Publications by authors named "Klemens Raile"

50 Publications

Shaping Workflows in Digital and Remote Diabetes Care During the COVID-19 Pandemic via Service Design: Prospective, Longitudinal, Open-label Feasibility Trial.

JMIR Mhealth Uhealth 2021 04 5;9(4):e24374. Epub 2021 Apr 5.

Charité - Universitätsmedizin Berlin, Department of Paediatric Endocrinology and Diabetes, Berlin, Germany.

Background: The COVID-19 pandemic poses new challenges to health care providers and the delivery of continuous care. Although many diabetes technologies, such as insulin pumps and continuous glucose monitors, have been established, the data from these devices are rarely assessed. Furthermore, telemedicine has not been sufficiently integrated into clinical workflows.

Objective: We sought to remotely support children with type 1 diabetes and their caregivers, enhance the clinical outcomes and quality of life of children with diabetes, increase multiple stakeholders' engagement with digital care via a participatory approach, evaluate the feasibility of using an interoperable open-source platform in a university hospital setting, and analyze the success factors and barriers of transitioning from conventional care to digital care.

Methods: Service design methods were used to adapt clinical workflows. Remote consultations were performed on a monthly and on-demand basis. Diabetes device data were uploaded from patients' homes to an open-source platform. Clinical and patient-reported outcomes were assessed before, during, and after the COVID-19 lockdown period in Germany.

Results: A total of 28 children with type 1 diabetes and their caregivers enrolled in this study and completed 6 months of remote visits. Of these 28 participants, 16 (57%) also opted to attend at least one of their regular visits remotely. After 3 months of remote visits, participants' time in range (P=.001) and time in hyperglycemia (P=.004) significantly improved, and their time in hypoglycemia did not increase. These improvements were maintained during the COVID-19 lockdown period (ie, between months 3 and 6 of this study). Participants' psychosocial health improved after 6 months.

Conclusions: Remote consultations and commonly shared data access can improve the clinical outcomes and quality of life of children with type 1 diabetes, even during challenging circumstances. A service design approach helped with the delivery of comprehensive and holistic solutions that accounted for the needs of multiple stakeholders. Our findings can inform the future integration of digital tools into clinical care during and beyond the pandemic.

Trial Registration: German Clinical Trials Register DRKS00016170; https://tinyurl.com/skz4wdk5.
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http://dx.doi.org/10.2196/24374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023381PMC
April 2021

[Is it possible to prevent diabetic ketoacidosis at diagnosis of pediatric type 1 diabetes? Lessons from the COVID-19 pandemic].

Monatsschr Kinderheilkd 2021 Jan 8:1-8. Epub 2021 Jan 8.

Institut für Epidemiologie und medizinische Biometrie, ZIBMT, Universität Ulm, Ulm, Deutschland.

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.
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http://dx.doi.org/10.1007/s00112-020-01108-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791536PMC
January 2021

Phosphatidylinositol 4-kinase β mutations cause nonsyndromic sensorineural deafness and inner ear malformation.

J Genet Genomics 2020 10 28;47(10):618-626. Epub 2020 Oct 28.

Experimental and Clinical Research Center (ECRC), A Joint Cooperation Between the Charité Medical Faculty and the Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Lindenberger Weg.80, Berlin, 13125, Germany. Electronic address:

Congenital hearing loss is a common disorder worldwide. Heterogeneous gene variation accounts for approximately 20-25% of such patients. We investigated a five-generation Chinese family with autosomal-dominant nonsyndromic sensorineural hearing loss (SNHL). No wave was detected in the pure-tone audiometry, and the auditory brainstem response was absent in all patients. Computed tomography of the patients, as well as of two sporadic SNHL cases, showed bilateral inner ear anomaly, cochlear maldevelopment, absence of the osseous spiral lamina, and an enlarged vestibular aqueduct. Such findings were absent in nonaffected persons. We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4KB gene (p.Gln121Arg) encoding phosphatidylinositol 4-kinase β (PI4KB) from the patients in this family. In addition, 3 missense PI4KB (p.Val434Gly, p.Glu667Lys, and p.Met739Arg) mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases. No such mutations were present within 600 Chinese controls, the 1000 genome project, gnomAD, or similar databases. Depleting pi4kb mRNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment, mimicking the patient phenotypes. Moreover, overexpression of 4 human missense PI4KB mutant mRNAs in zebrafish embryos resulted in impaired hearing function, suggesting dominant-negative effects. Taken together, our results reveal that PI4KB mutations can cause SNHL and inner ear malformation. PI4KB should be included in neonatal deafness screening.
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http://dx.doi.org/10.1016/j.jgg.2020.07.008DOI Listing
October 2020

Open-Source Technology for Real-Time Continuous Glucose Monitoring in the Neonatal Intensive Care Unit: Case Study in a Neonate With Transient Congenital Hyperinsulinism.

J Med Internet Res 2020 12 4;22(12):e21770. Epub 2020 Dec 4.

Charité - Universitätsmedizin Berlin, Department of Neonatology, Berlin, Germany.

Background: Use of real-time continuous glucose monitoring (rtCGM) systems has been shown to be a low-pain, safe, and effective method of preventing hypoglycemia and hyperglycemia in people with diabetes of various age groups. Evidence on rtCGM use in infants and in patients with conditions other than diabetes remains limited.

Objective: This case study describes the off-label use of rtCGM and the use of an open-source app for glucose monitoring in a newborn with prolonged hypoglycemia secondary to transient congenital hyperinsulinism during the perinatal period.

Methods: The Dexcom G6 rtCGM system (Dexcom, Inc) was introduced at 39 hours of age. Capillary blood glucose checks were performed regularly. In order to benefit from customizable alert settings and detect hypoglycemic episodes, the open-source rtCGM app xDrip+ was introduced at 9 days of age.

Results: Time in range (45-180 mg/dL) for interstitial glucose remained consistently above 90%, whereas time in hypoglycemia (<45 mg/dL) decreased. Mean glucose was maintained above 70 mg/dL at 72 hours of life and thereafter. Daily sensor glucose profiles showed cyclic fluctuations that were less pronounced over time.

Conclusions: While off-label use of medication is both common practice and a necessity in newborn infants, there are few examples of off-label uses of medical devices, rtCGM being a notable exception. Real-time information allowed us to better understand glycemic patterns and to improve the quality of glycemic control accordingly. Severe hypoglycemia was prevented, and measurement of serum levels of insulin and further lab diagnostics were performed much faster, while the patient's individual burden caused by invasive procedures was reduced. Greater customizability of threshold and alert settings would be beneficial for user groups with glycemic instability other than people with diabetes, and for hospitalized newborn infants in particular. Further research in the field of personal and off-label rtCGM use, efficacy studies evaluating the accuracy of low glucose readings, and studies on the differences between algorithms in translating raw sensor data, as well as customization of commercially available rtCGM systems, is needed.
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http://dx.doi.org/10.2196/21770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748959PMC
December 2020

Comorbidity of inflammatory bowel disease in children and adolescents with type 1 diabetes.

Acta Paediatr 2021 04 18;110(4):1353-1358. Epub 2020 Nov 18.

Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, and German Centre for Diabetes Research, DZD, Munich-Neuherberg, Germany.

Aim: To determine the prevalence of inflammatory bowel disease (IBD) in patients with type 1 diabetes (T1D) and to characterise patients with both diseases.

Methods: Data of 65.147 patients with T1D ≤18 years of 379 centres in Germany and Austria participating in the DPV initiative were analysed. A total of 63 children had comorbid IBD; IBD prevalence was 0.1%. Regression models were used to analyse differences in metabolic control, acute complications and steroid intake.

Results: Mean BMI-SDS in patients with T1D and IBD was lower (-0.15 ± 0.11) compared to patients with T1D only (0.27 ± 0.00, p < .001). Patients with T1D and IBD had a significantly higher use of steroids (22% ± 0.05% vs. 1% ± 0.00, p < .001) and a significantly higher rate of severe hypoglycaemic events per patient year (0.33 ± 0.07 vs. 0.16 ± 0.00, p = .001). No differences were found in HbA1c levels, insulin dose and occurrence of DKA.

Conclusion: Although children and adolescents with T1D and IBD take steroids more often, they suffer from severe hypoglycaemia more frequently and have a lower BMI-SDS. These findings might be explained by chronic intestinal inflammation leading to malabsorption, malnutrition and increased severe hypoglycaemia.
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http://dx.doi.org/10.1111/apa.15643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984099PMC
April 2021

[Care of children and adolescents with type 1 diabetes: solutions for technical and psychosocial challenges].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020 Jul;63(7):856-863

Interdisziplinäres Sozialpädiatrisches Zentrum, Universitätsmedizin Berlin, Charité, Berlin, Deutschland.

Type 1 diabetes mellitus is the most common endocrine disease in children and adolescents below age 15 years. A cure for the autoimmune disease against the insulin-secreting beta cells is still not in sight. Nevertheless, in recent years technical advances in innovation concerning glucose sensor technology, insulin pumps, and new algorithms that regulate insulin delivery have led to a constant improvement of metabolic control achieved in children and adolescents with type 1 diabetes.This review article shows the current care situation of children and adolescents with type 1 diabetes and their parents. The multidisciplinary care in specialized pediatric diabetes teams of pediatric diabetologists, diabetes educators, social workers, and psychotherapists has been established for many years and has set grounds for a very good quality of care for children and adolescents with type 1 diabetes in Germany. The focus is on diabetes education, in particular self-management, psychosocial support and intervention, and the inclusion of children and adolescents with diabetes in school, kindergarten, and daycare centers. We also address new, social developments in the online diabetes community. A current example is the patient-operated ecosystem of the Do-It-Yourself Artificial Pancreas System (DIY APS) movement, which, as a patient-operated, open-source project, has meanwhile also become an innovator for industry. Finally, we highlight related opportunities and shifts in classical doctor-patient roles.
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http://dx.doi.org/10.1007/s00103-020-03162-3DOI Listing
July 2020

Evidence on User-Led Innovation in Diabetes Technology (The OPEN Project): Protocol for a Mixed Methods Study.

JMIR Res Protoc 2019 Nov 19;8(11):e15368. Epub 2019 Nov 19.

Department of Paediatric Endocrinology and Diabetes, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Digital innovations in health care have traditionally followed a top-down pathway, with manufacturers leading the design and production of technology-enabled solutions and those living with chronic conditions involved only as passive recipients of the end product. However, user-driven open-source initiatives in health care are becoming increasingly popular. An example is the growing movement of people with diabetes, who create their own "Do-It-Yourself Artificial Pancreas Systems" (DIYAPS).

Objective: The overall aim of this study is to establish the empirical evidence base for the clinical effectiveness and quality-of-life benefits of DIYAPS and identify the challenges and possible solutions to enable their wider diffusion.

Methods: A research program comprising 5 work packages will examine the outcomes and potential for scaling up DIYAPS solutions. Quantitative and qualitative methodologies will be used to examine clinical and self-reported outcome measures of DIYAPS users. The majority of members of the research team live with type 1 diabetes and are active DIYAPS users, making Outcomes of Patients' Evidence With Novel, Do-It-Yourself Artificial Pancreas Technology (OPEN) a unique, user-driven research project.

Results: This project has received funding from the European Commission's Horizon 2020 Research and Innovation Program, under the Marie Skłodowska-Curie Action Research and Innovation Staff Exchange. Researchers with both academic and nonacademic backgrounds have been recruited to formulate research questions, drive the research process, and disseminate ongoing findings back to the DIYAPS community and other stakeholders.

Conclusions: The OPEN project is unique in that it is a truly patient- and user-led research project, which brings together an international, interdisciplinary, and intersectoral research group, comprising health care professionals, technical developers, biomedical and social scientists, the majority of whom are also living with diabetes. Thus, it directly addresses the core research and user needs of the DIYAPS movement. As a new model of cooperation, it will highlight how researchers in academia, industry, and the patient community can create patient-centric innovation and reduce disease burden together.

International Registered Report Identifier (irrid): PRR1-10.2196/15368.
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http://dx.doi.org/10.2196/15368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891827PMC
November 2019

deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells.

Proc Natl Acad Sci U S A 2019 10 16;116(40):19983-19988. Epub 2019 Sep 16.

Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz German Center for Diabetes Research (DZD e.V.) Munich, University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany.

Pancreatic β cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair β cell function and cause diabetes. is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of in mouse β cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining β cell function and diabetes prevention.
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http://dx.doi.org/10.1073/pnas.1903678116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778207PMC
October 2019

Real-World Use of Do-It-Yourself Artificial Pancreas Systems in Children and Adolescents With Type 1 Diabetes: Online Survey and Analysis of Self-Reported Clinical Outcomes.

JMIR Mhealth Uhealth 2019 07 30;7(7):e14087. Epub 2019 Jul 30.

Department of Paediatric Endocrinology and Diabetes, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Patient-driven initiatives have made uptake of Do-it-Yourself Artificial Pancreas Systems (DIYAPS) increasingly popular among people with diabetes of all ages. Observational studies have shown improvements in glycemic control and quality of life among adults with diabetes. However, there is a lack of research examining outcomes of children and adolescents with DIYAPS in everyday life and their social context.

Objective: This survey assesses the self-reported clinical outcomes of a pediatric population using DIYAPS in the real world.

Methods: An online survey was distributed to caregivers to assess the hemoglobin A levels and time in range (TIR) before and after DIYAPS initiation and problems during DIYAPS use.

Results: A total of 209 caregivers of children from 21 countries responded to the survey. Of the children, 47.4% were female, with a median age of 10 years, and 99.4% had type 1 diabetes, with a median duration of 4.3 years (SD 3.9). The median duration of DIYAPS use was 7.5 (SD 10.0) months. Clinical outcomes improved significantly, including the hemoglobin A levels (from 6.91% [SD 0.88%] to 6.27% [SD 0.67]; P<.001) and TIR (from 64.2% [SD 15.94] to 80.68% [SD 9.26]; P<.001).

Conclusions: Improved glycemic outcomes were found across all pediatric age groups, including adolescents and very young children. These findings are in line with clinical trial results from commercially developed closed-loop systems.
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http://dx.doi.org/10.2196/14087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691673PMC
July 2019

HDAC4 mutations cause diabetes and induce β-cell FoxO1 nuclear exclusion.

Mol Genet Genomic Med 2019 05 9;7(5):e602. Epub 2019 Apr 9.

Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty, Max-Delbrueck-Center for Molecular Medicine (MDC), Berlin, Germany.

Background: Studying patients with rare Mendelian diabetes has uncovered molecular mechanisms regulating β-cell pathophysiology. Previous studies have shown that Class IIa histone deacetylases (HDAC4, 5, 7, and 9) modulate mammalian pancreatic endocrine cell function and glucose homeostasis.

Methods: We performed exome sequencing in one adolescent nonautoimmune diabetic patient and detected one de novo predicted disease-causing HDAC4 variant (p.His227Arg). We screened our pediatric diabetes cohort with unknown etiology using Sanger sequencing. In mouse pancreatic β-cell lines (Min6 and SJ cells), we performed insulin secretion assay and quantitative RT-PCR to measure the β-cell function transfected with the detected HDAC4 variants and wild type. We carried out immunostaining and Western blot to investigate if the detected HDAC4 variants affect the cellular translocation and acetylation status of Forkhead box protein O1 (FoxO1) in the pancreatic β-cells.

Results: We discovered three HDAC4 mutations (p.His227Arg, p.Asp234Asn, and p.Glu374Lys) in unrelated individuals who had nonautoimmune diabetes with various degrees of β-cell loss. In mouse pancreatic β-cell lines, we found that these three HDAC4 mutations decrease insulin secretion, down-regulate β-cell-specific transcriptional factors, and cause nuclear exclusion of acetylated FoxO1.

Conclusion: Mutations in HDAC4 disrupt the deacetylation of FoxO1, subsequently decrease the β-cell function including insulin secretion, resulting in diabetes.
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http://dx.doi.org/10.1002/mgg3.602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503015PMC
May 2019

Evaluation of a rare glucose-dependent insulinotropic polypeptide receptor variant in a patient with diabetes.

Diabetes Obes Metab 2019 05 19;21(5):1168-1176. Epub 2019 Feb 19.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Institute of Experimental Pediatric Endocrinology, Berlin, Germany.

Aims: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that augments insulin secretion in pancreatic β-cells via its glucose-dependent insulinotropic polypeptide receptor (GIPR). Recent genome-wide association studies identified a single nucleotide variant (SNV) in the GIPR encoding gene (GIPR), rs1800437, that is associated with obesity and insulin resistance. In the present study, we tested whether GIPR variants contribute to obesity and disturb glucose homeostasis or diabetes in specific patient populations.

Materials And Methods: Exon sequencing of GIPR was performed in 164 children with obesity and insulin resistance and in 80 children with paediatric-onset diabetes of unknown origin. The Study of Health in Pomerania (SHIP) cohort, comprising 8320 adults, was screened for the GIPR variant Arg217Leu. GIPR variants were expressed in COS-7 cells and cAMP production was measured upon stimulation with GIP. Cell surface expression was determined by ELISA. Protein homology modelling of the GIPR variants was performed to extract three-dimensional information of the receptor.

Results: A heterozygous missense GIPR variant Arg217Leu (rs200485112) was identified in a patient of Asian ancestry. Functional characterization of Arg217Leu revealed reduced surface expression and signalling after GIP challenge. The homology model of the GIPR structure supports the observed functional relevance of Arg217Leu.

Conclusion: In vitro functional studies and protein homology modelling indicate a potential relevance of the GIPR variant Arg217Leu in receptor function. The heterozygous variant displayed partial co-segregation with diabetes. Based on these findings, we suggest that GIPR variants may play a role in disturbed glucose homeostasis and may be of clinical relevance in homozygous patients.
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http://dx.doi.org/10.1111/dom.13634DOI Listing
May 2019

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

J Clin Endocrinol Metab 2019 03;104(3):845-855

Institute of Epidemiology and Medical Biometry, Central Institute for Biomedical Technology, University of Ulm, Ulm, Germany.

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.
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http://dx.doi.org/10.1210/jc.2018-01696DOI Listing
March 2019

ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents.

Pediatr Diabetes 2018 10;19 Suppl 27:47-63

The Children's Hospital at Westmead and Discipline of Child Health and Adolescent Health, University of Sydney, Sydney, Australia.

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http://dx.doi.org/10.1111/pedi.12772DOI Listing
October 2018

Diabetes mellitus in pediatric solid organ recipients without and with cystic fibrosis: An analysis from the German-Austrian diabetes database (Diabetes Patienten Verlaufsdokumentation).

Pediatr Diabetes 2018 11 22;19(7):1191-1197. Epub 2018 Aug 22.

Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.

Introduction: Posttransplantation diabetes mellitus (PTDM) increases the risk of cardiovascular disease, graft loss, and decreased survival. Follow-up treatment after solid organ transplantation (SOT) needs to focus on, inter alia, maintaining balanced glucose metabolism. This study aimed to ascertain the prevalence of PTDM and describe patient characteristics in the large DPV (Diabetes Patienten Verlaufsdokumentation) pediatric diabetes database.

Methods: DPV data of 71 902 patients from the January 01, 1995 to January 04, 2015 period were analyzed for patients with and without cystic fibrosis (CF) after SOT (kidney, liver, heart, and lung). Multivariable analysis served to assess differences between SOT patient groups at risk for developing diabetes.

Results: Out of 109 SOT patients, 51 had CF; 72.5% received steroids and 62% were additionally given tacrolimus. PTDM developed in 45% of CF patients and 12% of non-CF patients. SOT patients were older at diabetes onset (mean age, 12.50 ± 3.98 years), shorter (height z-score, -1.67 ± 1.25), and lighter (weight z-score, -1.59 ± 1.57) than non-SOT diabetes patients (P < 0.01). With transplantation, glycated hemoglobin (HbA1c) was significantly lower and treatment for hypertension and dyslipidemia was increased. Among SOT patients, weight and body mass index (BMI) z-scores were significantly lower in patients with CF-related diabetes (P < 0.05).

Conclusions: SOT was present in 6.6% of children with diabetes, and this might aggravate the risk of cardiovascular disease in populations with already increased rates of hypertension and dyslipidemia. Dystrophy and short stature were also present, particularly in transplant recipients with CF and diabetes. Comorbidities and long-term consequences call for multidisciplinary collaboration.
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http://dx.doi.org/10.1111/pedi.12725DOI Listing
November 2018

Investigation of Naturally Occurring Single-Nucleotide Variants in Human TAAR1.

Front Pharmacol 2017 24;8:807. Epub 2017 Nov 24.

Institute of Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universitt zu Berlin, Berlin, Germany.

Activation of trace amine-associated receptor 1 (TAAR1) in endocrine pancreas is involved in weight regulation and glucose homeostasis. The purpose of this study was the identification and characterization of potential variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for variants was performed in 314 obese or overweight patients with impaired insulin secretion. The detected variants were functionally characterized concerning TAAR1 cell surface expression and signaling properties and their allele frequencies were determined in the population-based Study of Health in Pomerania (SHIP). Three heterozygous carriers of the single nucleotide missense variants p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ille171Leu (I171L, rs200795344) were detected in the patient cohort. While p.Ser49Leu and p.Ille171Leu were found in obese/overweight patients with slightly impaired glucose homeostasis, p.Arg23Cys was identified in a patient with a complete loss of insulin production. Functional characterization revealed a like wild-type function for I171L, partial loss of function for S49L and a complete loss of function for R23C. The frequency of the R23C variant in 2018 non-diabetic control individuals aged 60 years and older in the general population-based SHIP cohort was lower than in the analyzed patient sample. Both variants are rare in the general population indicating a recent origin in the general gene pool and/or the consequence of pronounced purifying selection, in line with the obvious detrimental effect of the mutations. In conclusion, our study provides hints for the existence of naturally occurring variants with potential relevance for weight regulation and glucose homeostasis.
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http://dx.doi.org/10.3389/fphar.2017.00807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705543PMC
November 2017

Asthma in children and adolescents with type 1 diabetes in Germany and Austria: Frequency and metabolic control.

Pediatr Diabetes 2018 06 8;19(4):727-732. Epub 2017 Dec 8.

Institute of Epidemiology and Medical Biometry, University of Ulm, ZIBMT, Ulm, Germany.

Objective: To investigate the prevalence of asthma in young patients with type 1 diabetes mellitus (T1D) from Austria and Germany and its influence on their metabolic control.

Methods: This prospective, multicenter observational cohort study was based on the DPV-registry (German/Austrian DPV initiative) including 51 926 patients with T1D (<20 years). All clinical data were documented prospectively. To identify patients with additional asthma, the entry of the diagnosis asthma as well as asthma medication was used for classification.

Results: 1755 patients (3.4%) of the cohort had the diagnosis asthma or received asthma-specific drugs. Patients with asthma needed higher insulin doses (0.88 ± 0.3 vs 0.84 ± 0.3 U/kg, P < .01) and had decreased height-standard deviation score (SDS) (-0.002 ± 1.04 vs 0.085 ± 1.02, P < .01); they were more often males (61% vs 52%, P < .01), had an increased body mass index (BMI)-SDS (0.31 ± 0.89 vs 0.28 ± 0.89, P = .04) and experienced more severe hypoglycemia (4.5 [4.2; 4.8] vs 3.2 [3.2; 3.3] events/100 pts. years, P < .01). Glycated hemoglobin A1c (HbA1c) did not differ between patients with and without asthma overall, only sub groups (corticosteroids vs leukotriene antagonist and corticosteroids vs sympatomimetics) revealed differences. No influence of asthma medication on metabolic control or BMI-SDS could be found.

Conclusion: In our DPV-database, frequency of asthma and T1D seems similar to the prevalence of asthma in the healthy German background population. The concomitant diagnosis of asthma and T1D had minor influence on metabolic control and diabetes complication rate, although there was no difference in HbA1c overall. Patients with both diseases seem to be slightly growth restricted and require slightly higher insulin doses.
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http://dx.doi.org/10.1111/pedi.12618DOI Listing
June 2018

Primary sulphonylurea therapy in a newborn with transient neonatal diabetes attributable to a paternal uniparental disomy 6q24 (UPD6).

Diabetes Obes Metab 2018 02 5;20(2):474-475. Epub 2017 Oct 5.

Institute of Experimental Pediatric Endocrinology, Charité University Medicine Berlin, Berlin, Germany.

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http://dx.doi.org/10.1111/dom.13085DOI Listing
February 2018

Pulse pressure in children and adolescents with type 1 diabetes mellitus in Germany and Austria.

Pediatr Diabetes 2014 May;15(3):236-43

Department of Pediatrics, University Hospital Jena, Jena, Germany.

Background: Impaired blood pressure regulation contributes to the development of diabetic complications. The influence of systolic (SBP) vs.diastolic blood pressure (DBP) is still controversial. Peripheral pulse pressure(PP), the difference between SBP and DBP, is an indicator for arterial stiffness. Only little data are available for PP in children. Therefore, we studied PP regulation in type 1 diabetic children and adolescents.Methods: Blood pressure values of 46 737 patients with T1DM younger than 20 years are documented in the DPV database and were compared with the control populations of the '4th report on high blood pressure (4th report)’ and the German KIGGS study.

Results: PP is increased in 63% (4th report) or 67% (KIGGS) of the patients,respectively. The rate of increased PP remains stable between 59 and 68%,irrespective of sex, age, and the control population. Absolute PP is elevated independently of the control population (PP T1DM 49.13±11.1 vs. 4th report 45.38 ± 3 vs. KIGGS 44.58 ± 4.6 mmHg; all p<0.0001, Wilcoxon test)and increases with age in both sexes. Age, male sex, diabetes duration, insulin dose, and body mass index (BMI) are independent factors contributing to elevated absolute PP levels and to the prevalence of wide PP. HbA1c is negligible negatively related to increased PP levels (multiple linear regression).

Conclusions: In T1DM increased PP is a marker for accelerated arterial stiffness and aging and should be considered as an additional risk factor in the treatment of diabetic children. Elevated PP in children with T1DM may contribute to the high risk for early development of atherosclerosis.
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http://dx.doi.org/10.1111/pedi.12083DOI Listing
May 2014

Tracking of metabolic control from childhood to young adulthood in type 1 diabetes.

J Pediatr 2014 Nov 20;165(5):956-61.e1-2. Epub 2014 Aug 20.

Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.

Objective: This prospective longitudinal survey was designed to follow patients with diabetes from disease onset in childhood over an extended period of time including puberty until young adulthood with respect to metabolic control.

Study Design: An electronic diabetes patient documentation system used in diabetes centers in Austria and Germany was utilized for standardized data collection. Complete documentation of metabolic control for prepuberty (≤ 13 years), puberty (14-19 years), and adulthood (≥ 20 years) was available in 1146 patients.

Results: Median age at diabetes manifestation was 7.2 (IQR 4.7-9.4) years; 49% were male. In the prepubertal stage, median glycated hemoglobin A1c (HbA1c) was 7.5 (IQR 6.8-8.3), during puberty 8.0 (IQR 7.3-8.9), and after puberty 7.8 (IQR 7.1-9.0). A significant intra-individual correlation was found for prepuberty to puberty HbA1c levels (R = 0.55, P < .001), puberty to adulthood (R = 0.59, P < .001), as well as prepuberty to adulthood (R = 0.30, P < .001). When patients were divided into tertiles of prepubertal HbA1c, HbA1c increased in all 3 groups over time, however, significant group differences tracked into adulthood (P < .001 at all stages). A regression model identified pre-pubertal HbA1c as a significant and relevant predictor of metabolic control in young adulthood adjusted for confounders (P < .001).

Conclusions: This survey provides evidence for long-term tracking of metabolic control from childhood until adulthood, suggesting an early focus on metabolic control.
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http://dx.doi.org/10.1016/j.jpeds.2014.07.001DOI Listing
November 2014

Recessive mutations in PCBD1 cause a new type of early-onset diabetes.

Diabetes 2014 Oct 21;63(10):3557-64. Epub 2014 May 21.

Experimental and Clinical Research Center, Charité Medical Faculty and Max-Delbrück Center for Molecular Medicine, Berlin, Germany

Mutations in several genes cause nonautoimmune diabetes, but numerous patients still have unclear genetic defects, hampering our understanding of the development of the disease and preventing pathogenesis-oriented treatment. We used whole-genome sequencing with linkage analysis to study a consanguineous family with early-onset antibody-negative diabetes and identified a novel deletion in PCBD1 (pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 α), a gene that was recently proposed as a likely cause of diabetes. A subsequent reevaluation of patients with mild neonatal hyperphenylalaninemia due to mutations in PCBD1 from the BIODEF database identified three additional patients who had developed HNF1A-like diabetes in puberty, indicating early β-cell failure. We found that Pcbd1 is expressed in the developing pancreas of both mouse and Xenopus embryos from early specification onward showing colocalization with insulin. Importantly, a morpholino-mediated knockdown in Xenopus revealed that pcbd1 activity is required for the proper establishment of early pancreatic fate within the endoderm. We provide the first genetic evidence that PCBD1 mutations can cause early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. This condition responds to and can be treated with oral drugs instead of insulin, which is important clinical information for these patients. Finally, patients at risk can be detected through a newborn screening for phenylketonuria.
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http://dx.doi.org/10.2337/db13-1784DOI Listing
October 2014

Occurrence of giant focal forms of congenital hyperinsulinism with incorrect visualization by (18) F DOPA-PET/CT scanning.

Clin Endocrinol (Oxf) 2014 Dec 19;81(6):847-54. Epub 2014 May 19.

Institut für experimentelle pädiatrische Endokrinologie, Charité Universitätsmedizin, Berlin, Germany.

Context: Congenital hyperinsulinism (CHI) is a rare disease characterized by severe hypoglycaemic episodes due to pathologically increased insulin secretion from the pancreatic beta cells. When untreated, CHI might result in irreversible brain damage and death. Currently, two major subtypes of CHI are known: a focal form, associated with local distribution of affected beta cells and a nonfocal form, affecting every single beta cell. The identification of focal forms is important, as the patients can be cured by limited surgery. (18) F DOPA-PET/CT is an established non-invasive approach to differentiate focal from nonfocal CHI.

Objective: The purpose of this study was to identify possible limitations of (18) F DOPA-PET/CT scan in patients with focal forms nonfocal CHI.

Design: A retrospective chart review of 32 patients (from 2008 through 2013) who underwent (18) F DOPA-PET/CT and partial pancreatectomy for focal CHI at the reference centres in Berlin, Germany and London, UK.

Results: In most cases (n = 29, 90·7%), (18) F DOPA-PET/CT was sufficient to localize the complete focal lesion. However, in some patients (n = 3, 9·3%), (18) F DOPA-PET/CT wrongly visualized only a small portion of the focal lesion. In this group of patients, a so-called 'giant focus' was detected in histopathological analysis during the surgery.

Conclusions: Our data show that in most patients with focal CHI (18) F DOPA-PET/CT correctly predicts the size and anatomical localisation of the lesion. However, in those patients with a 'giant focal' lesion (18) F DOPA-PET/CT is unreliable for correct identification of 'giant focus' cases.
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http://dx.doi.org/10.1111/cen.12473DOI Listing
December 2014

Meglitinide analogues in adolescent patients with HNF1A-MODY (MODY 3).

Pediatrics 2014 Mar 24;133(3):e775-9. Epub 2014 Feb 24.

Department of Pediatric Endocrinology and Diabetology, Charité University Children's Hospital, Berlin, Germany; and.

For pediatric patients with hepatocyte nuclear factor-1A (HNF1A)-maturity-onset diabetes of the young (MODY 3), treatment with sulfonylureas is recommended. In adults with HNF1A-MODY, meglitinide analogues achieve lower postprandial glucose levels and pose a lower risk of delayed hypoglycemia compared with sulfonylureas. This therapy has not yet been reviewed in pediatric patients. We report on meglitinide analogue treatment in 3 adolescents with HNF1A-MODY. Case 1 (14-year-old girl) was diagnosed asymptomatically but had an hemoglobin A1c (HbA1c) level of 7.4%; her father had been recently diagnosed with HNF1A-MODY. With repaglinide, her HbA1c level decreased to 5.5%, with no hypoglycemic episodes. Case 2 (14-year-old boy) was diagnosed incidentally with glucosuria (HbA1c level: 7.0%) and was treated with insulin. After the HNF1A-MODY diagnosis, he was switched to glibenclamide. Due to several hypoglycemic episodes, treatment was changed to nateglinide and his HbA1c level decreased to 6.2% with no further hypoglycemic episodes. Case 3 (11-year-old girl) presented with polyuria and polydipsia (HbA1c level: 10.1%) and was initially treated with insulin. After the HNF1A-MODY diagnosis, treatment was changed to repaglinide. She was obese (BMI: 28.8 kg/m(2); z-score: +2.2), and glucose control with repaglinide alone was insufficient. Therefore, neutral protamine Hagedorn insulin (0.27 U/kg per day) was added. With this combination therapy, her HbA1c level decreased to 8.2%. The use of meglitinides in these 3 adolescent patients was well tolerated and effective. Furthermore, hypoglycemic episodes were rare compared with treatment with insulin or sulfonylureas. We therefore suggest considering meglitinides as the primary oral treatment option for adolescents suffering from HNF1A-MODY.
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http://dx.doi.org/10.1542/peds.2012-2537DOI Listing
March 2014

Higher relative risk for multiple sclerosis in a pediatric and adolescent diabetic population: analysis from DPV database.

Diabetes Care 2014 29;37(1):96-101. Epub 2013 Aug 29.

Corresponding author: Susanne Bechtold,

OBJECTIVE Type 1 diabetes and multiple sclerosis (MS) are typical autoimmune diseases in children and young adults. We assessed the co-occurrence of type 1 diabetes and MS by estimating the relative risk (RR) for MS in a pediatric and adolescent diabetic population and looked for possible influencing factors. RESEARCH DESIGN AND METHODS Within the Diabetes Patienten Verlaufsdokumentation (DPV)-Wiss Project, from January 1995 to October 2012, data from 56,653 patients with type 1 diabetes were collected in 248 centers in Germany and Austria. Published data on German and Mid-European MS prevalence were taken for comparison. Multivariable regression analysis was used to identify confounders for co-occurrence of type 1 diabetes and MS. RESULTS The RR for MS in patients with type 1 diabetes was estimated at 3.35-4.79 (95% CI 1.56-7.21 and 2.01-11.39, respectively). Immigration status in all patients (P < 0.05) and the presence of thyroid antibodies in male patients only (P = 0.05) were identified as influencing factors on MS incidence within the DPV database. The month-of-birth pattern revealed that risk was higher during the spring and summer months in the population with type 1 diabetes and MS in comparison with the population with type 1 diabetes. CONCLUSIONS The present cohort study demonstrates a higher risk of co-occurrence of MS in a pediatric and adolescent diabetic population. Immigration status and thyroid antibodies in male patients were independent risk indicators for the incidental rate of MS. Diabetic patients born during spring and summer had a higher risk for the development of MS. We suggest that environmental factors modulate the individual's risk for the co-occurrence of both diseases.
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http://dx.doi.org/10.2337/dc13-1414DOI Listing
July 2015

Two novel GATA6 mutations cause childhood-onset diabetes mellitus, pancreas malformation and congenital heart disease.

Horm Res Paediatr 2013 26;79(4):250-6. Epub 2013 Apr 26.

Max Delbrück Center for Molecular Medicine, Charité, Berlin, Germany.

Background: GATA6 mutations are the most frequent cause of pancreatic agenesis and diabetes in human sporadic cases. In families, dominantly inherited mutations show a variable phenotype also in terms of endocrine and exocrine pancreatic disease. We report two novel GATA6 mutations in an independent cohort of 8 children with pancreas aplasia or hypoplasia and diabetes.

Methods: We sequenced GATA6 in 8 children with diabetes and inborn pancreas abnormalities, i.e. hypoplasia or aplasia in which other known candidate genes causing monogenic diabetes and pancreatic defects had been excluded.

Results: We found two novel heterozygous GATA6 mutations (c.951_954dup and c.754_904del) in 2 patients with sporadic pancreas hypoplasia, diabetes and severe cardiac defects (common truncus arteriosus and tetralogy of Fallot), but not in the remaining 6 patients. GATA6 mutations in carriers exhibited hypoplastic pancreas with absent head in 1 patient and with increased echogenicity and decreasing exocrine function in the other patient. Additionally, hepatobiliary malformations and brain atrophy were found in 1 patient.

Conclusion: Our 2 cases with novel GATA6 mutations add more phenotype characteristics of GATA6 haploinsufficiency. In agreement with an increasing number of published cases, the wide phenotypic spectrum of GATA6 diabetes syndrome should draw the attention of both pediatric endocrinologists and geneticists.
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http://dx.doi.org/10.1159/000348844DOI Listing
December 2013

Predicting the optimal basal insulin infusion pattern in children and adolescents on insulin pumps.

Diabetes Care 2013 Jun 12;36(6):1507-11. Epub 2013 Feb 12.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics,Christian-Albrechts-University of Kiel, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Objective: We aimed at developing and cross-validating a mathematical prediction model for an optimal basal insulin infusion pattern for children with type 1 diabetes on continuous subcutaneous insulin infusion therapy (CSII).

Research Design And Methods: We used the German/Austrian DPV-Wiss database for quality control and scientific surveys in pediatric diabetology and retrieved all CSII patients <20 years of age (November 2009). A total of 1,248 individuals from our previous study were excluded (dataset 1), resulting in 6,063 CSII patients (dataset 2) (mean age 10.6 ± 4.3 years). Only the most recent basal insulin infusion rates (BRs) were considered. BR patterns were identified and corresponding patients sorted by unsupervised clustering. Logistic regression analysis was applied to calculate the probabilities for each BR pattern. Equations were based on both independent datasets separately, and probabilities for BR patterns were cross-validated using typical test patients.

Results: Of the 6,063 children, 5,903 clustered in one of four major circadian BR patterns, confirming our previous study. The oldest age-group (mean age 12.8 years) was represented by 2,490 patients (42.18%) with a biphasic dawn-dusk pattern (BC). A broad single insulin maximum at 9-10 p.m. (F) was unveiled by 853 patients (14.45%) (mean age 6.3 years). Logistic regression analysis revealed that age, to a lesser extent duration of diabetes, and partly sex predicted BR patterns. Cross-validation revealed almost identical probabilities for BR patterns BC and F in the two datasets but some variation in the remaining two BR patterns.

Conclusions: Reconfirmation of four key BR patterns in two very large independent cohorts supports that these patterns are realistic approximations of the circadian distribution of insulin needs in children with type 1 diabetes. Prediction of an optimal pattern a priori can improve initiation and clinical follow-up of CSII in children and adolescents. In addition, these BR patterns represent valuable information for insulin-infusion algorithms in closed-loop CSII.
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http://dx.doi.org/10.2337/dc12-1705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661794PMC
June 2013

Long-term lanreotide treatment in six patients with congenital hyperinsulinism.

Horm Res Paediatr 2012 14;78(2):106-12. Epub 2012 Aug 14.

Institute of Experimental Paediatric Endocrinology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Medical treatment is a substantial therapeutic measure to achieve glycemic control and prevent hypoglycemic brain damage without surgery in patients with congenital hyperinsulinism (CHI). However, only few drugs are available and even fewer are approved as a medical therapy to maintain normal blood glucose levels. The established therapies are demanding for caregivers and complicated by different side effects such as gastrointestinal symptoms, hypertrichosis, and obesity. Therefore, it is important to develop new strategies to improve blood glucose control.

Methods: We report the use of the very-long-acting somatostatin analogue lanreotide autogel in 6 patients with CHI over a mean duration of 40.8 months. Blood glucose levels before and after the start and dosage titration of lanreotide in these patients are compared.

Results: In 3 of 6 patients, switching to lanreotide raised mean blood glucose levels and reduced individually as well as overall the risk for hypoglycemic episodes (odds ratio 0.38) significantly.

Conclusion: Lanreotide autogel can be used as an alternative pharmacological treatment and may be beneficial in conservatively treated patients with CHI.
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http://dx.doi.org/10.1159/000341525DOI Listing
February 2013

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

N Engl J Med 2012 Feb;366(5):433-42

Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.

Background: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.

Methods: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.

Results: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.

Conclusions: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).
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http://dx.doi.org/10.1056/NEJMoa1107096DOI Listing
February 2012

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.

Eur J Endocrinol 2012 Mar 23;166(3):493-501. Epub 2011 Dec 23.

Charité - Universitätsmedizin Berlin, Paediatric Endocrinology and Diabetology, University Hospital for Children and Adolescents, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.

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.
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http://dx.doi.org/10.1530/EJE-11-0695DOI Listing
March 2012