Three-variate trajectories of metabolic control, body mass index, and insulin dose: Heterogeneous response to initiation of pump therapy in youth with type 1 diabetes.

OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) in youths with type 1 diabetes (T1D) is often associated with lower HbA1c, lower total daily insulin dose (TDD), and lower body mass index (BMI) compared with multiple daily injections (MDI). Individual responses to CSII are diverse. The aim was to identify unique three-variate patterns of HbA1c, BMI standard deviation score (SDS), and TDD after switching to CSII. METHODS: Five thousand one hundred and thirty-three youths (≤20 years; 48% boys; median age at pump start 12.5 years) with T1D duration ≥3 years at CSII initiation were selected from the multicenter DPV registry. We applied group-based multitrajectory modeling to identify groups of individuals following similar trajectories. Measurements were aggregated quarterly during a 3-year follow-up period. Trajectory variables were changes of HbA1c, BMI-SDS, and TDD from baseline (delta = quarterly aggregated values at each time point [i] minus the respective baseline value). RESULTS: Four groups of diverging Delta-HbA1c, Delta-BMI-SDS, and Delta-TDD patterns were identified. All showed improvements in HbA1c during the first 3 months. Group 1 (12%) was characterized by modest HbA1c increase thereafter, TDD reduction, and stable BMI-SDS. In Group 2 (39%), increasing HbA1c, decreasing BMI-SDS, and stable TDD were found. By contrast, sustainably improved HbA1c, increasing BMI-SDS, and stable TDD were observed in Group 3 (32%). Group 4 (17%) was characterized by increasing levels for HbA1c, BMI-SDS, and TDD. Between-group differences in baseline HbA1c, BMI-SDS, TDD as well as in sex ratio, age at diabetes onset and at pump start were observed. CONCLUSIONS: Definite trajectories of glycemic control, BMI, and TDD over 3 years after CSII initiation were identified in youths with T1D allowing a more personalized treatment recommendation.

Are psychiatric disorders associated with thyroid hormone therapy in adolescents and young adults with type 1 diabetes?

BACKGROUND: To evaluate the association between thyroid autoimmunity and psychiatric disorders (depression, anxiety, eating disorder, schizophrenia or attention-deficit/hyperactivity disorder) among adolescents and young adults with type 1 diabetes (11-25 years). METHODS: We compared 9368 type 1 diabetes patients with thyroid autoimmunity (3789 of them treated with levothyroxine) with 62 438 type 1 diabetes patients without any thyroid disease from a multicentre diabetes patient follow-up registry (DPV) in terms of psychiatric disorders. Thyroid autoimmunity was defined as documented diagnosis of Hashimoto thyroiditis or positive antibodies against thyroid peroxidase or thyroglobulin. Multivariable logistic regression models were used to calculate odds ratios for the respective psychiatric disorders in type 1 diabetes patients with thyroid autoimmunity (overall and stratified by levothyroxine therapy) compared to type 1 diabetes patients without thyroid diseases (reference). RESULTS: Of the 9368 patients with thyroid autoimmunity, 62% were female with a median (Q1-Q3) age of 16.3 (14.2-17.6) years. Thyroid autoimmunity (with or without levothyroxine therapy) revealed a slight, but significant higher chance for depression (odds ratio [OR], 1.35, 95% confidence interval [CI], 1.19, 1.52), eating disorder (OR, 1.25, CI, 1.03, 1.51), attention-deficit/hyperactivity disorder (OR, 1.22, CI, 1.07, 1.39) and schizophrenia (OR, 1.63, CI, 1.04, 2.56). In individuals with prescribed levothyroxine therapy because of thyroid dysfunction significantly higher odds for depression (OR, 1.63, CI, 1.34, 1.99), anxiety (OR, 1.60, CI, 1.18, 2.18), and attention-deficit/hyperactivity disorder (OR, 1.71, CI, 1.38, 2.12) were observed compared to reference. Thyroid autoimmunity without required levothyroxine therapy revealed no differences to the reference group. CONCLUSIONS: Patients on levothyroxine had significantly higher odds for psychiatric disorders, but thyroid autoimmunity in terms of high antibody levels only did not show higher odds for any psychiatric disorder.

Significant reduction of ketoacidosis at diabetes onset in children and adolescents with type 1 diabetes-The Stuttgart Diabetes Awareness Campaign, Germany.

BACKGROUND: To prevent the potentially life-threatening complication, diabetic ketoacidosis (DKA) at type 1 diabetes onset in children and adolescents, awareness campaigns can lead to a significant reduction of DKA. As in Germany, the incidence of DKA at diabetes onset had remained at a constant rate over the last 15 years and increasing numbers of very young children present with higher risk for DKA we decided to set up the Stuttgart Ketoacidosis Awareness Campaign. METHODS: Over 3 years (2015-2017) the campaign was conducted using information flyers and posters illustrating the typical symptoms of diabetes at school entry health examinations at the Public Health Department, in day-care facilities, in all pediatric practices and by regular public activities. The period between 2011 and 2013 was selected as a reference period. RESULTS: Approximately 17 000 children, median age 4.5 years, and their families were informed about the campaign during the preschool health examination. A total of 118 children and adolescents were treated with newly diagnosed type 1 diabetes compared with 127 during the reference period. During the campaign the incidence of DKA decreased significantly from 28% to 16%. CONCLUSIONS: Awareness campaigns like the Stuttgart Ketoacidosis Awareness Campaign about the typical clinical symptoms of type 1 diabetes can significantly reduce the risk for DKA at diabetes onset. Important factors for the success of our campaign were the close cooperation between the children's hospital and the public health department, the targeted approach of families, teachers, and pediatricians and the duration of the campaign over 3 years.

Type 1 diabetes and epilepsy in childhood and adolescence: Do glutamic acid decarboxylase autoantibodies play a role? Data from the German/Austrian/Swiss/Luxembourgian DPV Registry.

AIMS: We aimed to analyze the relationship between epilepsy and glutamic acid decarboxylase autoantibodies (GADA) in patients with type 1 diabetes mellitus (T1DM) and the impact of GADA on demographic, clinical, and metabolic data in T1DM patients with epilepsy. METHODS: We searched for patients with T1DM ≤20 years and GADA measurements, and within this group for patients with epilepsy. We formed groups: T1DM + Epilepsy + GADA positive; T1DM + Epilepsy + GADA negative; T1DM + GADA positive; T1DM + GADA negative. We used logistic regression to analyze the relationship between epilepsy and GADA with odds ratio adjusted for sex, duration of diabetes (DOD), and age at diabetes onset (ADO). We used logistic regression with odds ratio adjusted for DOD and ADO onset using epilepsy as a dependent variable and GADA, HbA1c, ketoacidosis, severe hypoglycemia (SH), sex, celiac disease, and autoimmune thyroiditis as independent variables. We conducted regression analyses adjusted for sex, DOD, and ADO to analyze differences in clinical/metabolic parameters between the groups. RESULTS: Epilepsy was not more frequent in GADA-positive patients (GPP). Logistic regression including all patients with GADA measurements showed that hypoglycemia with coma (HC) correlated with epilepsy when compared to no SH. We found no differences in clinical and metabolic data between GPP and GADA-negative patients (GNP) with epilepsy. SH occurred more often in GPP with epilepsy in comparison to GPP without epilepsy. GNP with epilepsy had a higher rate of HC than GPP without epilepsy. CONCLUSION: We found no relationship between epilepsy and GADA. A relationship between T1DM and epilepsy might be explainable by SH.

Twelve-month outcome in juvenile proliferative lupus nephritis: results of the German registry study.

BACKGROUND: Children presenting with proliferative lupus nephritis (LN) are treated with intensified immunosuppressive protocols. Data on renal outcome and treatment toxicity is scare. METHODS: Twelve-month renal outcome and comorbidity were assessed in 79 predominantly Caucasian children with proliferative LN reported to the Lupus Nephritis Registry of the German Society of Paediatric Nephrology diagnosed between 1997 and 2015. RESULTS: At the time of diagnosis, median age was 13.7 (interquartile range 11.8-15.8) years; 86% showed WHO histology class IV, nephrotic range proteinuria was noted in 55%, and median estimated glomerular filtration rate amounted to 75 ml/min/1.73 m2. At 12 months, the percentage of patients with complete and partial remission was 38% and 41%, respectively. Six percent of patients were non-responders and 15% presented with renal flare. Nephrotic range proteinuria at the time of diagnosis was associated with inferior renal outcome (odds ratio 5.34, 95% confidence interval 1.26-22.62, p = 0.02), whereas all other variables including mode of immune-suppressive treatment (e.g., induction treatment with cyclophosphamide (IVCYC) versus mycophenolate mofetil (MMF)) were not significant correlates. Complications were reported in 80% of patients including glucocorticoid toxicity in 42% (Cushingoid appearance, striae distensae, cataract, or osteonecrosis), leukopenia in 37%, infection in 23%, and menstrual disorder in 20%. Growth impairment, more pronounced in boys than girls, was noted in 78% of patients. CONCLUSIONS: In this cohort of juvenile proliferative LN, renal outcome at 12 months was good irrespectively if patients received induction treatment with MMF or IVCYC, but glucocorticoid toxicity was very high underscoring the need for corticoid sparing protocols. Graphical abstract.

Early Onset Diabetes in Two Children due to Progeria, a Monogenic Disease of DNA Repair

Progeria syndrome is a rare disorder in childhood which causes accelerated systemic aging. Due to the accelerated aging process, disorders which normally occur only in old age will appear in these children at a much younger age. We report two children with progeria syndrome, in whom fulminant diabetes mellitus manifested at a very early age.

Worse Metabolic Control and Dynamics of Weight Status in Adolescent Girls Point to Eating Disorders in the First Years after Manifestation of Type 1 Diabetes Mellitus: Findings from the Diabetes Patienten Verlaufsdokumentation Registry.

OBJECTIVE: To assess indications of eating disorders in girls with type 1 diabetes mellitus (T1DM). STUDY DESIGN: In total 31 556 girls aged >6 months and <23 years of age with T1DM from the Diabetes Patienten Verlaufsdokumentation (DPV) cohort were analyzed including 155 (0.49%) girls with anorexia nervosa, 85 (0.27%) girls with bulimia nervosa, 45 (0.14%) girls with binge eating disorder, and 229 (0.73%) girls with eating disorders not otherwise specified. Patient characteristics, weight changes, numbers of patients with severe hypoglycemia and diabetic ketoacidosis (DKA), changes of glycosylated hemoglobin A1c (HbA1c) levels, use of pumps, and prevalence of celiac disease and autoimmune thyroiditis were compared between girls with and without eating disorders. Multiple logistic regression analyses were performed. RESULTS: Eating disorders were significantly associated with late pubertal age, nonusage of pumps, no migration background, increased HbA1c levels, increased frequencies of DKA and severe hypoglycemia, and celiac disease were not related to eating disorders. Significant differences in HbA1c levels, prevalence of DKA and severe hypoglycemia between girls with and without eating disorders were already detectable in the first years after onset of T1DM. A decrease of body mass index (BMI)-SDS increased the risk for comorbid anorexia nervosa (7.1-fold [95% CI 3.6-14.3] compared with stable BMI-SDS, 6.9-fold [95%CI 3.4-14.1] compared with increase of BMI-SDS). CONCLUSIONS: Poor metabolic control and increased rates of DKA and severe hypoglycemia in the first years after manifestation of T1DM can be hints for eating disorders in girls with T1DM, and weight loss is specific for anorexia nervosa. These clinical features should lead to screening for eating disorders especially at a late pubertal age.

Effects of growth hormone treatment on adult height in severely short children with X-linked hypophosphatemic rickets.

BACKGROUND: We recently showed that a 3-year growth hormone (GH) treatment improves linear growth in severely short children with X-linked hypophosphatemic rickets (XLH). It is unknown if GH therapy increases adult height in XLH patients. METHODS: We carried out a follow-up analysis of a randomized controlled open-label GH study in short prepubertal children with XLH on phosphate and active vitamin D treatment. The changes in SD scores (SDS) of height, sitting height, leg and arm length, and sitting height index (i.e., the ratio between sitting height and height) were analyzed in 11 out of 16 patients followed-up until adult height. RESULTS: At baseline, XLH patients showed disproportionately short stature with reduced standardized height (-3.2 ± 0.6), sitting height (-1.7 ± 0.6), leg (-3.7 ± 0.7) and arm (-2.5 ± 0.8) length, and markedly elevated sitting height index (3.3 ± 0.6; each p < 0.01 versus healthy children). In GH-treated patients, adult height, sitting height, leg length, and arm length exceeded baseline values by 0.7 SDS, 1.7 SDS, 0.7 SDS, and 1.2 SDS respectively, although this was only significant for sitting height. In controls, no significant changes in linear body dimensions were noted. Adult height did not statistically differ between groups (-2.4 ± 0.7 vs -3.3 ± 1.2, p = 0.082). GH did not exaggerate body disproportion. CONCLUSIONS: Growth hormone treatment did not significantly increase adult height in this group of short children with XLH, which may be at least partly due to the small number of patients included in our study.

"Let the Algorithm Do the Work": Reduction of Hypoglycemia Using Sensor-Augmented Pump Therapy with Predictive Insulin Suspension (SmartGuard) in Pediatric Type 1 Diabetes Patients.

BACKGROUND: A sensor-augmented insulin pump (SAP) using the MiniMed® 640G system with SmartGuard™ technology allows an automatic stop of insulin delivery based on prediction of low glucose levels. Since pediatric patients are particularly prone to hypoglycemia, this device may offer additional protection beyond conventional sensor-augmented therapy. METHODS: This prospective, pediatric multicenter user evaluation assessed 6 weeks of SAP with SmartGuard (threshold setting for hypoglycemia: 70 mg/dL) compared to a preceding period of 2 weeks with SAP only. The primary outcome was the potential reduction in the frequency of hypoglycemic episodes and hypoglycemic intensity (area under the curve [AUC] and time <70 mg/dL). RESULTS: The study included 24 patients with at least 3 months of insulin pump use (average age: 11.6 ± 5.1 years, 15 female, average type 1 diabetes duration: 7.5 ± 4.2 years, mean ± SD) who had on average 3.2 ± 1.0 predictive suspensions/patient/day. The mean sensor glucose minimum during suspension was 78 ± 6 mg/dL and the average suspension time was 155 ± 47 min/day. Use of SmartGuard in patients treated as per the protocol (n = 18) reduced the number of instances in which the glucose level was <70 mg/dL (1.02 ± 0.52 to 0.72 ± 0.36; P = 0.027), as well as AUC <70 mg/dL (0.76 ± 0.73 to 0.38 ± 0.24; P = 0.027) and the time/day the level fell below 70 mg/dL (73 ± 56 to 31 ± 22 min). The reduction of hypoglycemia was not associated with a significant change in mean glucose concentration (171 ± 26 to 180 ± 19 mg/dL, P = 0.111) and HbA1c (7.5% ± 0.5% to 7.6% ± 0.7%, (P = 0.329). Manual resumption of insulin delivery followed by carbohydrate intake resulted in significantly higher glucose levels 1 h after suspension compared to SmartGuard suspensions with automatic resume (190.8 ± 26.5 vs. 138.7 ± 10.3 mg/dL; P < 0.001). CONCLUSIONS: SmartGuard technology significantly reduced the risk for hypoglycemia in pediatric type 1 diabetes patients without increasing HbA1c. Patients must be educated that when using combining predictive low-glucose insulin suspension technology, extra carbohydrate intake in response to an alarm combined with manual resumption is likely to cause rebound hyperglycemia. The best results were achieved when the user did not interfere with pump operation.

SPECTRUM.

BACKGROUND: Optimal usage of continuous glucose monitoring (CGM) requires adequate training of the users. Providing patients with a CGM system without such a training usually doesn't lead to the intended improvement in metabolic control. METHODS: In Germany we developed a structured training program ("SPECTRUM") to ensure a high quality standard for the use of CGM systems. RESULTS: This program is suitably for patients of all age groups and is applicable to all CGM systems and all forms of insulin therapy. A curriculum was also developed so that training centers with less experience with CGM could become capable of offering comprehensive CGM training. CONCLUSIONS: We believe that usage of such a program can be an important step forward in achieving more widespread acceptance and use of CGM systems. Translations in other languages and evaluation with a controlled clinical trial are planned.

Lipoprotein-associated phospholipase A2 activity and low-density lipoprotein subfractions after a 2-year treatment with atorvastatin in adolescents with type 1 diabetes.

BACKGROUND: The objective of the study was to assess the effect of atorvastatin on inflammation markers and low-density lipoprotein (LDL) subfractions. METHODS: In a prospective, randomized, double-blind pilot study involving 28 adolescents with type 1 diabetes (T1D), lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, high-sensitivity C-reactive protein (hsCRP), and subfractions of LDL were measured at baseline, after 1 year and 2 years of treatment with atorvastatin (10 mg/day) vs. placebo. RESULTS: For the atorvastatin group, we found posttreatment reductions of Lp-PLA2 activity (p<0.001), LDL cholesterol (p=0.001), non-small dense LDL cholesterol (p<0.001), total cholesterol (p<0.001), and apolipoprotein B (apo B) (p<0.001), whereas small dense LDL cholesterol and hsCRP did not change significantly. CONCLUSIONS: In adolescents with T1D, long-term treatment with atorvastatin is safe and may reduce cardiovascular risk by significant decreases of Lp-PLA2 activity and LDL cholesterol.

20 Years of Pediatric Benchmarking in Germany and Austria: Age-Dependent Analysis of Longitudinal Follow-Up in 63,967 Children and Adolescents with Type 1 Diabetes.

BACKGROUND: To investigate changes in diabetes treatment over the last two decades in three age-groups of children and adolescents with type 1 diabetes (T1D) from Germany and Austria. METHODS: 63,967 subjects (<18yr) with T1D documented between 1995 and 2014 from the DPV-database were included and stratified according to age (0.5-<6, 6-<12, 12-<18yr). Regression models were applied for insulin regimens (<3 and ≥4 injection time points/day, or continuous subcutaneous insulin infusion (CSII)), use of rapid- and long acting insulin analogues, NPH insulin, and frequency of self-monitoring of blood glucose (SMBG)/day. Models were adjusted for sex, diabetes duration, and migration background. P-value for trend was given. FINDINGS: The number of subjects with <3 injection time points/day decreased from 1995 to 2014 to <5% in all age-groups (p<0.0001). Proportion of patients with ≥4 injections/day increased until the early 2000s, and then declined until 2014. This trend was not found in 6-<12yr olds (p = 0.3403). CSII increased in all age-groups (p<0.0001) with the highest increase in children <6 years (from 0.4% to 79.2%), and the lowest increase in 12-<18 year olds (from 1.0% to 38.9%). NPH insulin decreased in all age-groups (p<0.0001). Insulin analogues, especially rapid-acting, became more frequent in all age-groups (p<0.0001), accounting for 78.4% in 2014 for all subjects. The highest use was found in the youngest children (in 2014: 85.6%), the lowest use in 6-<12 year olds (in 2014: 72.9%). The number of SMBG/day increased from 2.2 to 6.4 with a similar rise in all age-groups (p<0.0001). Frequency was highest in subjects <6yr. CONCLUSIONS: In all age-groups, T1D treatment was intensified over the last 20 years. Age-specific differences in trends were particularly observed in the number of patients on CSII, in the number of patients with 4 or more injections/day, and in the frequency of SMBG/day.

Comorbidity of type 1 diabetes and juvenile idiopathic arthritis.

OBJECTIVE: To analyze the prevalence of juvenile idiopathic arthritis (JIA) and diabetes end points in pediatric patients with type 1 diabetes. STUDY DESIGN: Patients with type 1 diabetes, recorded from 1995 up to September 2013 in the Diabetes Patienten Verlaufsdokumentation database (n = 54,911, <16 years of age, 47% girls), were analyzed. The patients' height, weight, and body mass index SDS, glycosylated hemoglobin A1c (HbA1c); insulin dose; hypertension and dyslipidemia prevalence; rate of hypoglycemic events; and ketoacidosis were compared between patients with and without JIA. To adjust for age, sex, diabetes duration, and migration background, data were analyzed in hierarchic multivariable regression models. RESULTS: The prevalence of JIA in type 1 diabetes was 106 of 54,911 patients; 66% were girls. Diabetes onset was earlier in children with JIA (7.2 years vs 8.3 years, P = .04). Children with JIA were smaller (SDS: -0.22 vs 0.09, P = .004). Correspondingly, weight SDS was lower in patients with JIA (-0.02 vs 0.22, P = .01). Body mass index SDS did not differ. HbA1c was marginally lower in children with JIA (63 mmol/mol [8.0%] vs 67 mmol/mol [8.3%], P = .06). Insulin requirement was greater in patients with JIA (1.03 vs 0.93 insulin units/weight/day, P = .003). Hypertension and dyslipidemia were comparable in both groups. CONCLUSIONS: The JIA-prevalence in patients with type 1 diabetes (0.19%) was considerably greater than in the general population (0.05%). Growth is influenced negatively by JIA. Surprisingly, HbA1c was somewhat lower in children with JIA, possibly because of a more intensive treatment or a latent hemolysis caused by the inflammation.

Decreased levels of homoarginine and asymmetric dimethylarginine in children with type 1 diabetes: associations with cardiovascular risk factors but no effect by atorvastin.

OBJECTIVES: To investigate homoarginine and asymmetric dimethylarginine (ADMA) in controls compared to children with type 1 diabetes (T1D) and if homoarginine and ADMA are affected by atorvastatin. METHODS: Homoarginine and ADMA levels of 28 T1D patients were compared to levels of 41 controls. In T1D patients, homoarginine and ADMA were determined at baseline, 1 year, and 2 years at daily 10 mg atorvastatin or placebo within a double-blind study. RESULTS: At baseline, both homoarginine and ADMA were lower (p<0.001) in T1D patients compared to controls. In T1D patients, homoarginine and ADMA were not influenced by atorvastatin. Inverse correlations between homoarginine and HbA1c (p<0.001) and between ADMA and systolic blood pressure (p=0.005) and pulse pressure (p=0.003) were shown. CONCLUSIONS: Homoarginine and ADMA levels are decreased and associated with cardiovascular risk factors in children with T1D without being affected by atorvastatin.

Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study.

BACKGROUND: The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently. METHODS: In a prospective, multicenter study among 106 pediatric kidney allograft recipients aged 11.4 ± 5.9 years, we investigated the epidemiology of EBV infection and the relationship between EBV load, EBV serology, and EBV-related morbidity (posttransplant lymphoproliferative disease [PTLD] or symptomatic EBV infection, defined as flu-like symptoms or infectious mononucleosis). RESULTS: EBV primary infection occurred in 27 of 43 (63%) seronegative patients and reactivation/reinfection in 28 of 63 (44%) seropositive patients. There was no association between the degree or duration of EBV load and EBV-related morbidity: The vast majority (17 of 18 [94%]) of patients with a high, persistent EBV load remained PTLD-free throughout a follow-up of 5.0 ± 1.3 years, while 2 of 3 (66%) patients with EBV-related PTLD exhibited only a low EBV load beforehand. Eight of 18 (44%) patients with a high, persistent EBV load remained asymptomatic during a follow-up of 5.3 ± 2.9 years. Multivariate analysis identified the EBV high-risk (D(+)/R(-)) serostatus (odds ratio [OR], 7.07; P < .05), the presence of human leukocyte antigen (HLA)-DR7 (OR, 5.65; P < .05), and the intensity of the immunosuppressive therapy (OR, 1.53; P < .01) as independent risk factors for the development of a symptomatic EBV infection. CONCLUSIONS: Presence of EBV high-risk seroconstellation, HLA-DR7, and intensity of immunosuppressive therapy are significant risk factors for a symptomatic EBV infection, whereas there is no close association between the degree or duration of EBV load and EBV-related morbidity. Clinical Trials Registration. NCT00963248.