Hydroxychloroquine in Stage 1 Type 1 Diabetes.

OBJECTIVE: Innate immune responses may be involved in the earliest phases of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: To test whether blocking innate immaune cells modulated progression of the disease, we randomly assigned 273 individuals with stage 1 T1D to treatment with hydroxychloroquine (n = 183; 5 mg/kg per day to a maximum of 400 mg) or placebo (n = 90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e., two or more islet autoantibodies with abnormal glucose tolerance). RESULTS: After a median follow-up of 23.3 months, the trial was stopped prematurely by the data safety monitoring board because of futility. There were no safety concerns in the hydroxychloroquine arm, including in annual ophthalmologic examinations. Preplanned secondary analyses showed a transient decrease in the glucose average area under the curve to oral glucose in the hydroxychloroquine-treated arm at month 6 and reduced titers of anti-GAD and anti-insulin autoantibodies and acquisition of positive autoantibodies in the hydroxychloroquine arm (P = 0.032). CONCLUSIONS: We conclude that hydroxychloroquine does not delay progression to stage 2 T1D in individuals with stage 1 disease. Drug treatment reduces the acquisition of additional autoantibodies and the titers of autoantibodies to GAD and insulin.

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining ß-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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Innate inflammation drives NK cell activation to impair Treg activity.

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 ß-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.

Application of a Genetic Risk Score to Racially Diverse Type 1 Diabetes Populations Demonstrates the Need for Diversity in Risk-Modeling.

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.

Depressive Symptoms at Critical Times in Youth With Type 1 Diabetes: Following Type 1 Diabetes Diagnosis and Insulin Pump Initiation.

PURPOSE: Depressive symptoms occur at various times during the life cycle in persons with type 1 diabetes. We investigated depressive symptoms prospectively in youth with new-onset type 1 diabetes and in those beginning pump therapy. METHODS: Youth with type 1 diabetes (N = 96), ages 10-17 years, completed the Children's Depression Inventory (CDI) at baseline and at 1, 6, and 12 months after diabetes onset or pump start; scores ≥13 indicated clinical elevation. The change in depressive symptoms and the association between CDI score and hemoglobin A1c (HbA1c) level were assessed over 1 year. RESULTS: The new-onset group (n = 54) had an HbA1c level of 11.4% ± 2.5%. The pump group (n = 42) had a diabetes duration of 4.1 ± 3.4 years and an HbA1c level of 8.3% ± 1.3%. The baseline median CDI was 5.0 in both groups and remained low over time (ranging from 2.0 to 3.5). Most youth (new onset 72%, pump 81%) scored <13 at all times. Those with a CDI score of ≥13 in month 1 had 9-fold (95% confidence interval: 3-28) and 11-fold (95% confidence interval: 3-38) higher risks of CDI score of ≥13 at 6 and 12 months, respectively, than those with a CDI score of <13. New-onset youth with a CDI score of ≥13 in month 1 had a higher HbA1c level at 6 months (8.3% ± 1.7%) than new-onset youth with a CDI score of <13 (7.2% ± 1.6%, p = .04). CONCLUSIONS: CDI scores over 1 year were similar in the new-onset and pump groups. Youth with elevated CDI in the first month after diagnosis or pump start were significantly more likely to have a CDI score of ≥13 at 6 or 12 months, supporting recommendations to screen for depressive symptoms because of persistence over time. Those with new-onset diabetes and depressive symptoms in the first month had higher HbA1c at 6 months; confirmatory research is needed.

Examination of Psychosocial and Physiological Risk for Bulimic Symptoms in Youth With Type 1 Diabetes Transitioning to an Insulin Pump: A Pilot Study.

Objectives: This study tested hypotheses drawn from a risk model positing that psychosocial risk plus disease-related and treatment factors contribute to bulimic symptoms in youth with type 1 diabetes (T1D) transitioning to an insulin pump. The goal of this study was to examine whether disease-related factors, particularly disease- and treatment-based disruption in hunger and satiety, contribute to report of bulimic symptoms in youth with T1D after accounting for psychosocial risk factors. Methods: 43 youth (ages 10-17, 54% female) with established T1D were recruited before transition from multiple daily injections to insulin-pump therapy from three tertiary pediatric diabetes centers. Participants completed measures of bulimic symptoms, depressive symptoms dietary restraint, and the Diabetes Treatment and Satiety Scale, a diabetes-specific questionnaire assessing hunger and satiety cues and eating behavior in response to blood glucose levels and treatment. Results: Hierarchical multiple regression was used to assess contributions of psychosocial and disease-based risk to report of bulimic symptoms. After assessing the contributions of body mass index, body image dissatisfaction, and dietary restraint, a significant 2-way interaction emerged between depression and diabetes-related uncontrollable hunger related to bulimic symptoms (ß = 1.82, p < .01). Conclusions: In addition to psychosocial risk, disease- and treatment-based hunger and satiety dysregulation appear to be important factors contributing to report of bulimic symptoms in youth with T1D. These preliminary findings have significant treatment implications for bulimic symptoms in youth with T1D.

T cells display mitochondria hyperpolarization in human type 1 diabetes.

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.

Depressive Symptoms, Emotion Dysregulation, and Bulimic Symptoms in Youth With Type 1 Diabetes: Varying Interactions at Diagnosis and During Transition to Insulin Pump Therapy.

This study evaluated the associations between depressive symptoms, emotion dysregulation and bulimic symptoms in youth with type 1 diabetes (T1D) in the context of the diagnosis and treatment of T1D. Study participants were 103 youth in 2 distinct groups: newly diagnosed (New) or transitioning to pump therapy (continuous subcutaneous insulin infusion [CSII]; "Pump"), who completed questionnaires regarding symptoms of depression, emotion dysregulation, and bulimia. Glycemic control (A1c), height, weight, and questionnaires were evaluated within 10 days of diagnosis (n = 58) or at education/clinic visit before starting insulin utilizing CSII (n = 45). In the newly diagnosed group, only depression accounted for significant variance in bulimia scores (ß = .47, P < .01). For the group with disease treatment experience (Pump), but not for the newly diagnosed group (New), greater depressive symptoms and emotion dysregulation were associated with greater bulimic symptoms. Depressive symptoms and emotion dysregulation, an indicator of poor coping/behavioral control, could help explain adoption of disordered eating behaviors in youth with T1D who are transitioning to pump therapy.

Serum polybrominated diphenyl ether concentrations and thyroid function in young children.

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: ß=0.32, 95% confidence interval (CI): -0.09, 0.74; third quartile: ß=0.44, 95% CI: 0.04, 0.85; and fourth quartile: ß=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.

Outcomes analysis of radioactive iodine and total thyroidectomy for pediatric Graves' disease.

BACKGROUND: The majority of pediatric patients with Graves' disease will ultimately require definitive therapy in the form of radioactive iodine (RAI) ablation or thyroidectomy. There are few studies that directly compare the efficacy and complication rates between RAI and thyroidectomy. We compared the relapse rate as well as the acute and long-term complications of RAI and total thyroidectomy among children and adolescents with Graves' disease treated at our center. METHODS: Medical records from 81 children and adolescents with a diagnosis of Graves' disease who received definitive therapy over a 12-year period were reviewed. RESULTS: Fifty one patients received RAI and 30 patients underwent thyroidectomy. The relapse rate was not significantly different between RAI and thyroidectomy (12.1% vs. 0.0%, p=0.28). There were no acute or long-term complications in the RAI group, but there were eight cases of hypoparathyroidism (two transient and six permanent) in the thyroidectomy group. None of the patients developed a recurrent laryngeal nerve injury. CONCLUSIONS: RAI is a safe and effective option for treatment of children and adolescents with Graves' disease. In light of the rate of permanent hypoparathyroidism seen at our center with thyroidectomy and previously published long-term safety of RAI, we recommend RAI as the first line treatment for children and adolescents with Graves' disease. For those centers performing thyroidectomies, we recommend that each center select 1-2 high-volume pediatric surgeons to perform all thyroid procedures, allowing individuals to increases case volume and potentially decrease long-term complications of thyroidectomy.

Inter-individual variation in weaning among rhesus macaques (Macaca mulatta): Serum stable isotope indicators of suckling duration and lactation.

Weaning is a transition in early development with major implications for infant survival and well-being, and for maternal lifetime reproductive success. The particular strategy a primate mother adopts in rearing her offspring represents a negotiation between her ability to invest and her need to invest, and can be considered adaptive and influenced by biological and social factors. Any investigation into how and why maternal weaning strategies differ among non-human primates is limited by the precision of the measurement tool used to assess infants' weaning ages. Stable carbon and nitrogen isotope analysis of soft tissues (e.g., hair, nails, feces, urine, blood) offers an objective means of monitoring the weaning status of infants. In this study, we assess stable isotope ratios in blood serum from 14 captive rhesus macaque dyads (Macaca mulatta) at infant ages 2, 5, 6, 7, 8, and 10 months to estimate the timing of weaning events. Male infants wean earlier than female infants. Infants with the lowest birth weights wean latest. Most infants wean upon reaching 2.5 times their birth weights, sooner than when weaning elsewhere has been predicted for captive cercopithecine primates. The longest weaning periods (ca. 10 months) are observed among infants of small mothers. The shortest weaning period, between 2 and 5 months, was among the lowest ranking dyad. Parity and mothers' ages had no discernible effect on the timing of weaning events. The stable carbon and nitrogen isotope values of dams during lactation are significantly different than those of a non-lactating adult female outgroup, raising questions about the suitability and selection of adult comparative baselines in studies where lactating mothers cannot be sampled longitudinally (e.g., bioarchaeology; paleontology). Am. J. Primatol. 78:1113-1134, 2016. © 2015 Wiley Periodicals, Inc.

Growth velocity and weaning δ(15)N "Dips" during ontogeny in Macaca mulatta.

OBJECTIVES: A "dip" in the stable nitrogen isotope ratios (δ(15)N) of subadults in the late weaning/early post-weaning phase of growth and development has been observed. Speculatively, this is the mechanism of positive nitrogen balance operating among rapidly growing subadults. An alternate hypothesis for δ(15)N dips is that during weaning, subadults eat lower-(15)N foods than adults. METHODS: This study explores the role of positive nitrogen balance in affecting δ(15) N variation of growing subadults by comparing growth velocity with stable carbon isotope (δ(13)C) and δ(15)N ratios of blood serum from captive rhesus macaques (Macaca mulatta) (n = 14) with controlled diets during the first 10 months of life. RESULTS: During the first six months, δ(15)N values are inversely correlated with growth in some of the anthropometrics (weight and sagittal circumference). Dips in some infants' δ(15)N values below their mothers' values are observed at the end of the weaning period. However, during this time frame, δ(15)N values of the infants are not correlated with anthropometric indices. Serum stable isotope ratios of lactating and non-lactating adult females differ significantly. CONCLUSIONS: Growth in body mass and size explains some of the variation in infant δ(15)N values, but are not responsible for dips in the late weaning/early post-weaning phase. It is advised that future research evaluate the extent to which growth in other body systems affects nitrogen balance and δ(15)N dips during ontogeny, and expand on isotopic differences between lactating and non-lactating females.

A novel TRPS1 gene mutation causing trichorhinophalangeal syndrome with growth hormone responsive short stature: a case report and review of the literature.

The role of growth hormone (GH) and its therapeutic supplementation in the trichorhinophalangeal syndrome type I (TRPS I) is not well delineated. TRPS I is a rare congenital syndrome, characterized by craniofacial and skeletal malformations including short stature, sparse, thin scalp hair and lateral eyebrows, pear-shaped nose, cone shaped epiphyses and hip dysplasia. It is inherited in an autosomal dominant manner and caused by haploinsufficiency of the TRPS1 gene. We report a family (Mother and 3 of her 4 children) with a novel mutation in the TRPS1 gene. The diagnosis was suspected only after meeting all family members and comparing affected and unaffected siblings since the features of this syndrome might be subtle. The eldest sibling, who had neither GH deficiency nor insensitivity, improved his growth velocity and height SDS after 2 years of treatment with exogenous GH. No change in growth velocity was observed in the untreated siblings during this same period. This report emphasizes the importance of examining all family members when suspecting a genetic syndrome. It also demonstrates the therapeutic effect of GH treatment in TRPS I despite normal GH-IGF1 axis. A review of the literature is included to address whether TRPS I is associated with: a) GH deficiency, b) GH resistance, or c) GH-responsive short stature. More studies are needed before recommending GH treatment for TRPS I but a trial should be considered on an individual basis.

Do obese children with diabetic ketoacidosis have type 1 or type 2 diabetes?

OBJECTIVE: Many obese children with unprovoked diabetic ketoacidosis (DKA) display clinical features of type 2 diabetes during follow up. We describe the clinical presentation, autoimmune markers and the long-term course of obese and lean children with DKA. RESEARCH DESIGN AND METHODS: We reviewed the medical records on the initial acute hospitalization and outpatient follow-up care of 21 newly diagnosed obese and 20 lean children with unprovoked DKA at Emory University affiliated children's hospitals between 1/2003 and 12/2006. RESULTS: Obese children with DKA were older and predominantly male, had acanthosis nigricans, and had lower prevalence of autoantibodies to islet cells and glutamic acid decarboxylase than lean children. Half of the obese, but none of the lean children with DKA achieve near-normoglycemia remission and discontinued insulin therapy during follow-up. Time to achieve remission was 2.2±2.3 months. There were no differences on clinical presentation between obese children who achieved near-normoglycemia remission versus those who did not. The addition of metformin to insulin therapy shortly after resolution of DKA resulted in lower hemoglobin A1c (HbA1c) levels, higher rates of near-normoglycemia remission, and lower frequency of DKA recurrence. Near-normoglycemia remission, however, was of short duration and the majority of obese patients required reinstitution of insulin treatment within 15 months of follow-up. CONCLUSION: In contrast to lean children with DKA, many obese children with unprovoked DKA display clinical and immunologic features of type 2 diabetes during follow-up. The addition of metformin to insulin therapy shortly after resolution of DKA improves glycemic control, facilitates achieving near-normoglycemia remission and prevents DKA recurrence in obese children with DKA.

Improved access to subspecialist diabetes care by telemedicine: cost savings and care measures in the first two years of the FITE diabetes project.

We have used telemedicine clinics supplemented by online education to provide effective care for children with diabetes. Before the programme began, the mean interval between visits was 149 days; in year 1 of the programme it was 98 days, and in year 2 it was 89 days. Before the programme, there were on average 13 hospitalizations a year (47 days) and this decreased to 3.5 hospitalizations a year (5.5 days). Emergency department visits decreased from 8 to 2.5 per year. On 10 occasions after the programme started, ketosis was managed by telephone intervention alone, relying on family-initiated calls. Over 90% of patients and family members expressed satisfaction with the telemedicine service and wished to continue using it. In all, 95% felt little self-consciousness. Over 90% felt their privacy was respected. The programme saved US dollar 27,860 per year. The present study demonstrated improved access to specialized health care via telemedicine in combination with online education improved health status and reduced costs by reducing hospitalizations and emergency department visits.

Cerebral edema in childhood diabetic ketoacidosis: natural history, radiographic findings, and early identification.

OBJECTIVE: Children who develop cerebral edema (CE) during diabetic ketoacidosis (DKA) exhibit definable signs and symptoms of neurological collapse early enough to allow intervention to prevent brain damage. Our objective was to develop a model for early detection of CE in children with DKA. RESEARCH DESIGN AND METHODS: A training sample of 26 occurrences of DKA complicated by severe CE and 69 episodes of uncomplicated DKA was reviewed. Signs of neurological disease were incorporated into a bedside evaluation protocol that was applied to an independent test sample of 17 patients previously reported to have developed symptomatic CE during treatment for DKA. Head computed tomograms and their reports were reviewed. RESULTS: The protocol allowed 92% sensitivity and 96% specificity for the recognition of CE sufficiently early for intervention. The diagnostic criteria were fulfilled in two temporal patterns, defining early- and late-onset CE. Although initial computed tomograms were often normal, the findings also included diffuse CE and focal brain injury, the latter only in patients with an early onset of abnormal neurological signs. CONCLUSIONS: CE may occur in the absence of acute changes on head computed tomograms. Early detection of CE at the bedside using an evidence-based protocol permits intervention in time to prevent permanent brain damage.