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Ludwig-Seibold CU, Holder M, Rami B, Raile K, Heidtmann B, Holl RW; for the DPV Science Initiative, the German Working Group for insulin pump treatment in pediatric patients and the German BMBF Competence Network Diabetes. Continuous glucose monitoring in children, adolescents, and adults with type 1 diabetes mellitus: analysis from the prospective DPV diabetes documentation and quality management system from Germany and Austria. Objective: To determine frequency, duration, and relationship of continuous glucose monitoring (CGM) to glycemic control and rate of hypoglycemia in children and adults in Germany and Austria. Research design and methods: From 59 920 patients documented in the DPV (Diabetessoftware zur prospektiven Verlaufsdokumentation) database, 144 385 sensor days of 2874 patients using CGM between January 2008 and September 2010 were analyzed. Results: Overall, 4.8% of patients used CGM. In pediatric patients, study period (p = 0.0309), age (p = 0.0140), insulin dose (p 30 d) had significantly lower HbA1c (p < 0.0016). Severe hypoglycemia was not reduced in patients using CGM for

OBJECTIVE To evaluate the relationship between media consumption habits, physical activity, socioeconomic status, and glycemic control in youths with type 1 diabetes. RESEARCH DESIGN AND METHODS In the cross-sectional study, self-report questionnaires were used to assess media consumption habits, physical activity, and socioeconomic status in 296 children, adolescents, and young adults with type 1 diabetes. Clinical data and HbA1c levels were collected. Risk factors were analyzed by multiple regression. RESULTS Youths with type 1 diabetes (aged 13.7 ± 4.1 years, HbA1c 8.7 ± 1.6%, diabetes duration 6.1 ± 3.3 years) spent 2.9 ± 1.8 h per day watching television and using computers. Weekly physical activity was 5.1 ± 4.5 h. Multiple regression analysis identified diabetes duration, socioeconomic status, and daily media consumption time as significant risk factors for glycemic control. CONCLUSIONS Diabetes duration, socioeconomic status, and daily media consumption time, but not physical activity, were significant risk factors for glycemic control in youths with type 1 diabetes.

BackgroundMutations of the preproinsulin gene (INS) account for both permanent neonatal diabetes (PND) and adult-onset diabetes. The molecular mechanism of complete INS deletion has recently been published and we now add clinical data of homozygous and heterozygous subjects as well as the detailed mapping of the 646 bp deletion of the INS gene.MethodsLocation and size of the INS deletion was mapped in one case with PND and INS genotype of the whole family was further characterized by breakpoint-spanning PCR. The phenotype of monoallelic loss of INS was studied in 33 adult family members of a large consanguineous kindred with INS deletion.ResultsThe 646 bp deletion was found in two individuals with PND that included exons 1 and 2 of the INS gene (chr11: g.2138434_2139080del646) and results in loss of approximately half of the preproinsulin protein. The two boys with homozygous INS deletion (D/D) presented with reduced birth weight, PND within the first 24 h of life and complete absence of C-peptide. Adult family members with the N/D had diabetes onset with earliest 25 years, while the oldest subject without diabetes was 45 years. INS-deletion-diabetes was initially treated with oral antidiabetic drugs but then transferred to insulin within 5–16 years. Overall, N/D-subjects (n=11) had a higher risk to develop insulin-dependent diabetes up to the fifth decade, if compared with normal subjects (n=22).ConclusionComplete loss of the human INS gene results in neonatal diabetes, while heterozygous INS deletion is a strong risk factor for developing insulin-dependent diabetes at adult age.

Leptin inhibits insulin secretion from pancreatic β-cells, and in turn, insulin stimulates leptin biosynthesis and secretion from adipose tissue. Dysfunction of this adipoinsular feedback loop has been proposed to be involved in the development of hyperinsulinemia and type 2 diabetes mellitus. At the molecular level, leptin acts through various pathways, which in combination confer inhibitory effects on insulin biosynthesis and secretion. The aim of this study was to identify molecular mechanisms of leptin action on insulin secretion in pancreatic β-cells. To identify novel leptin-regulated genes, we performed subtraction PCR in INS-1 β-cells. Regulated expression of identified genes was confirmed by RT-PCR and Northern and Western blotting. Furthermore, functional impact on β-cell function was characterized by insulin-secretion assays, intracellular Ca2+ concentration measurements, and enzyme activity assays. PP-1α, the catalytic subunit of protein phosphatase 1 (PP-1), was identified as a novel gene down-regulated by leptin in INS-1 pancreatic β-cells. Expression of PP-1α was verified in human pancreatic sections. PP-1α mRNA and protein expression is down-regulated by leptin, which culminates in reduction of PP-1 enzyme activity in β-cells. In addition, glucose-induced insulin secretion was inhibited by nuclear inhibitor of PP-1 and calyculin A, which was in part mediated by a reduction of PP-1-dependent calcium influx into INS-1 β-cells. These results identify a novel molecular pathway by which leptin confers inhibitory action on insulin secretion, and impaired PP-1 inhibition by leptin may be involved in dysfunction of the adipoinsular axis during the development of hyperinsulinemia and type 2 diabetes mellitus.

The aim of this study was to analyse the risk profile for diabetic retinopathy under real-life conditions in a large cohort of patients with type 1 diabetes.Patients (n = 18,891) with childhood, adolescent or adult onset of type 1 diabetes from the prospective German Diabetes Documentation System survey were analysed. A total of 8,784 patients fulfilled the inclusion criterion, which was availability of retinopathy status. Retinopathy grading (any retinopathy, advanced retinopathy), treatment regimens and risk factors were prospectively recorded and tested as covariates by Kaplan-Meier analysis and logistic regression.Any retinopathy was present in 27.4% and advanced retinopathy (severe non-proliferative or proliferative diabetic retinopathy) in 8.0% of the cohort. After 40 years of diabetes, the cumulative proportion of patients with any retinopathy and advanced retinopathy was 84.1% and 50.2%, respectively. In multiple regression analysis, risk factors for any retinopathy were diabetes duration (OR 1.167 per year), HbA(1c)7.0% (53 mmol/mol) (OR 2.225), smoking (OR 1.295) and male sex (OR 1.187) (p 0.0001 for all). Young age at onset (5 vs 15 years at disease onset) was protective (0.410, p 0.0001). No glycaemic threshold was detected for retinopathy protection. Risk factors for advanced retinopathy were duration (1.124 per year, p 0.0001), male sex (1.323, p = 0.0020), HbA(1c)7.0% (53 mmol/mol) (1.499, p 0.0001), triacylglycerol1.7 mmol/l (1.398, p = 0.0013) and blood pressure 140/90 mmHg (1.911, p 0.0001).The prevalence of retinopathy remains significant in type 1 diabetes. Any improvement of metabolic control and non-smoking is protective, while hypertension affects progression to severe levels under real-life conditions. These data reinforce the validity of multifactorial concepts for morbidity protection in type 1 diabetes.

The 2008-released FDA safety report described a potential association between use of MMF and progressive multifocal leukoencephalopathy. We here report the case of an 11-yr-old kidney transplanted boy suffering from PML who showed rapid improvement parallel to withdrawal of MMF. This case contributes to the increasing knowledge on side effects of MMF treatment in children.

Hofer SE, Heidtmann B, Raile K, Frohlich-Reiterer E, Lilienthal E, Berghaeuser MA, Holl RW for the DPV-Science-Initiative and the German working group for insulin pump treatment in pediatric patients. Discontinuation of insulin pump treatment in children, adolescents, and young adults. A multicenter analysis based on the DPV database in Germany and Austria. Background: Insulin pump therapy is well established in the treatment of children and adolescents with type 1 diabetes. Most studies focus on outcome parameters like hemoglobin A1c (HbA1c), hypoglycemia, and quality of life, whereas few reports address patients who discontinue pump therapy. Objective: This survey focuses on the discontinuation rate of insulin pump treatment in the pediatric and young adult age group. Subjects and methods: The prospective multicenter Diabetes Patienten Verlausdokumentation (DPV) (electronic diabetes patient documentation system) database has been established since 1990 and is broadly used in Germany and Austria. All pump users among the participating centers documented since 1995 were included in this analysis. Results: In total, 11 710 patients with type 1 diabetes were recorded as treated with insulin pumps. In total, 463 patients (4%) switched from insulin pump treatment to multiple daily injections (MDI). In the group of patients who stopped with pump treatment, the mean duration of pump therapy was 1.7 yr (SE ± 0.06 yr), 60.5% of patients were female. Subdivided into age groups, the discontinuation rate was lowest in the age group < 5 yr (0.1%), followed by the groups aged 5–10 yr (0.3%) and 15–20 yr (0.8%). The group aged 10–15 yr showed the highest rate of discontinuation (2%). Conclusions: The discontinuation rate of insulin pump therapy is, in general, low (4%). The younger the patients at the time of initiating insulin pump treatment, the lower is the discontinuation rate. The highest rate was seen in adolescents aged 10–15 yr. Girls stopped insulin pump treatment more often than boys (60.5% vs. 39.5%).

Arterial blood pressure was followed in 868 patients with type 1 diabetes aged 6.0-19.9 years in 95 centers in Germany and Austria.European blood pressure reference data for 28,043 children and adolescents were used with respect to age and sex. Data were stratified into three groups: prepubertal, pubertal, and postpubertal.Up to 4% of the participants in the younger age-groups and 13.9% of the postpubertal patients exhibited blood pressure values97th centile. Blood pressure levels correlated with A1C level and BMI Z score. Tracking of blood pressure revealed that children with elevated blood pressure had higher blood pressure in adolescence and young adulthood.Patients with higher blood pressure in childhood showed elevated blood pressure later in life. We need to focus on the diagnosis of hypertension in children with type 1 diabetes and to study the efficacy of early intervention.

Fragestellung: Arterieller Blutdruck (RR) und Hypertoniehaufigkeit als kardiovaskulare Risikofaktoren wurden bei 868 Patienten mit Typ-1-Diabetes aus 95 Zentren in Deutschland und Osterreich im Langzeitverlauf im Altersbereich von 6,0 bis 19,9 Jahren untersucht. Methodik: Bei den Patienten wurden mindestens 1–4 mal jahrlich body mass index (BMI), HbA1c und Ruhe-RR (sphygmomanometrisch oder mittels Dinamap, Critikon) bestimmt. Die Daten wurden konform mit der Deklaration von Helsinki im Zeitraum von 1977 bis 2006 erhoben und mittels der DPV Datenbank ausgewertet. 1353 Patienten wurden getestet, 962 eingeschlossen, komplette Datensatze fur alle 3 Altersbereiche lagen fur 868 Patienten vor (432 weiblich, 436mannlich, Alter bei Diagnose 5,9±2,4 Jahre). Europaische RR- Referenzwerte von 28043 Kindern und Jugendlichen wurden zum Vergleich herangezogen. Alle Daten wurden nach Geschlecht und Alter stratifiziert in die Kohorten 6,0–9,9 Jahre (prapubertar), 10,0–15,9 Jahre (pubertar) und 16,0–19,9 Jahre (postpubertar). RR und BMI wurden mit der LMS-Methode analysiert (box-cox-power-Transformation, z-Score), auserdem wurden Pearson Korrelation, Kruskal Wallis und Wilcoxon Tests angewendet. Ergebnisse: Innerhalb der 3 Alterskohorten lagen die mittleren Werte (±Standardabweichung) fur HbA1c bei 7,4±1,4%, 7,9±1,3%, 8,4%±1,7, fur BMI z-Score bei 0,24±0,73, 0,37±0,78, 0,60±0,89, fur systolischen RR bei 106±7, 116±8, 127±11mmHg, fur diastolischen RR bei 65±6, 68±7, 72±7mmHg. Der mittlere RR z-Score stieg mit zunehmendem Alter an. In den beiden jungeren Altersgruppen hatten 4% der Patienten einen RR uber der 97. Perzentile, hingegen 13,9% in der postpubertaren Gruppe. RR sowie BMI z-Score korrelierten signifikant mit dem HbA1c-Wert. Eine Verlaufsanalyse („Tracking“) des RR ergab, dass prapubertare Patienten mit erhohtem systolischem oder diastolischem RR auch in der Pubertat und postpubertar signifikant dauerhaft hohere RR-Werte aufwiesen als Kinder mit niedrigerem RR im prapubertaren Zeitraum. Schlussfolgerungen: RR-Messungen bei jungen Menschen mit Diabetes haben schon fruhzeitig eine hohe Aussagekraft fur die Abschatzung des spateren kardiovaskularen Risikos. Hypertensive Risiken manifestieren sich bei jungen Patienten mit Typ-1-Diabetes fruh im Leben und sind daher einer fruhzeitigen Intervention zuganglich.

Kontext: Die aktuelle Klassifikation (ADA 1997, DDG-EBL 2007) unterscheidet zwei Kategorien des Typ-1-Diabetes mellitus: Autoimmun-vermittelten Typ-1A-Diabetes mit Nachweis von Betazell-Autoantikorpern und „idiopathischen“ Typ-1B, der durch fehlenden Antikorpernachweis und den Ausschluss von bekannten, monogenetischen Diabetesformen (MODY) charakterisiert ist. Diese Studie soll erstmals eine padiatrische Kohorte mit idiopathischem Typ-1B-Diabetes mellitus bezuglich klinischer und biochemischer Parameter im Vergleich zu Autoantikorper-positiven, gematchten Kontrollen, charakterisieren. Methodik: Insgesamt 31 Patienten von insgesamt 635 kontinuierlich betreuten Kindern und Jugendlichen mit Diabetes erfullten die klinischen Kriterien fur „idiopathischen“ Typ-1B-Diabetes mit 1) fehlendem Nachweis von Autoantikorpern innerhalb der ersten 12 Monate nach Manifestation (IA-2A, GAD65A oder ICA), 2) fehlendem Nachweis von monogenetischem Diabetes (Gene: GCK, HNF1A, HNF4A, HNF1B, HNF1B-Deletion) sowie 3) Ausschluss von neonatalem Diabetes (Manifestation 2 IE/kg/d) oder klinischen Syndromen. Aus einer Kontrollkohorte von 274 Patienten mit Nachweis von IA-2A und/oder GAD65A bei Manifestation wurden mittels retrogradem 2:1 Matching (Kriterien: 1. Geschlecht, 2. Alter bei Manifestation) 62 Kontrollen (Typ-1A-Kohorte) gewahlt und deren prospektiv dokumentierte Verlaufsdaten (DPV-Datenbank) im Vergleich zur Typ-1B-Kohorte analysiert. Ergebnisse: Kinder und Jugendliche mit Typ-1B-Diabetes mellitus zeigten keinen signifikanten Unterschied der klinischen Parameter bei Manifestation (Mittelwerte Typ-1B vs. Typ-1A: initialer pH 7,32 vs. 7,26; Hyperglykamie: 484 vs. 489mg/dl; HbA1c 12,4 vs. 11,5%). Beide Kohorten unterschieden sich auch innerhalb der ersten 24 Monate nach Manifestation (Analysen nach 3, 6, 12, 18, 24 Monaten) nicht signifikant bez. HbA1c-Verlauf und Insulinbedarf (U/kg/d). Lediglich der BMI-SDS war nach 12 bzw. 24 Monaten in der Typ-1B-Kohorte signifikant niedriger (Typ-1B vs. Typ-1A, 12 Monate: 0,15 vs. 0,64, p=0,014; 24 Monate: 0,21 vs. 0,64; p=0,022). Schlussfolgerungen: In dieser padiatrischen Kohorte mit Typ-1B-Diabetes besteht kein wesentlicher klinischer Unterschied in den Manifestationsparametern oder in klinischen Parametern zum Diabetesverlauf (HbA1c, Insulinbedarf) innerhalb der ersten 24 Monate. Diabetes Typ-1B mit Manifestation im Kindes- und Jugendalter kann daher nicht nach klinischen Kriterien von Typ-1A abgegrenzt werden. Bisherige Analysen in Erwachsenen Patienten mit idiopathischem bzw. AK-negativem Diabetes zeigten, dass unter der Diagnose des Typ-1B-Diabetes mellitus unterschiedliche Pathogenesen zusammengefasst sind, im wesentlichen

To give an up-to-date profile of nephropathy and the involvement of risk factors in a large, prospective cohort of patients with type 1 diabetes and largely pediatric and adolescent onset of disease.A total of 27,805 patients from the nationwide, prospective German Diabetes Documentation System survey were included in the present analysis. Inclusion criteria were at least two documented urine analyses with identical classification. Urine analyses, treatment regimens, diabetes complications, and risk factors were recorded prospectively. Baseline characteristics were age at diagnosis 9.94 years (median [interquartile range 5.8-14.3]), age at last visit 16.34 years (12.5-22.2), and follow-up time 2.5 years (0.43-5.3). Cumulative incidence of nephropathy was tested by Kaplan-Meier analysis and association with risk factors by logistic regression.Nephropathy was classified as normal in 26,605, microalbuminuric in 919, macroalbuminuric in 78, and end-stage renal disease (ESRD) in 203 patients. After calculated diabetes duration of 40 years, 25.4% (95% CI 22.3-28.3) had microalbuminuria and 9.4% (8.3-11.4) had macroalbuminuria or ESRD. Risk factors for microalbuminuria were diabetes duration (odds ratio 1.033, P0.0001), A1C (1.13, P0.0001), LDL cholesterol (1.003, P0.0074), and blood pressure (1.008, P0.0074), while childhood diabetes onset (1.011, P0.0001) was protective. Male sex was associated with the development of macroalbuminuria.Diabetes duration, A1C, dyslipidemia, blood pressure, and male sex were identified as risk factors for nephropathy. Therefore, besides the best possible metabolic control, early diagnosis and prompt treatment of dyslipidemia and hypertension is mandatory in patients with type 1 diabetes.

Objective: Type 1 diabetes mellitus (T1DM) leads to increased serum levels of the soluble leptin receptor (sOB-R) by an as yet unknown cellular mechanism. The aim of our study was to investigate potential metabolic factors that may be associated with the induction of the sOB-R release from its membrane receptor. Materials and methods: Twenty-five children (aged between 1.5 and 17.0 years) were studied at the onset of T1DM. Blood samples were collected before (n = 25), during the first 18 h (mean ± S.D. 11.1 ± 4.3 h, n = 16) and 92 h (47.5 ± 22.5 h; n = 14) after beginning insulin therapy. Serum sOB-R and leptin levels were determined by in-house immunoassays. Results: The sOBR-level and the molar sOB-R/leptin ratio were significantly higher before than after starting insulin treatment (P < 0.05). In contrast, leptin levels were significantly lower (P < 0.05) before insulin therapy. The correlation between sOB-R and blood glucose (r = 0.49; P < 0.05), as well as sOB-R with parameters of ketoacidosis, such as pH (r = −0.72), base excess (r = −0.70), and bicarbonate (r = −0.69) (P < 0.0001) at diagnosis of T1DM remained significant during the first 18 h of insulin treatment. Multiple regression analysis revealed that base excess predicted 41.0% (P < 0.001), age 16.4% (P < 0.05), and height SDS 13.9% (P < 0.01) of the sOB-R variance. Conclusions: Metabolic decompensation in children with new onset T1DM is associated with dramatic changes of the leptin axis; serum levels of sOB-R are elevated and of leptin are reduced. The molar excess of sOB-R over leptin (median 11.3) in this condition may contribute to leptin insensitivity. Upregulation of the soluble leptin receptor appears to be a basic mechanism to compensate for intracellular substrate deficiency and energy-deprivation state.

OBJECTIVE. Normal to severely decreased bone mineral density has been reported in children with type 1 diabetes. To detect possible abnormalities in bone mineralization, geometry, and muscle bone unit, we measured selective parameters in children with type 1 diabetes using peripheral quantitative computed tomography. METHODS. Measurements of the radius by peripheral quantitative computed tomography were made to assess cortical and trabecular bone characteristics as well as muscle mass in 88 patients (42 girls, 46 boys) at a mean age of 11.7 ± 3.0 years, a mean disease duration of 5.6 ± 3.7 years, and a mean manifestation age of type 1 diabetes of 6.1 ± 3.5 years. Height, weight, Tanner stage, insulin regimen, and glycosylated hemoglobin values were recorded. Bone metabolism was studied by measurement of bone formation and bone resorption parameters. Dynamic muscle force was measured using a grip strength device. RESULTS. Overall, cortical, trabecular, and total bone mineral density were within the reference range. Total and cortical bone cross-sectional area and muscle mass were low in prepubertal patients, and total cross-sectional area was low in early puberty. Adolescent patients showed normal bone and muscle parameters. Grip strength and recreational physical activity were normal in all in relation to a healthy reference population. In a subgroup of 18 patients, early manifestation of type 1 diabetes was detected as a risk factor for altered bone development with significantly reduced cortical bone mineral density and total, cortical, and muscle cross-sectional area (−0.9 ± 1.3 SD, −2.1 ± 1.3 SD, −1.6 ± 0.7 SD, and −1.0 ± 0.7 SD, respectively). Bone characteristics were not influenced by metabolic control, disease duration, or insulin regimen. CONCLUSIONS. Manifestation of type 1 diabetes at an early age may impair bone development. Longitudinal data are needed to determine whether this impairment persists into adolescence and adulthood.

Cohen syndrome (CS) is an autosomal recessive disorder with variability in the clinical manifestations, characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in the gene COH1 have been found in an ethnically diverse series of patients. Brief clinical descriptions of 24 patients with CS are provided. The patients were from 16 families of different ethnic backgrounds and between 2.5 and 60 years of age at assessment. DNA samples from all patients were analysed for mutations in COH1 by direct sequencing. Splice site mutations were characterised using reverse transcriptase PCR analysis from total RNA samples. In this series, we detected 25 different COH1 mutations; 19 of these were novel, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in frame deletions, and 1 missense mutation. We observed marked variability of developmental and growth parameters. The typical facial gestalt was seen in 23/24 patients. Early onset progressive myopia was present in all the patients older than 5 years. Widespread pigmentary retinopathy was found in 12/14 patients assessed over 5 years of age. We present evidence for extended allelic heterogeneity of CS, with the vast majority of mutations leading to premature termination codons in COH1. Our data confirm the broad clinical spectrum of CS with some patients lacking even the characteristic facial gestalt and pigmentary retinopathy at school age.

Background The function and survival of pancreatic β-cells strongly depend on glucose concentration and on autocrine secretion of peptide growth factors. NGF and its specific receptors TrkA and p75NTR play a pivotal role in islet survival and glucose-dependent insulin secretion. We therefore investigated whether or not glucose concentration influences expression of TrkA and p75NTR in rat islets and in INS-1E β-cells at the mRNA and protein level (INS-1E). Methods Gene expression of the NGF receptors TrkA and p75NTR but also of the metabolic gene liver-type pyruvate kinase (L-PK) and the neurotrophin receptors TrkB and TrkC was studied by semi-quantitative PCR and by real-time PCR in islets and INS-1E β-cells. Results In rat islets, high glucose exposure (25 mmol/l) increased gene expression of TrkA, p75NTR and L-PK. Expression of TrkA, p75NTR and L-PK reflected insulin secretion at the respective glucose concentration. In rat INS-1E insulinoma cells, expression of L-PK and p75NTR was suppressed by low glucose as in the islets, while expression of TrkA was strongly increased by low glucose levels and thus was regulated differently than in islets. Expression of TrkB and TrkC was not regulated by glucose concentration at all. TrkA protein was regulated in the same fashion as its mRNA expression, while p75NTR protein was not significantly regulated within 24 h. Conclusion Glucose interacts with gene expression of TrkA and p75NTR that are strongly involved in β-cell growth and glucose-dependent insulin secretion. The fact that TrkA expression is regulated the opposite way in islets and in INS-1E β-cells might reflect their specific grade of differentiation and tendency to proliferate.

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), an autosomal dominant syndrome in which eyelid malformation is associated with (type I BPES) or without premature ovarian failure (type II BPES). Mutations of a putative winged helix/forkhead transcription factor FOXL2 account for both types of BPES. We report on a 16-year-old adolescent girl with blepharophimosis and ptosis. Subsequently she developed oligomenorrhea, secondary amenorrhea for 6 months, and an extremely large cyst of one ovary. The cyst contained 8 l of cyst fluid and histopathology displayed a large corpus luteum cyst. Following laparotomy, gonadotropin levels were elevated (LH 17.2 U/l, FSH 29.4 U/l) and estradiol levels decreased (67 pmol/l). Because of clinical aspects of BPES and abnormal ovarian function we suspected a mutation of herFOXL2gene and found a new in-frame mutation (904_939dup36) on one allele, leading to a 12 alanine expansion within the polyalanine domain. We conclude that theFOXL2mutation 904_939dup36 may account not only for blepharophimosis and ptosis but also for ovarian dysfunction and growth of the large corpus luteum cyst. In contrast to knownFOXL2mutations with polyalanine expansions and association with BPES type II, clinical aspects of our girl may indicate some degree of ovarian dysfunction that might finally lead to BPES type I with premature ovarian failure.

Glucose and the peptide growth factors insulin, IGF-I and IGF-II strongly regulate beta cell mass. Furthermore, beta cell expression of IGF-I receptor (Igf1r) and insulin receptor (Insr) is mandatory for several steps of insulin secretion. We hypothesised that glucose concentration might regulate expression of Igf1r, Insr and insulin receptor-related receptor (Insrr) in islets and beta cells. Moreover, since the ratio of ATP:ADP is the most important intracellular mechanism involved in insulin secretion, and since depletion of ATP leads to AMP accumulation, we evaluated the role of AMP-activated protein kinase (AMPK) in glucose-dependent receptor regulation. In rat islets, high glucose exposure (25 mmol/l) increased gene expression of Igf1r, Insr and Insrr but also of the metabolic glycolysis gene liver-type pyruvate kinase (Pklr) compared with intermediate (6.2 mmol/l) or low glucose concentration (1.6 mmol/l) after 24 h. In rat INS-1E beta cells, only Pklr expression was suppressed by low glucose as in islets, while Insr and Insrr were suppressed by high and increased by low glucose levels. Igf1r expression was suppressed by both high- and low- glucose concentration. Activation of AMPK by 5-amino-imidazolecarboxamide riboside (AICAR, 0.5 mmol/l) suppressed Pklr expression, but strongly stimulated gene expression of Igf1r, Insr and Insrr. Protein expression of IR and IGF-IR reflected glucose and AICAR-regulated mRNA expression of both receptors in INS-1E cells. We conclude that glucose directly interacts with islet and beta cell expression of growth factor receptors that are mandatory for both beta cell growth and insulin secretion. Stimulation of Igf1r and Insr gene expression by the AMPK-activator AICAR might indicate involvement of AMPK in the regulation of Igf1r, Insr and Insrr expression in beta cells.

Changes in food consumption and exercise are fuel-ing a worldwide increase in obesity in children andadolescents. As a consequence of this dramaticdevelopment an increasing rate of type 2 diabetesmellitus has been recorded in children and adolescentsaround the world. Both genetic and environmentalfactors contribute to the pathogenesis of type 2diabetes. Preventive programmes fighting obesity inchildren should be developed on a large scale. It isthe prevention of obesity that will help to reversethe emerging epidemic of type 2 diabetes. Preventiveprogrammes should focus on exercise training andreduction of sedatory behaviour such as televisionviewing, should encourage healthy nutrition andsupport general education programmes, since lowerschool education is clearly associated with higherobesity rates and hence susceptibility to acquiretype 2 diabetes. Until recently it has been assumedthat type 2 diabetes mellitus occurs only rarely ata young age. In the mid 1990s, investigators around theworld began to observe an increasing incidence of type2 diabetes. This observation followed a strikingincrease in both the prevalence and the degree ofobesity in children [1–7]. This review summarizes thepresently available data on type 2 diabetes in childrenand adolescents and points to the danger of diabetickidney disease at a young age.

The objective of the present study was to investigate putative changes in pediatric diabetes care at one institution between 1969 and 1998.A structured questionnaire was used to analyze all medical records from the Hospital for Children and Adolescents of the University of Leipzig, Germany, from 1969 to 1998, in order to review the number of cases of type 1 diabetes mellitus and the length of hospital stay of children with diabetes during the 30-yr period.Between 1969 and 1998, 441 children and adolescents (211 boys and 230 girls) with newly diagnosed diabetes mellitus type 1 were treated at the Hospital for Children and Adolescents in Leipzig. The number of patients newly diagnosed increased from 55 between 1969 and 1973 to 105 between 1994 and 1998 (p0.0003). The initial therapy and diabetes education were carried out in an in-patient setting. The average duration of hospital stay was 36 d in the years 1969-73, and 17 d in the years 1994-98 (p0.0002). This reduction of time spent in hospital was achieved by establishing structured training courses and exact planning of treatment in relation to the degree of illness at presentation.The number of patients with type 1 diabetes mellitus receiving care in this single institution between the years 1969 and 1998 has increased continuously. With the help of quality-assured structured training courses in a clinic for pediatric diabetes care, a dramatic reduction of the duration of hospital stay was achieved.

Insulin-like growth factor-I (IGF-I) was found to promote proliferation, cell survival, and inhibition of apoptosis. But in some instances, IGF-I was found to mildly induce apoptosis, i. e. Fas-mediated apoptosis in human MG63 osteosarcoma cells. In the present study, we intended to further investigate IGF-I dependent pathways leading either to proliferation and cell survival or to cell death. MG63 osteosarcoma cells were treated with serum free medium alone or in combination with IGF-I, a neutralizing antibody against the human IGF-I receptor (alphaIR-3) or non-immune control IgG (1) for two to six days. We investigated cell survival (cell count), proliferation (CD71-FACS), apoptosis (Annexin-V-FACS, Caspase-3 activity, PCD) and anti-apoptosis (112-Ser Bad phosphorylation), and regulation of IGF-I receptor surface expression (IGF-I receptor-FACS). We found that IGF-I treatment (48 h) stimulated cell growth and proliferation, but also mildly induced apoptosis. IGF-I activated specific apoptotic pathways (Caspase-3 activation, Annexin-V binding and DNA degradation), as well as anti-apoptotic signals (Bad phosphorylation at serine 112). alphaIR-3 blocked cell proliferation, strongly induced apoptosis, and inhibited Bad-phosphorylation. Thus, IGF-I treatment overall resulted in increased tumour cell mass, despite a detectable stimulation of apoptosis; in other words proliferation exceeded cell death. If IGF-I was first added on day 0, 2, or 4 of serum free culture, we found decreasing IGF-I specific effects on proliferation and apoptosis. In parallel, we found a down-regulation of IGF-I receptors (FACS) by serum withdrawal, which was partly reversed if IGF-I was added. Therefore receptor number might have an impact on IGF-I function in MG63 cells. In conclusion, co-activation of apoptosis and proliferation by IGF-I might result in higher cell turnover in MG63 osteosarcoma cells. Furthermore, in sarcomas or carcinomas showing clinical association to IGF-I levels and malignancy, IGF-I dependent apoptosis and proliferation could be a significant mechanism of malignant tumour growth.

Approximately 10 percent of infants with intrauterine growth retardation remain small, and the causes of their growth deficits are often unclear. We postulated that mutations in the gene for the insulin-like growth factor I receptor (IGF-IR) might underlie some cases of prenatal and postnatal growth failure.We screened two groups of children for abnormalities in the IGF-IR gene. In one group of 42 patients with unexplained intrauterine growth retardation and subsequent short stature, we used single-strand conformation polymorphism analysis, followed by direct DNA sequencing of any abnormalities found. A second cohort consisted of 50 children with short stature who had elevated circulating IGF-I concentrations. Complete sequencing of the IGF-IR gene was performed with DNA from nine children. We also studied a control group of 43 children with normal birth weights.In the first cohort, we identified one girl who was a compound heterozygote for point mutations in exon 2 of the IGF-IR gene that altered the amino acid sequence to Arg108Gln in one allele and Lys115Asn in the other. Fibroblasts cultured from the patient had decreased IGF-I-receptor function, as compared with that in control fibroblasts. No such mutations were found in the 43 controls. In the second group, we identified one boy with a nonsense mutation (Arg59stop) that reduced the number of IGF-I receptors on fibroblasts. Both children had intrauterine growth retardation and poor postnatal growth.Mutations in the IGF-IR gene that lead to abnormalities in the function or number of IGF-I receptors may also retard intrauterine and subsequent growth in humans.

We investigated the effects of glucose and beta-cell growth factors (IGF-I, IGF-II, bFGF) on growth and apoptosis in the presence and absence of apoptosis inducing cytokines (IFNgamma, Il-1beta, TNFalpha). Rat INS-1E beta-cell viability was measured by WST-1 viability assay and cell counting, apoptosis by FACS analysis of annexin-V-FITC and fluorescein-dUTP (TUNEL-staining)-positive cells. Glucose alone maintained INS-1E beta-cell viability at high physiological concentrations (6.2-12.5 mmol/l), addition of IGF-II alone or in combination with bFGF further increased these glucose effects. The cytokines IFNg and IL-1beta, but not TNFalpha strongly induced INS-1E beta-cell apoptosis. Interestingly, glucose alone induced apoptosis at extremely low or very high concentrations. In combination with IFNg, low glucose (1.6 mmol/l) increased apoptosis by 25.6% (1SD 5.0%) and high glucose (50 mmol/l) by 22.8% (1SD 2.8%) compared to 12.5 mmol/l glucose. In contrast, glucose failed to modulate IL-1beta-induced apoptosis. Most importantly, IGF-II and bFGF inhibited apoptosis induced by IFNg, but not by IL-1beta. Therefore, IGF signaling, supported by bFGF and optimal glucose levels, maintains beta-cell viability in vitro. Cytokines IFNg and IL-1beta differentially interfere with intracellular signaling cascades stimulated by IGFs and bFGF or glucose, respectively.

Adrenocortical tumours (ACT) are a rare but important cause of virilisation in infancy and childhood. Four cases of virilising ACT are presented. Two girls (age 0.9 years and 3.9 years) and two boys (age 6.2 years and 6.4 years) had symptoms and signs of virilisation before the age of 6 years. Diagnosis of a virilising adrenal tumour was confirmed by laboratory tests, diagnostic imaging and histology. However, one female patient was misdiagnosed and treated for 3 months as atypical congenital adrenal hyperplasia. Ultrasonography of the adrenal region could not visualise the tumour in three out of four cases. The most sensitive method of diagnostic imaging was MRI. In all cases, treatment consisted of complete surgical resection of the adrenal tumour by open abdominal surgery. Immunohistochemistry was performed in all patients and in two patients there was an overexpression of p53, indicating p53 mutation and in three cases the ki67 proliferation index was greater than 5%. The classification of ACT in childhood is extremely difficult. Histology scores adapted from adrenal tumours in adults and molecular markers are under investigation, but there is still not enough clinical experience since ACT are so rare. Conclusion:long-term follow-up is mandatory not only because of the uncertainty in classification of adrenocortical tumours, but also for observation of growth and pubertal development.

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.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.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).This survey provides evidence for long-term tracking of metabolic control from childhood until adulthood, suggesting an early focus on metabolic control.

OBJECTIVE—Arterial blood pressure was followed in 868 patients with type 1 diabetes aged 6.0–19.9 years in 95 centers in Germany and Austria. RESEARCH DESIGN AND METHODS—European blood pressure reference data for 28,043 children and adolescents were used with respect to age and sex. Data were stratified into three groups: prepubertal, pubertal, and postpubertal. RESULTS—Up to 4% of the participants in the younger age-groups and 13.9% of the postpubertal patients exhibited blood pressure values >97th centile. Blood pressure levels correlated with A1C level and BMI Z score. Tracking of blood pressure revealed that children with elevated blood pressure had higher blood pressure in adolescence and young adulthood. CONCLUSIONS—Patients with higher blood pressure in childhood showed elevated blood pressure later in life. We need to focus on the diagnosis of hypertension in children with type 1 diabetes and to study the efficacy of early intervention.

The article by Home et al. (1) in the May issue of Diabetes Care prompted us to respond and comment on the current practice of reporting on clinical trials when insulin analogs are concerned. While a cure for type 1 diabetes has not yet been achieved, comprehensive, multidisciplinary treatment strategies have lead the way to offer patients and their families a near-normal life and affected children a near-normal life expectancy. Multiple injections, insulin pump therapy, and frequent blood glucose measurements have provided the basis for better quality of life and good metabolic control in people with type 1 diabetes. However, the value of insulin analogs is still in question (2). There is no doubt that industry has invested vast resources to develop new insulin types for safety and efficacy reasons. …

Activating mutations in the KCNJ11 gene, which code for the ATP-sensitive K+ channel subunit Kir6.2, are the most common cause of permanent neonatal diabetes. Recently, a switch from insulin treatment to oral sulfonylurea has been proposed if genetic testing reveals sulfonylurea-sensitive KCNJ11 mutations (1). Until now, hurdles for early treatment were 1 ) the time until the mutation analysis is finished and 2 ) the lack of knowledge about adverse effects of glibenclamide in …

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

Aims: Several commercial and open-source automated insulin dosing (AID) systems have recently been developed and are now used by an increasing number of people with diabetes (PwD). This systematic review explored the current status of real-world evidence on the latest available AID systems in helping to understand their safety and effectiveness. Methods: A systematic review of real-world studies on the effect of commercial and open-source AID system use on clinical outcomes was conducted employing a devised protocol (PROSPERO ID 257354). Results: Of 441 initially identified studies, 21 published 2018-2021 were included: 12 for Medtronic 670G; one for Tandem Control-IQ; one for Diabeloop DBLG1; two for AndroidAPS; one for OpenAPS; one for Loop; three comparing various types of AID systems. These studies found that several types of AID systems improve Time-in-Range and haemoglobin A1c (HbA1c ) with minimal concerns around severe hypoglycaemia. These improvements were observed in open-source and commercially developed AID systems alike. Conclusions: Commercially developed and open-source AID systems represent effective and safe treatment options for PwD of several age groups and genders. Alongside evidence from randomized clinical trials, real-world studies on AID systems and their effects on glycaemic outcomes are a helpful method for evaluating their safety and effectiveness.

Continuous subcutaneous insulin infusion (CSII) has become increasingly popular as a form of intensified insulin therapy in adolescents with type 1 diabetes mellitus (DM). One reported drawback was increased weight gain in adolescents after initiation of insulin pump therapy. In a prospective, longitudinal, non-randomized and case controlled study, we followed 12 adolescents (mean age 13.6 yr, 8 males, 4 females) from 6 months before the start of CSII to 12 months on CSII. These 12 adolescents with DM on CSII were matched for age, gender, HbA1c, duration of DM, and body mass index (BMI) with 12 adolescents who continued on multiple injection therapy (MIT). In addition, six of the 12 adolescents on CSII intended to control their weight by means of the insulin pump. These six vs six adolescents within the CSII group were further analyzed for weight development and eating habits. Clinical indications for CSII were dawn phenomenon, night-time hypoglycemia and patient request for more flexibility in DM management. All patients had been in satisfactory metabolic control on MIT. After 12 months of CSII, the daily insulin requirement remained significantly lower than 18 months before (0.79 +/- 0.11 vs 1.02 +/- 27 U/kg/d, p = 0.034) and number of daily meals was lower (4.1 +/- 0.9 vs 6.5 +/- 0.7, p = 0.006). Mean initial HbA1c was 7.4% in the MIT and CSII patients, and remained comparable between these two groups. BMI was not different between the CSII and MIT group over the entire study period. However, those adolescents on CSII who intended to control their weight by means of the insulin pump were able to achieve relative weight loss during the,first 6 months on CSII. Two patients of the CSII group had one severe hypoglycemic episode with loss of consciousness. In conclusion, CSII does not lead to weight gain by itself, but allows sufficient weight control without a negative effect on metabolic control. The general threat of weight gain in patients who switch to insulin pump therapy must be pointed out, and the role of eating habits and caloric content of food should play a central role in insulin pump educational programs.