levels, expressed as quartiles and as log-transformed continuous variables, and markers of thyroid function. BDE-47, 99, 100 and 153 were detected in >60% of samples, and were summed (∑PBDE). PBDE congeners and ∑PBDE were positively associated with thyroid-stimulating hormone (TSH). A log-unit increase in ∑PBDE was associated with a 22.1% increase in TSH (95% CI: 2.0%, 47.7%). Compared with children in the lowest quartile of ∑PBDE exposure, children in higher quartiles had greater TSH concentrations as modeled on the log-scale (second quartile: β=0.32, 95% confidence interval (CI): −0.09, 0.74; third quartile: β=0.44, 95% CI: 0.04, 0.85; and fourth quartile: β=0.49, 95% CI: 0.09, 0.89). There was also a tendency toward lower total T4 and higher free T3 with increasing PBDE exposure. Results suggest that exposure to PBDEs during childhood subclinically disrupts thyroid hormone function, with impacts in the direction of hypothyroidism.
•First study in US children on polybrominated diphenyl ethers and thyroid function.•PBDE serum levels were positively associated with thyroid-stimulating hormone.•Suggestion of lower total thyroxine and higher free triiodothyronine.•Subclinical disruption of thyroid hormones in the direction of hypothyroidism.
Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or ...prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.
We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests.
A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline.
Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.
Prior studies identified HLA class-II and 57 additional loci as contributors to genetic susceptibility for type 1 diabetes (T1D). We hypothesized that race and/or ethnicity would be contextually ...important for evaluating genetic risk markers previously identified from Caucasian/European cohorts. We determined the capacity for a combined genetic risk score (GRS) to discriminate disease-risk subgroups in a racially and ethnically diverse cohort from the southeastern U.S. including 637 T1D patients, 46 at-risk relatives having two or more T1D-related autoantibodies (≥2AAb
), 790 first-degree relatives (≤1AAb
), 68 second-degree relatives (≤1 AAb
), and 405 controls. GRS was higher among Caucasian T1D and at-risk subjects versus ≤ 1AAb
relatives or controls (P < 0.001). GRS receiver operating characteristic AUC (AUROC) for T1D versus controls was 0.86 (P < 0.001, specificity = 73.9%, sensitivity = 83.3%) among all Caucasian subjects and 0.90 for Hispanic Caucasians (P < 0.001, specificity = 86.5%, sensitivity = 84.4%). Age-at-diagnosis negatively correlated with GRS (P < 0.001) and associated with HLA-DR3/DR4 diplotype. Conversely, GRS was less robust (AUROC = 0.75) and did not correlate with age-of-diagnosis for African Americans. Our findings confirm GRS should be further used in Caucasian populations to assign T1D risk for clinical trials designed for biomarker identification and development of personalized treatment strategies. We also highlight the need to develop a GRS model that accommodates racial diversity.
IL-12 and IL-18 synergize to promote TH1 responses and have been implicated as accelerators of autoimmune pathogenesis in type 1 diabetes (T1D). We investigated the influence of these cytokines on ...immune cells involved in human T1D progression: natural killer (NK) cells, regulatory T cells (Tregs), and cytotoxic T lymphocytes (CTL). NK cells from T1D patients exhibited higher surface CD226 versus controls and lower CD25 compared to first-degree relatives and controls. Changes in NK cell phenotype towards terminal differentiation were associated with cytomegalovirus (CMV) seropositivity, while possession of IL18RAP, IFIH1, and IL2RA T1D-risk variants impacted NK cell activation as evaluated by immuno-expression quantitative trait loci (eQTL) analyses. IL-12 and IL-18 stimulated NK cells from healthy donors exhibited enhanced specific killing of myelogenous K562 target cells. Moreover, activated NK cells increased expression of NKG2A, NKG2D, CD226, TIGIT and CD25, which enabled competition for IL-2 upon co-culture with Tregs, resulting in Treg downregulation of FOXP3, production of IFNγ, and loss of suppressive function. We generated islet-autoreactive CTL “avatars”, which upon exposure to IL-12 and IL-18, upregulated IFNγ and Granzyme-B leading to increased lymphocytotoxicity of a human β-cell line in vitro. These results support a model for T1D pathogenesis wherein IL-12 and IL-18 synergistically enhance CTL and NK cell cytotoxic activity and disrupt immunoregulation by Tregs.
Working Model Summarizing the Hypothesized Contributions of Elevated IL-12 and IL-18 Levels Toward Failure in Immunoregulation and T1D Pathogenesis. In immune homeostasis (left), regulatory T cells (Treg) suppress activation and function of CD8+T cells, CD4+T cells and NK cells via various mechanisms including competition for IL-2. In settings of increased genetic risk for T1D, exposure to some environmental trigger(s) compound genetic defects to induce a break in tolerance (right), during which time IL-12 and IL-18 levels are elevated and NK cells upregulate CD25. This allows for direct competition with Tregs for IL-2, resulting in decreased Treg IL-2 signaling, STAT5 phosphorylation (pSTAT5), and FOXP3 expression, ultimately abrogating suppression. We hypothesize that this, together with enhanced production of cytokines and cytolytic proteins by CD4+conventional T cells and CD8+cytotoxic T cells, leads to augmented lysis of β-cells (right). Display omitted
•IL-12 & IL-18 enhance NK cell and antigen specific CD8 T cell killing.•Regulatory T cells (Tregs) lose suppressive capacity and produce IFN-γ.•Type 1 Diabetes candidate genes permit CD25 upregulation on NK cells.•NK cells exhibit altered receptor balance and are able to compete with Tregs for IL-2 in vitro.
Background and Aim: Suboptimal representation of race/ethnic minorities in clinical research contributes to critical gaps in our knowledge of diabetes in these populations. We aimed to evaluate the ...participation of AA and Hisp youth in an observational study in diabetes to assess factors impacting participation.
Methods: We studied 92 participants in the Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) that is currently enrolling youth (age 0-yrs) with non-secondary diabetes for collection of data and blood samples. We compared racial/ethnic distribution of actual vs. target enrollment and refusal rates by race/ethnicity. We analyzed qualitative data on reasons for study refusal.
Results: The racial/ethnic distribution of participants was 60.9% Hisp, 27.2% AA, 12.0% non-Hispanic white NHW and 0% other, vs. enrollment targets of 35.3% Hisp, 31.8% AA, 29.9% NHW and 3% other (p=0.001) . In the population of eligible candidates, 31.1% of the children were Hisp, 18.8% AA, 42.2% NHW and 7.9% other. Refusal rates were 20.0%, 16.7%, 38.9% and 100%, respectively, for Hisp, AA, NHW and other (p=0.072) . Among those who refused, the reasons noted were no interest in research (44.4% overall, 80% in AA youth) , blood draw (29.6% overall, 42.6% in Hisp youth) , no direct benefit to the participant (11.1%) , and being too busy (18.5%) or overwhelmed by the recent diabetes diagnosis (11.1%) . NHW youth cited the first 3 reasons, with similar frequency, for refusal.
Conclusions: Refusal rates were not elevated in AA and Hisp children compared with NHW. Actual enrollment was statistically different from the target, with over-representation of Hisp youth and underrepresentation of NHW youth. Facilitators of racial/ethnic minority participation in research studies may include diverse racial/ethnic distribution in the population where the study is conducted, a trusted environment, race/ethnicity concordance with research team members, and a minimally invasive study protocol.
Disclosure
M.J. Redondo: Advisory Panel; Provention Bio, Inc. M. Tosur: Advisory Panel; Provention Bio, Inc. A.B. Muir: None. S. Iftekhar: None. S. Deen: None. D.J. Perry: None. D.H. Glueck: None. K. Vehik: None. R.A. Oram: Consultant; Janssen Research & Development, LLC. Research Support; Randox R & D. W. Hagopian: Research Support; Janssen Research & Development, LLC. D. Dabelea: None. M.A. Atkinson: None.
Funding
NIH NIDDK RDK124395
T lymphocytes constitute a major effector cell population in autoimmune type 1 diabetes. Despite essential functions of mitochondria in regulating activation, proliferation, and apoptosis of T cells, ...little is known regarding T cell metabolism in the progression of human type 1 diabetes. In this study, we report, using two independent cohorts, that T cells from patients with type 1 diabetes exhibited mitochondrial inner-membrane hyperpolarization (MHP). Increased MHP was a general phenotype observed in T cell subsets irrespective of prior antigen exposure, and was not correlated with HbA1C levels, subject age, or duration of diabetes. Elevated T cell MHP was not detected in subjects with type 2 diabetes. T cell MHP was associated with increased activation-induced IFNγ production, and activation-induced IFNγ was linked to mitochondria-specific ROS production. T cells from subjects with type 1 diabetes also exhibited lower intracellular ATP levels. In conclusion, intrinsic mitochondrial dysfunction observed in type 1 diabetes alters mitochondrial ATP and IFNγ production; the latter is correlated with ROS generation. These changes impact T cell bioenergetics and function.
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