Characterisation and clinical outcomes in children and adolescents with diabetes according to newly defined subgroups: a cohort study from the DPV registry.

Background: Personalised therapy has emerged as a possibly more efficient approach taking disease heterogeneity into account. The aim of this study was to determine whether recently described subgroups of childhood diabetes have prognostic association with diabetes-specific complications and, therefore, might be a basis for personalised therapies. Methods: We applied a previously developed subgroup classification to pediatric patients (diabetes onset <18 years) from the prospective Diabetes Patient Follow-up (DPV) registry with documented data between January 1, 2000 and March 31, 2022, from diabetes centers in Germany, Austria, Switzerland, and Luxembourg. The classification required information on islet autoantibody status, age, haemoglobin A1c (HbA1c), and body-mass index (BMI-SDS) at disease manifestation, as well as follow up data after 2 and after 4 years, which was available in 22,719 patients. Patients without documented data on these parameters were excluded from the analysis. The cumulative risk of severe hypoglycemia, diabetic ketoacidosis (DKA), retinopathy, and nephropathy were analysed by Kaplan-Meier analyses over a median follow-up of 6.8 years (IQR 4.8-9.6). Findings: Patients were classified into 10 subgroups (P1-P7 islet autoantibody-positive, n = 19,811; N1-N3 islet autoantibody-negative, n = 2908). The groups varied markedly with respect to specific acute and chronic complications. Severe hypoglycemia was a characteristic feature in young islet autoantibody-positive subgroups P1, P3, P4 (10-year risk 46, 46 and 47%) and the islet autoantibody-negative groups N1, N2 (43 and 46%). Nephropathy was identified in patient groups P2 and P5 (10-year risk 16%), which had features of moderate disease such as preserved C-peptide, low HbA1c, and very low frequency of DKA at diabetes onset. Group P7, which was defined by a high BMI, was associated with poor metabolic control, DKA, and retinopathy. In contrast, islet autoantibody-negative patients with high BMI (N3) had a low risk for all four complications. Interpretation: Subgrouping of childhood diabetes at diabetes onset provided prognostic value for the development of acute and chronic diabetes-specific complications. Funding: The DPV initiative is supported by The German Ministry of Education and Research (BMBF) within the German Center for Diabetes Research, the diabetes surveillance of the Robert Koch Institute, the German Diabetes Association (DDG) and INNODIA.

Cough-induced chylothorax in a two-year-old boy - case report and review of the literature.

BACKGROUND: Chylothorax is a very rare form of pleural effusion in children, especially after the neonatal period, and predominantly occurs secondary to cardiothoracic surgery. It can lead to significant respiratory distress, immunodeficiency, and malnutrition. Effective treatment strategies are therefore required to reduce morbidity. CASE PRESENTATION: A previously healthy two-year old boy was admitted with history of heavy coughing followed by progressive dyspnea. The chest X-ray showed an extensive opacification of the right lung. Ultrasound studies revealed a large pleural effusion of the right hemithorax. Pleural fluid analysis delivered the unusual diagnosis of chylothorax, most likely induced by preceded excessive coughing. After an unsuccessful treatment attempt with a fat-free diet and continuous pleural drainage for two weeks, therapy with octreotide was initiated. This led to complete and permanent resolution of his pleural effusion within 15 days, without any side effects. CONCLUSIONS: Severe cough may be a rare cause of chylothorax in young children. Octreotide seems to be an effective and safe treatment of spontaneous or traumatic chylothorax in children. There is, however, a lack of comprehensive studies for chylothorax in children and many issues concerning diagnostic strategies and treatment algorithms remain.

Elevations in blood glucose before and after the appearance of islet autoantibodies in children.

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic ß cells and promote ß cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic ß cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.

Clinical presentation and long-term outcome of patients with KCNJ11/ABCC8 variants: Neonatal diabetes or MODY in the DPV registry from Germany and Austria.

OBJECTIVE: To describe clinical presentation/longterm outcomes of patients with ABCC8/KCNJ11 variants in a large cohort of patients with diabetes. RESEARCH DESIGN AND METHODS: We analyzed patients in the Diabetes Prospective Follow-up (DPV) registry with diabetes and pathogenic variants in the ABCC8/KCNJ11 genes. For patients with available data at three specific time-points-classification as K+ -channel variant, 2-year follow-up and most recent visit-the longitudinal course was evaluated in addition to the cross-sectional examination. RESULTS: We identified 93 cases with ABCC8 (n = 54)/KCNJ11 (n = 39) variants, 63 of them with neonatal diabetes. For 22 patients, follow-up data were available. Of these, 19 were treated with insulin at diagnosis, and the majority of patients was switched to sulfonylurea thereafter. However, insulin was still administered in six patients at the most recent visit. Patients were in good metabolic control with a median (IQR) A1c level of 6.0% (5.5-6.7), that is, 42.1 (36.6-49.7) mmol/mol after 2 years and 6.7% (6.0-8.0), that is, 49.7 (42.1-63.9) mmol/mol at the most recent visit. Five patients were temporarily without medication for a median (IQR) time of 4.0 (3.5-4.4) years, while two other patients continue to be off medication at the last follow-up. CONCLUSIONS: ABCC8/KCNJ11 variants should be suspected in children diagnosed with diabetes below the age of 6 months, as a high percentage can be switched from insulin to oral antidiabetic drugs. Thirty patients with diabetes due to pathogenic variants of ABCC8 or KCNJ11 were diagnosed beyond the neonatal period. Patients maintain good metabolic control even after a diabetes duration of up to 11 years.

Frequency of Ketoacidosis at Diagnosis of Pediatric Type 1 Diabetes Associated With Socioeconomic Deprivation and Urbanization: Results From the German Multicenter DPV Registry.

OBJECTIVE: To investigate whether socioeconomic deprivation and urbanization are associated with the frequency of diabetic ketoacidosis (DKA) at diagnosis of pediatric type 1 diabetes. RESEARCH DESIGN AND METHODS: Children and adolescents aged ≤18 years, living in Germany, with newly diagnosed type 1 diabetes documented between 2016 and 2019 in the Diabetes Prospective Follow-up Registry (DPV; Diabetes-Patienten-Verlaufsdokumentation), were assigned to a quintile of regional socioeconomic deprivation (German Index of Socioeconomic Deprivation) and to a degree of urbanization (Eurostat) by using their residence postal code. With multiple logistic regression models, we investigated whether the frequency of DKA at diagnosis was associated with socioeconomic deprivation or urbanization and whether associations differed by age-group, sex, or migration status. RESULTS: In 10,598 children and adolescents with newly diagnosed type 1 diabetes, the frequency of DKA was lowest in the least deprived regions (Q1: 20.6% [95% CI 19.0-22.4], and increased with growing socioeconomic deprivation to 26.9% [25.0-28.8] in the most deprived regions [Q5]; P for trend <0.001). In rural areas, the frequency of DKA at diagnosis was significantly higher than in towns and suburbs (intermediate areas) or in cities (27.6% [95% CI 26.0-29.3] vs. 22.7% [21.4-24.0], P < 0.001, or vs. 24.3% [22.9-25.7], P = 0.007, respectively). The results did not significantly differ by age-group, sex, or migration background or after additional adjustment for socioeconomic deprivation or urbanization. CONCLUSIONS: This study provides evidence that prevention of DKA at diagnosis by means of awareness campaigns and screening for presymptomatic type 1 diabetes should particularly target socioeconomically disadvantaged regions and rural areas.

Correlation of PET-MRI, Pathology, LOH, and Surgical Success in a Case of CHI With Atypical Large Pancreatic Focus.

Congenital hyperinsulinism (CHI) is a rare cause of severe hypoglycemia in newborns. In focal CHI, usually one activity peak in fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography-magnetic resonance imaging (PET-MRI) indicates one focal lesion and its resection results in cure of the child. We present the case of a 5-month-old girl with CHI. Mutational screening of genes involved in CHI revealed a heterozygous pathogenic variant in the ABCC8 gene, which was not detectable in the parents. 18F-DOPA PET-MRI revealed 2 distinct activity peaks nearby in the pancreatic body and neck. Surgical resection of the tissue areas representing both activity peaks resulted in long-lasting normoglycemia that was proven by a fasting test. Molecular analysis of tissue samples from various sites provided evidence that a single second genetic hit in a pancreatic precursor cell was responsible for the atypical extended pancreatic lesion. There was a close correlation in the resected areas of PET-MRI activity with focal histopathology and frequency of the mutant allele (loss of heterozygosity) in the tissue. Focal lesions can be very heterogenous. The resection of the most affected areas as indicated by imaging, histopathology, and genetics could result in complete cure.

Heterogeneity of DKA Incidence and Age-Specific Clinical Characteristics in Children Diagnosed With Type 1 Diabetes in the TEDDY Study.

OBJECTIVE: The Environmental Determinants of Diabetes in the Young (TEDDY) study is uniquely capable of investigating age-specific differences associated with type 1 diabetes. Because age is a primary driver of heterogeneity in type 1 diabetes, we sought to characterize by age metabolic derangements prior to diagnosis and clinical features associated with diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS: The 379 TEDDY children who developed type 1 diabetes were grouped by age at onset (0-4, 5-9, and 10-14 years; n = 142, 151, and 86, respectively) with comparisons of autoantibody profiles, HLAs, family history of diabetes, presence of DKA, symptomatology at onset, and adherence to TEDDY protocol. Time-varying analysis compared those with oral glucose tolerance test data with TEDDY children who did not progress to diabetes. RESULTS: Increasing fasting glucose (hazard ratio [HR] 1.09 [95% CI 1.04-1.14]; P = 0.0003), stimulated glucose (HR 1.50 [1.42-1.59]; P < 0.0001), fasting insulin (HR 0.89 [0.83-0.95]; P = 0.0009), and glucose-to-insulin ratio (HR 1.29 [1.16-1.43]; P < 0.0001) were associated with risk of progression to type 1 diabetes. Younger children had fewer autoantibodies with more symptoms at diagnosis. Twenty-three children (6.1%) had DKA at onset, only 1 (0.97%) of 103 with and 22 (8.0%) of 276 children without a first-degree relative (FDR) with type 1 diabetes (P = 0.008). Children with DKA were more likely to be nonadherent to study protocol (P = 0.047), with longer duration between their last TEDDY evaluation and diagnosis (median 10.2 vs. 2.0 months without DKA; P < 0.001). CONCLUSIONS: DKA at onset in TEDDY is uncommon, especially for FDRs. For those without familial risk, metabolic monitoring continues to provide a primary benefit of reduced DKA but requires regular follow-up. Clinical and laboratory features vary by age at onset, adding to the heterogeneity of type 1 diabetes.

Diabetic Ketoacidosis at Manifestation of Type 1 Diabetes in Childhood and Adolescence­Incidence and Risk Factors.

BACKGROUND: Diabetic ketoacidosis (DKA) is a potentially life-threatening metabolic disorder that can occur with manifestation of type 1 diabetes mellitus (T1D). The aim of this study was to analyze the incidence of DKA at the time of the diagnosis of T1D in childhood and adolescence, the risk factors, and regional approaches to reduce the incidence of ketoacidosis. METHODS: We investigated the proportion of patients under 18 years of age with DKA (defined as pH <7.3, severe DKA pH <7.1) at the manifestation of T1D in Germany in the period 2000-2019, based on data from the German-Austrian registry of diabetes (Diabetes-Patienten-Verlaufsdokumentation, DPV). The influence of the following factors was evaluated: year of manifestation, age, sex, family history of migration (MiH), and distance from the hospital. Moreover, data from the region with and the region without a pilot screening project from 2015 onwards were compared. RESULTS: Of the 41 189 patients with manifestation of T1D, 19.8% presented with DKA (n = 8154, slight increase [p <0.001] over the study period) and 6.1% (n = 2513) had severe DKA. Children under 6 years of age had DKA more often than adolescents (12-17 years) (21.7% versus 18.6%, OR 1.22 {95% CI: [1.14; 1.30]}). Girls had a higher rate of DKA than boys (20.5% versus 19.2%, OR 1.10 [1.03; 1.14]), and patients with MiH were more likely to have DKA than those without MiH (21.4% versus 18.2%, OR 1.40 [1.32; 1.48]). In the region with a pilot screening project, the DKA rate stayed the same, at 20.6%, while in the control region the rate was 22.7% with a decreasing tendency. CONCLUSION: The frequency of DKA at the time of diagnosis of T1D did not decrease between 2000 and 2019 and increased towards the end of the observation period. Children with MiH, children under 6, and girls were at a higher risk of DKA.

Frequency of Autoantibody-Negative Type 1 Diabetes in Children, Adolescents, and Young Adults During the First Wave of the COVID-19 Pandemic in Germany.

OBJECTIVE: The aim of this study was to investigate the frequency of newly diagnosed type 1 diabetes without evidence of autoimmunity and the respective frequencies of ketoacidosis in children, adolescents, and young adults during the coronavirus disease 2019 (COVID-19) pandemic in Germany compared with the previous decade. RESEARCH DESIGN AND METHODS: Based on data from the German Diabetes Prospective Follow-up Registry (DPV), we compared data from 715 children, adolescents, and young adults, newly diagnosed with type 1 diabetes during the COVID-19 pandemic in Germany between 1 March and 30 June 2020, with data from 5,428 children, adolescents, and young adults of the same periods from 2011 to 2019. Adjusted differences and relative risks (RRs) of negative ß-cell autoantibody test results and diabetic ketoacidosis were estimated using multivariable log-binomial regression analysis. An upper noninferiority test (margin 1%) was applied to evaluate whether the autoantibody-negativity rate in 2020 was not higher than that in 2011 to 2019. RESULTS: The estimated frequencies of autoantibody negativity in 2020 and 2011-2019 were 6.6% (95% CI 5.1-8.4) and 7.2% (95% CI 6.5-8.0), respectively, with an absolute difference of -0.68% (90% CI -2.07 to 0.71; P upper noninferiority = 0.023). The increase of the estimated frequency of diabetic ketoacidosis during the COVID-19 pandemic was similar between autoantibody-negative and -positive type 1 diabetes (adjusted RRs 1.28 [95% CI 0.80-2.05] and 1.57 [1.41-1.75], respectively). CONCLUSIONS: This study found no evidence that the COVID-19 pandemic leads to a significantly increased number of new cases with autoantibody-negative type 1 diabetes in children, adolescents, and young adults. In addition, autoantibody-negative type 1 diabetes showed no particular susceptibility to ketoacidosis, neither before nor during the pandemic.

Previous diabetic ketoacidosis as a risk factor for recurrence in a large prospective contemporary pediatric cohort: Results from the DPV initiative.

OBJECTIVE: To assess the role of previous episodes of diabetic ketoacidosis (DKA) and their time-lag as risk factors for recurring DKA in youth with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In a population-based analysis, data from 29,325 children and adolescents with T1D and at least 5 years of continuous follow-up were retrieved from the "Diabetes Prospective Follow-up" (DPV) multi-center registry in March 2020. Statistical analyses included unadjusted comparisons, logistic and negative binomial regression models. RESULTS: Among 29,325 patients with T1D, 86.0% (n = 25,219) reported no DKA, 9.7% (n = 2,833) one, and 4.3% (n = 1,273) more than one episode, corresponding to a DKA rate of 4.4 [95% CI: 4.3-4.6] per 100 patient-years. Female sex, migratory background, higher HbA1c values, higher daily insulin doses, a lower glucose monitoring frequency, and less CGM usage were associated with DKA. In patients with a previous episode, the DKA rate in the most recent year was significantly higher than in patients with no DKA (17.6 [15.9-19.5] vs. 2.8 [2.7-3.1] per 100 patient-years; p < 0.001). Multiple DKAs further increased the recurrence rate. The risk for DKA in the most recent year was higher in patients with an episode in the preceding year than in patients with no previous DKA (OR: 10.0 [95% CI: 8.6-11.8]), and remained significantly elevated 4 years after an episode (OR: 2.3 [1.6-3.1]; p < 0.001). CONCLUSIONS: Each episode of DKA is an independent risk factor for recurrence, even 4 years after an event, underlining the importance of a close follow-up after each episode.

[Is it possible to prevent diabetic ketoacidosis at diagnosis of pediatric type 1 diabetes? Lessons from the COVID-19 pandemic]. / Kann die Ketoacidose bei pädiatrischen Patienten mit Manifestation eines Diabetes mellitus Typ 1 vermieden werden? Lehren aus der COVID-19-Pandemie.

BACKGROUND: Diabetic ketoacidosis (DKA) is a life-threatening emergency in children and adolescents with manifestation of type 1 diabetes mellitus (DM1) and often associated with delayed diagnosis or previous diagnostic errors. During the coronavirus disease 2019 (COVID-19) lockdown period in Germany, less patients presented at emergency departments and private practices. OBJECTIVE: The aim of this study was to investigate the DKA risk in children and adolescents with DM1 manifestation during the COVID-19 lockdown and associated risk factors. MATERIAL AND METHODS: The frequency of DKA at DM1 onset in patients <18 years between 13 March and 13 May 2020 in pediatric diabetes centers was analyzed. The centers also documented their assessment, if the presentation was delayed or the diagnosis was not made on the first medical consultation. In order to analyze the influence of the risk factors on the frequency of DKA, the data from 2020 were compared with the same periods in 2018 and 2019 using multivariable linear and logistic regression. RESULTS: The data of 532 patients from 216 diabetes centers showed that the risk for DKA increased by 84.7% and the risk for severe DKA increased by 45.3% compared to the years 2018/2019. Children <6 years had the highest risk with an 141.6% increase for DKA and 97.0% for severe DKA compared to the previous years. Migration background was a risk factor independent of COVID-19. Of the patients 31% had either a delayed presentation or a missed diagnosis. CONCLUSION: During the COVID-19 lockdown the frequency of DKA and severe DKA at DM1 onset was significantly increased for children and adolescents in Germany. Age <6 years, migration background and delayed diagnosis were the main risk factors.

Thiamine-Responsive Megaloblastic Anemia-Related Diabetes: Long-Term Clinical Outcomes in 23 Pediatric Patients From the DPV and SWEET Registries.

OBJECTIVES: To describe clinical presentation and long-term outcomes in a large cohort of children diagnosed with thiamine-responsive megaloblastic anemia (TRMA)-related diabetes. METHODS: Data from the Diabetes Patienten Verlaufsdokumentation (DPV) and Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference (SWEET) registries were used to identify cases. Complementary information was collected through a chart review of each case. Descriptive analyses with medians and interquartile ranges and numbers (proportions) were tabulated. RESULTS: We identified 23 cases (52% male) in the 2 registries. Eighteen (78%) had genetic confirmation of TRMA. Median age at diabetes onset was 1.4 (quartiles 0.8 to 3.6) years and median age at initiation of thiamine treatment was 5.9 (2.4 to 12.4) years. At their most recent visit, patients' median age was 14.3 (8.1 to 17.5) years, glycated hemoglobin level was 6.9% (6.1% to 7.9%), insulin dose was 0.9 (0.4 to 1.2) units/kg per day and thiamine dose was 200 (100 to 300) mg/day. Three patients were not treated with insulin or antidiabetic drugs. There was no difference in diabetes outcomes in patients with initiation of thiamine ≤1 year after diabetes onset compared to patients with initiation of thiamine >1 year after diabetes onset. CONCLUSIONS: This is the longest case series of pediatric TRMA-related diabetes reported to date. Diabetes onset often occurs several years before initiation of thiamine supplementation. Early initiation of thiamine (within 1 year of diabetes onset) was not linked to improved diabetes outcome. However, the role of thiamine in pancreatic function needs further assessment. Patients with TRMA-related diabetes maintained good glycemic control even after 9 years (median) of follow up.

Diabetes management in Wolcott-Rallison syndrome: analysis from the German/Austrian DPV database.

BACKGROUND: Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure. This is the first multicentre approach that focuses on diabetes management in WRS. We searched the German/Austrian Diabetes-Patienten-Verlaufsdokumentation (DPV) registry and studied anthropometric characteristics, diabetes treatment, glycaemic control and occurrence of severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) in 11 patients with WRS. Furthermore, all local treatment centres were personally contacted to retrieve additional information on genetic characteristics, migration background and rate of consanguinity. RESULTS: Data were analysed at diabetes onset and after a median follow-up period of 3 (1.5-9.0) years (time from diagnosis to latest follow-up). Median age at diabetes onset was 0.2 (0.1-0.3) years, while onset was delayed in one patient (aged 16 months). Seventy percent of patients manifested with DKA. At follow-up, 90% of patients were on insulin pump therapy requiring 0.7 [0.5-1.0] IU of insulin/kg/d. More than two third of patients had HbA1c level ≥ 8%, 40% experienced at least one episode of SH in the course of the disease. Three patients died at 0.6, 5 and 9 years of age, respectively. To the best of our knowledge three patients carried novel mutations in EIF2AK3. CONCLUSION: Insulin requirements of individuals with WRS registered in DPV appear to be comparable to those of preschool children with well-controlled type 1 diabetes, while glycaemic control tends to be worse and episodes of SH tend to be more common. The majority of individuals with WRS in the DPV registry does not reach glycaemic target for HbA1c as defined for preschool children (< 7.5%). International multicentre studies are required to further improve our knowledge on the care of children with WRS.

Maternal Type 1 Diabetes Reduces Autoantigen-Responsive CD4+ T Cells in Offspring.

Autoimmunity against pancreatic ß-cell autoantigens is a characteristic of childhood type 1 diabetes (T1D). Autoimmunity usually appears in genetically susceptible children with the development of autoantibodies against (pro)insulin in early childhood. The offspring of mothers with T1D are protected from this process. The aim of this study was to determine whether the protection conferred by maternal T1D is associated with improved neonatal tolerance against (pro)insulin. Consistent with improved neonatal tolerance, the offspring of mothers with T1D had reduced cord blood CD4+ T-cell responses to proinsulin and insulin, a reduction in the inflammatory profile of their proinsulin-responsive CD4+ T cells, and improved regulation of CD4+ T cell responses to proinsulin at 9 months of age, as compared with offspring with a father or sibling with T1D. Maternal T1D was also associated with a modest reduction in CpG methylation of the INS gene in cord blood mononuclear cells from offspring with a susceptible INS genotype. Our findings support the concept that a maternal T1D environment improves neonatal immune tolerance against the autoantigen (pro)insulin.

Yield of a Public Health Screening of Children for Islet Autoantibodies in Bavaria, Germany.

IMPORTANCE: Public health screening for type 1 diabetes in its presymptomatic stages may reduce disease severity and burden on a population level. OBJECTIVE: To determine the prevalence of presymptomatic type 1 diabetes in children participating in a public health screening program for islet autoantibodies and the risk for progression to clinical diabetes. DESIGN, SETTING, AND PARTICIPANTS: Screening for islet autoantibodies was offered to children aged 1.75 to 5.99 years in Bavaria, Germany, between 2015 and 2019 by primary care pediatricians during well-baby visits. Families of children with multiple islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019. EXPOSURES: Measurement of islet autoantibodies. MAIN OUTCOMES AND MEASURES: The primary outcome was presymptomatic type 1 diabetes, defined by 2 or more islet autoantibodies, with categorization into stages 1 (normoglycemia), 2 (dysglycemia), or 3 (clinical) type 1 diabetes. Secondary outcomes were the frequency of diabetic ketoacidosis and parental psychological stress, assessed by the Patient Health Questionnaire-9 (range, 0-27; higher scores indicate worse depression; ≤4 indicates no to minimal depression; >20 indicates severe depression). RESULTS: Of 90 632 children screened (median [interquartile range {IQR}] age, 3.1 [2.1-4.2] years; 48.5% girls), 280 (0.31%; 95% CI, 0.27-0.35) had presymptomatic type 1 diabetes, including 196 (0.22%) with stage 1, 17 (0.02%) with stage 2, 26 (0.03%) with stage 3, and 41 who were not staged. After a median (IQR) follow-up of 2.4 (1.0-3.2) years, another 36 children developed stage 3 type 1 diabetes. The 3-year cumulative risk for stage 3 type 1 diabetes in the 280 children with presymptomatic type 1 diabetes was 24.9% ([95% CI, 18.5%-30.7%]; 54 cases; annualized rate, 9.0%). Two children had diabetic ketoacidosis. Median (IQR) psychological stress scores were significantly increased at the time of metabolic staging in mothers of children with presymptomatic type 1 diabetes (3 [1-7]) compared with mothers of children without islet autoantibodies (2 [1-4]) (P = .002), but declined after 12 months of follow-up (2 [0-4]) (P < .001). CONCLUSIONS AND RELEVANCE: Among children aged 2 to 5 years in Bavaria, Germany, a program of primary care-based screening showed an islet autoantibody prevalence of 0.31%. These findings may inform considerations of population-based screening of children for islet autoantibodies.

Cardivascular Risk Profile in Patients with Diabetes and Acromegaly or Cushing's Disease - Analysis from the DPV Database.

BACKGROUND: Although diabetes is a common complication of acromegaly or Cushing´s disease, there are only few detailed studies with a focus on cardiovascular risk, metabolic control or diabetes therapy. Here, we provide a comprehensive characterization from the longitudinal DPV (Diabetes Patienten Verlaufsdokumentation) registry. METHODS: Patients from the registry≥18 years of age with diabetes and acromegaly or Cushing´s disease were compared to patients with type 1 diabetes or type 2 diabetes using the statistical software SAS 9.4. RESULTS: Patients with diabetes and acromegaly (n=52) or Cushing's disease (n=15) were significantly younger at diabetes onset (median age 50.1 and 45.0 vs. 59.0 years in type 2 diabetes; both p<0.05). Dyslipidemia was common in both diseases (71.0% and 88.9% vs. 71.8% in type 2 diabetes; n.s.), while hypertension was most frequent in acromegaly (56.8% vs. 20.9% in type 1 diabetes, p<0.00001). 36.5% of patients with acromegaly and 46.7% with Cushing´s disease receive insulin, compared to 50.4% with type 2 diabetes. Oral antidiabetic drugs were used in 36.5% of patients with acromegaly and 40% with Cushing´s disease, with a predominance of biguanides and dipeptidyl peptidase-4 inhibitors. HbA1c was well controlled in both groups (median 7.0% and 6.5%; vs. 7.2% in type 2 diabetes). CONCLUSION: Patients with acromegaly are at a high risk for cardiovascular disease, reflected by dyslipidemia and hypertension. A high proportion of patients with diabetes in acromegaly or Cushing´s disease receives insulin. Based on a multicenter register, a sufficient number of patients with rare forms of diabetes can be analyzed.

Frequency and Characteristics of MODY 1 (HNF4A Mutation) and MODY 5 (HNF1B Mutation): Analysis From the DPV Database.

Objective: To characterize the initial presentation and clinical course of patients with hepatocyte nuclear factor (HNF) 4A‒ and HNF1B‒MODY in a multinational registry. Design, Setting, and Participants: Within the Diabetes Patienten Verlaufsdokumentation (DPV) registry, 44 patients with HNF4A- and 35 patients with HNF1B-MODY were characterized and compared with patients <20 years old with type 1 diabetes (T1D)/type 2 diabetes (T2D). Main Outcome Measure: Clinical and laboratory parameters, therapy, metabolic control, and extrapancreatic symptoms in patients with HNF1B-MODY. Results: Patients with both MODY types were significantly older than patients with T1D at diagnosis (HNF4A, 13.8 years, and HNF1B, 13.5 years, vs T1D, 8.8 years; P < 0.0001). Mean C-peptide at diagnosis was higher for HNF4A-MODY than for T1D (1.8 vs 0.9 ng/mL; P < 0.01); 36.4% of patients with HNF4A-MODY and 65.7% of patients with HNF1B-MODY were treated with insulin, whereas 20.5% and 8.6% received oral antidiabetics only (P < 0.05 and P < 0.01 vs T2D). At the most recent visit, glycated hemoglobin levels were lower in HNF4A- and HNF1B-MODY (mean, 6.5% and 6.1%) than in T1D (7.9%; P < 0.0001). In 40% of patients with HNF1B-MODY, extrapancreatic symptoms were reported. Several clinical predictors previously described to differentiate between MODY and T1D or T2D were revalidated by logistic regression analyses in this cohort. Conclusion: The DPV registry enabled us to precisely characterize phenotype and treatment in these two rare MODY types. Although phenotype of HNF4A- and HNF1B-MODY showed distinct differences from those of T1D and T2D, 38% of patients were initially misclassified as having T1D or T2D.