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.

The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study.

The aim of the study was a systematic evaluation of cognitive development in individuals with glutaric aciduria type 1 (GA1), a rare neurometabolic disorder, identified by newborn screening in Germany. This national, prospective, observational, multi-centre study includes 107 individuals with confirmed GA1 identified by newborn screening between 1999 and 2020 in Germany. Clinical status, development, and IQ were assessed using standardized tests. Impact of interventional and non-interventional parameters on cognitive outcome was evaluated. The majority of tested individuals (n = 72) showed stable IQ values with age (n = 56 with IQ test; median test age 11 years) but a significantly lower performance (median [IQR] IQ 87 [78-98]) than in general population, particularly in individuals with a biochemical high excreter phenotype (84 [75-96]) compared to the low excreter group (98 [92-105]; p = 0.0164). For all patients, IQ results were homogenous on subscale levels. Sex, clinical motor phenotype and quality of metabolic treatment had no impact on cognitive functions. Long-term neurologic outcome in GA1 involves both motor and cognitive functions. The biochemical high excreter phenotype is the major risk factor for cognitive impairment while cognitive functions do not appear to be impacted by current therapy and striatal damage. These findings implicate the necessity of new treatment concepts.

Impact of interventional and non-interventional variables on anthropometric long-term development in glutaric aciduria type 1: A national prospective multi-centre study.

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl-CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long-term outcome. This national prospective, observational, multi-centre study included 79 patients identified by NBS and investigated effects of interventional and non-interventional parameters on body weight, body length, body mass index (BMI) and head circumference as well as neurological parameters. Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non-adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS -1.07; P = .023) and body length (mean SDS -1.34; P = -.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (P < .001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS -0.20; P = .049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS -0.68; P = .016). In GA1, recommended long-term treatment is effective and allows for normal anthropometric long-term development up to adolescence, with gender- and excreter type-specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome.

Lower HbA1c in patients with type 1 diabetes and celiac disease who reached celiac-specific antibody-negativity-A multicenter DPV analysis.

OBJECTIVES: To study celiac-specific antibody status over 3 years in patients with type 1 diabetes and biopsy-proven celiac disease (T1D + CD). Furthermore, to determine clinical differences after diagnosis between patients reaching constant antibody-negativity (Ab-neg) and staying antibody-positive (Ab-pos). METHODS: A total of 608 pediatric T1D + CD patients from the multicenter DPV registry were studied longitudinally regarding their CD specific antibody-status. Differences between Ab-neg (n = 218) and Ab-pos (n = 158) patients 3 years after biopsy were assessed and compared with 26 833 T1D patients without CD by linear and logistic regression adjusted for age, gender, diabetes duration and migration background. RESULTS: Thirty-six percent of T1D + CD patients reached and sustained antibody-negativity 3 years after CD diagnosis. The median time until patients returned to Ab-neg was 0.86 (0.51;1.16) years. Three years after diagnosis, HbA1c was lowest in Ab-neg and highest in Ab-pos patients compared to T1D-only patients (adjusted mean (95%CI): 7.72 (7.51-7.92) % vs 8.44 (8.20-8.68) % vs 8.19 (8.17-8.21) %, adjusted P < 0.001, respectively). Total cholesterol, LDL-cholesterol and frequency of dyslipidemia were significantly lower in Ab-neg compared to T1D-only patients (167 (161-173) mg/dl vs 179 (178-179) mg/dl, P < .001; 90 (84-96) mg/dl vs 99 (98-99) mg/dl, P = .005; 15.7 (10.5-22.9) % vs 25.9 (25.2-26.6) %, P = .017). In longitudinal analyses over 6 years after diagnosis, a constantly higher HbA1c (P < .001) and a lower height-SDS (P = .044) was observed in Ab-pos compared to Ab-neg patients. CONCLUSION: Only one third of T1D + CD patients reached constant Ab-negativity after CD diagnosis. Achieving Ab-negativity after diagnosis seems to be associated with better metabolic control and growth, supposedly due to a higher adherence to therapy in general.

Influence of chronic diseases on the olfactory function in children.

The association between smell impairment and chronic diseases has been reported in some studies in adults. Such information is not available for chronic diseases in children. The aim of this study was to examine olfactory function of children with chronic diseases such as diabetes mellitus type 1, hypothyroidism, and bronchial asthma in combination with allergic rhinitis in comparison to healthy controls. The data were obtained from n = 205 participants (104 boys, 101 girls) between the age of 6 and 17 years. Seventy-eight of the participants were healthy controls, n = 43 had diabetes mellitus type 1, n = 50 suffer from allergic rhinitis or bronchial asthma, and 34 presented a reduced function of their thyroid in medical history. All participants underwent olfactory testing including olfactory threshold using "Sniffin' Sticks" and odor identification using the "U-Sniff" test. In addition, a depression inventory and cognitive testing using the Ravens Progressive Matrices was performed. No significant difference in olfactory function was observed for any of the chronic diseases in children in comparison to healthy controls. Further analysis showed a trend in significance for a subpopulation of children with bronchial asthma and comorbidities performed worse on the olfactory threshold test compared to patients with bronchial asthma without comorbidities. Pediatric patients suffering from chronic diseases scored higher on the depression inventory compared to healthy controls.Conclusion: In conclusion, this study demonstrates that the influence of chronic diseases (bronchial asthma, diabetes mellitus type 1 and hypothyroidism) on olfactory function in childhood, if any, seems to be insignificant. This is partly in contrast to adult patients. Further research should be conducted in a subgroup of patients with bronchial asthma, allergic rhinitis, and atopic dermatitis or other comorbidities to better understand the association of allergic diathesis and olfactory function and the putative pathogenesis of olfactory dysfunction. What is known: • The association between smell impairment and chronic diseases has been reported in some studies in adults. • Such information is not available for chronic diseases in children. What is new: • The influence of chronic diseases (bronchial asthma, diabetes mellitus type 1, and hypothyroidism) on olfactory function in childhood, if any, seems to be insignificant. • In patients with bronchial asthma and allergic rhinitis, only a subgroup of patients with additional comorbidity (atopic dermatitis) showed a tendency to a reduced sense of smell.

Newborn screening: A disease-changing intervention for glutaric aciduria type 1.

OBJECTIVE: Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programs has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive. METHODS: This prospective, observational, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 women with GA1 identified by positive NBS results of their unaffected children. RESULTS: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study. INTERPRETATION: NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979.

Comparison of glycemic and metabolic control in youth with type 1 diabetes with and without antipsychotic medication: analysis from the nationwide German/Austrian Diabetes Survey (DPV).

OBJECTIVE: The objective of this study was to explore metabolic risk factors and glycemic control in youth with type 1 diabetes treated with typical or atypical antipsychotics. RESEARCH DESIGN AND METHODS: Data for 60,162 subjects with type 1 diabetes up to the age of 25 years registered in the nationwide German/Austrian Diabetes Survey were included in the analysis. BMI; HbA1c; treatment strategy; prevalence of hypertension, dyslipidemia, microalbuminuria, and retinopathy; frequency of hypoglycemia and diabetic ketoacidosis (DKA); and immigrant status among subjects treated with typical or atypical antipsychotics were compared with those without antipsychotic medication and analyzed by regression analysis. RESULTS: A total of 291 subjects with type 1 diabetes (median diabetes duration 7.2 years) received antipsychotic medications (most commonly risperidone). Subjects treated with antipsychotics had a higher BMI (P = 0.004) and dyslipidemia was more frequent (P = 0.045) compared with subjects not receiving antipsychotic medication. Frequencies of severe hypoglycemia and DKA were significantly higher in subjects receiving antipsychotics (P < 0.001). The prevalences of hypertension, microalbuminuria, and retinopathy were not different. In subjects treated with typical antipsychotics, glycemic control did not differ compared with those who did not receive antipsychotic medications. By contrast, subjects treated with atypical antipsychotics had higher HbA1c levels (P = 0.022). CONCLUSIONS: This analysis from a real-life survey demonstrated that subjects with antipsychotic medication had worse glycemic control and a higher rate of acute complications compared with those without antipsychotic medication. Health care teams caring for youth with type 1 diabetes taking antipsychotic medication need to know about these findings. We suggest monitoring metabolic risk factors as well as providing diabetes education about prevention of acute complications.

Subclinical hypothyroidism and dyslipidemia in children and adolescents with type 1 diabetes mellitus.

OBJECTIVE: Recent epidemiological evidence suggests that subclinical hypothyroidism (SCH), defined as elevated TSH concentrations with normal circulating levels of triiodothyronine (T3) and thyroxine (T4), is associated with dyslipidemia and cardiovascular disease in adult populations. As currently no data are available on the prevalence of SCH and its potential association with lipoprotein profile in children and adolescents with type 1 diabetes (T1DM), we investigated the prevalence of SCH and associated lipid levels in young diabetic patients. DESIGN AND METHODS: Cross-sectional analysis of 22,747 children, adolescents, and young adults (age <25 years) with T1DM with normal T3 and T4 and either normal TSH (≥0.5 to <4.0 mIU/l, euthyroid group) or elevated TSH (≥4.0 to <25.0 mIU/l, SCH group) and simultaneous measurement of serum lipid and lipoprotein status. RESULTS: The prevalence rate of SCH in the study population was 7.2%. Adjusted for age, gender, diabetes duration, current insulin dose, HbA1c, and BMI z-score, patients with SCH had significantly higher levels of total cholesterol (178.7 vs 175.3 mg/dl, P<0.001) and LDL-cholesterol (97.0 vs 93.7 mg/dl, P<0.001) compared with euthyroid patients. CONCLUSIONS: SCH is a common finding in children, adolescents, and young adults with T1DM. SCH is associated with increased levels of total cholesterol, and LDL-cholesterol adjusted for potential confounders. SCH-associated increases in lipid and lipoprotein levels may therefore add to an increased long-term cardiovascular risk in young patients with T1DM.

Natural course of untreated microalbuminuria in children and adolescents with type 1 diabetes and the importance of diabetes duration and immigrant status: longitudinal analysis from the prospective nationwide German and Austrian diabetes survey DPV.

OBJECTIVE: To identify risk factors for the development and progression of untreated persistent microalbuminuria in children and adolescents with type 1 diabetes. DESIGN AND METHODS: A total number of 683 children and adolescents with type 1 diabetes recruited from the prospective nationwide German and Austrian diabetes survey (DPV) were included in the analysis. Inclusion criteria were onset of type 1 diabetes under the age of 11 years, diabetes duration of more than 1 year and continuous follow-up over 5 years with at least two documented urine analyses per year. Subjects treated with angiotensin-converting enzyme inhibitors were excluded. Risk factors such as sex, body mass index SDS, diabetes duration, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, systolic and diastolic blood pressure, and immigrant status were analysed by logistic regression. RESULTS: At baseline (age 10.5 ± 0.1 years, diabetes duration 4.6 ± 2.4 years and HbA1c 7.4 ± 1.1%), 75.6% of children had normoalbuminuria, 15.7% had intermittent microalbuminuria, 8.6% had persistent microalbuminuria and 0.1% had macroalbuminuria. After a follow-up of 5 years, 59.4% of adolescents continued to have normoalbuminuria, 18.4% had progression, 15.2% had regression of microalbuminuria, and in 6.9% of the subjects, microalbuminuria remained unchanged. We found significant associations between persistent microalbuminuria at baseline and during each year of follow-up (P < 0.0001). Logistic regression analysis identified diabetes duration and immigrant status as significant factors for microalbuminuria (P = 0.009 and P = 0.009). CONCLUSIONS: The survey in a real-world setting shows that diabetes duration and immigrant status are risk factors for the development and progression of untreated microalbuminuria in children and adolescents with type 1 diabetes.

Incidence of childhood diabetes in children aged less than 15 years and its clinical and metabolic characteristics at the time of diagnosis: data from the Childhood Diabetes Registry of Saxony, Germany.

AIMS: The Childhood Diabetes Registry in Saxony, Germany, examined the incidence and metabolic characteristics of childhood diabetes. METHODS: In the federal state of Saxony, newly diagnosed cases of diabetes in children and adolescents aged less than 15 years were registered continuously from 1999 until 2008. Family history, date of diagnosis, clinical and laboratory parameters were obtained. Reported cases were ascertained by public health departments as an independent data source and verified using the capture- recapture method. RESULTS: A total of 865 children and adolescents with newly diagnosed diabetes were registered in Saxony. About 96% of them were classified as having type 1 diabetes, 0.6% had type 2 diabetes, 2.4% had maturity-onset diabetes of the young (MODY), and 1.4% had other types of diabetes. The age-standardized incidence rate of type 1 diabetes was estimated at 17.5 per 100,000 children per year. Completeness of ascertainment as calculated by the capture-recapture method amounted to 93.6%. At the time of diagnosis, 27.1% of children with type 1 diabetes had ketoacidosis, 1.5% had a blood pH <7.0, and 1.1% were unconscious. CONCLUSION: The registry provided data about the incidence rates and clinical presentation of childhood diabetes in a defined German population. We observed higher incidence rates compared to previous surveys.

Unusual radiological presentation of tuberous sclerosis complex with leptomeningeal angiomatosis associated with a hypomorphic mutation in the TSC2 gene.

Tuberous sclerosis complex is an autosomal dominant disorder affecting primarily the central nervous system, skin, and kidney caused by mutations in the TSC1 and TSC2 genes. Diagnosis is established with the identification of various neurocutaneous symptoms and multiple organ system hamartomas. The authors report on a 9-year-old patient with episodes of vertigo and headache followed by full spontaneous recovery. There was no history of seizures, mental retardation, or other neurologic sequelae, and psychomotor development was normal. Magnetic resonance imaging revealed pial angiomatosis of the left cerebellum and calcifications in the left parieto-occipital lobe consistent with the diagnosis of Sturge-Weber syndrome. At the age of 13, multiple renal angiomyolipomas and a single hypomelanotic macule were found, and subsequent imaging revealed several cortical tuberi. The diagnosis was confirmed by sequence analysis, which identified a novel missense mutation p.Ala460Thr in exon 13 of the TSC2 gene. Thus, mild tuberous sclerosis due to a hypomorphic mutation in TSC2 may present with isolated leptomeningeal angiomatosis.

Autonomic blood pressure control in children and adolescents with type 1 diabetes mellitus.

INTRODUCTION: Increased daytime blood pressure and reduced nocturnal dipping can already be found in children with type 1 diabetes mellitus. We hypothesized that impaired baroreflex sensitivity can cause this abnormal blood pressure behavior in children and adolescents with type 1 diabetes, reflecting an early stage of diabetic autonomic neuropathy. METHODS: In the present study, we monitored beat-to-beat blood pressure and pulse interval non-invasively with portapres in 38 patients with type 1 diabetes (7-18 yr) and 14 non-diabetic subjects (5-17 yr). The Trigonometric Regressive Spectral Analysis was used to assign spontaneous oscillations of blood pressure and pulse interval to defined frequency bands between 0.003 and 1.0 Hz and to calculate baroreflex sensitivity. Correlations with diabetes-specific data like hemoglobin A1c (HbA1c) and with 24-h blood pressure measurements were calculated. RESULTS: The diabetic subjects displayed significantly less variance of blood pressure and pulse interval in the high frequency (HF) bands and a lower BRS. BRS decreased with higher HbA1c and daily insulin dose. We also saw significant changes in spectral variance of blood pressure and pulse interval with these parameters. Patients with higher sympathetic activity (LF/HF-ratio) during daytime measurements displayed more nocturnal dipping. CONCLUSION: Our data evidence impaired baroreflex sensitivity in children and adolescents with type 1 diabetes mellitus. We suggest spectral analysis of spontaneous blood pressure and pulse interval oscillations during night sleep to further pursue the role of baroreflex sensitivity in the etiology of the non-dipping phenomenon in diabetic patients.

Daily insulin requirement of children and adolescents with type 1 diabetes: effect of age, gender, body mass index and mode of therapy.

DESIGN: The purpose of this study was to generate insulin dose (ID) percentiles for children and adolescents with type 1 diabetes mellitus (DM1) having the opportunity to assess this important parameter in relation to age and sex. METHODS: Daily IDs per weight (ID/kg) were recorded in 22,177 patients with DM1 (3-25 years of age, DM1 duration of more than 2 years, 48% female) and ID percentiles (ID-Perc) were created statistically. The ID-Perc were compared between male and female, and between multiple insulin injection therapy (MIT) and continuous s.c. insulin infusion (CSII). A multivariate regression analysis was performed for ID in the third year of DM1 with ID/kg, body weight, age, gender, and insulin delivery regimen as variables. RESULTS: The 50th ID-Perc (P50) varied among 0.67 IU/kg (age 3 years), 0.93 IU/kg (13 years), and 0.70 IU/kg (23 years) increasing from early childhood to adolescence and decreasing toward adulthood. Highest P50 ID was found at 12 years in females (0.94 IU/kg) and at 14 years in males (0.92 IU/kg). Using ICT, the ID was significantly higher compared with CSII (P50: 0.94 IU/kg versus 0.79 IU/kg at 13 years). In multivariate regression analysis, ID was significantly (P>0.001) associated with age, gender, and insulin delivery regime. CONCLUSION: The ID-Perc were significantly different during various periods of childhood and were influenced by gender, body weight, and insulin injection regimes. Therefore, the presented data 1) provide evidence to interpret individual ID in children and adolescents with DM1 and 2) more specifically identify children with unusually high (insulin resistance and non-compliance) or low (MODY and persistent remission) insulin requirement.

Parental preference of prandial insulin aspart compared with preprandial human insulin in a basal-bolus scheme with NPH insulin in a 12-wk crossover study of preschool children with type 1 diabetes.

OBJECTIVES: Preprandial insulin injection in preschool children is complicated by irregular eating habits. Postprandial injection of rapid-acting insulin analogs such as insulin aspart (IAsp) offers the convenience of adjusting insulin dose to match food consumed. This trial compared safety and efficacy - including parental treatment satisfaction - of two basal-bolus regimens [IAsp plus Neutral Protein Hagedorn (NPH) insulin vs. regular human insulin (HI) plus NPH] in preschool children with type 1 diabetes. METHODS: This study is a randomized, 12-wk, crossover trial comparing IAsp and regular HI in 26 children (17 boys and 9 girls; age: 2.4-6.9 yr). Regular HI was injected 30 min before and IAsp after or shortly before meals. Treatment satisfaction was assessed by a modified version of the WHO Diabetes Treatment Satisfaction Questionnaire (DTSQ-M). RESULTS: Glycemic control for IAsp treatment was not different from that for regular HI treatment as assessed by mean postprandial blood glucose increment (IAsp vs. regular HI: 2.0 vs. 1.6 mmol/L), fructosamine (300 vs. 302 micromol/L), and hemoglobin A(1c) (HbA(1c)) (7.7 vs. 7.6%). The relative risk of hypoglycemia was not significantly different [relative risk for IAsp/regular HI (95% CI): 1.06 (0.96-1.17), p = 0.225]. Mean total daily insulin dose (0.7 U/kg) remained constant throughout the trial with both treatments. The DTSQ-M score tended to be better for IAsp and reached statistical significance regarding the parental satisfaction with continuing IAsp treatment (p < 0.05). CONCLUSION: In preschool children, a basal-bolus treatment scheme with postprandial IAsp as bolus insulin was equally effective and safe compared with preprandial regular HI, although the parents showed a preference for the IAsp treatment.

Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY).

Maturity-onset diabetes of the young is a genetically heterogeneous autosomal dominant form of diabetes mellitus, characterized by an early age at onset and a primary defect in beta-cell function. Forty families with a clinical presentation suggestive of MODY were screened for the most common MODY subtypes caused by mutations in the genes encoding glucokinase (GCK, MODY2) and hepatocyte nuclear 1-alpha (HNF1A/TCF1, MODY3). Overall, 14 mutations were found (35%) giving a relative frequency of 22.5% and 12.5% for MODY2 and MODY3, respectively. Five of the nine GCK mutations identified were novel and included two deletions, two nonsense, and one splice site mutation. The GCK splice donor mutation was shown to result in an aberrant transcript owing to the recruitment of a cryptic splice site. The translated protein is predicted to contain an in frame insertion of nine amino acids. Among the five HNF1A mutations identified, three were novel comprising one missense mutation, one deletion, and one insertion. In addition, several novel polymorphisms within GCK were identified and their allele frequencies estimated. Knowledge of the genetic cause of MODY has significant impact on therapeutic decision making and may help to identify family members at risk for diabetes.