Association of insulin-manipulation and psychiatric disorders: A systematic epidemiological evaluation of adolescents with type 1 diabetes in Austria.

BACKGROUND/OBJECTIVE: The aim of this study was to systematically assess the association of insulin-manipulation (intentional under- and/or overdosing of insulin), psychiatric comorbidity and diabetes complications. METHODS: Two diagnostic interviews (Diabetes-Self-Management-Patient-Interview and Children's-Diagnostic-Interview for Psychiatric Disorders) were conducted with 241 patients (age 10-22) with type 1 diabetes (T1D) from 21 randomly selected Austrian diabetes care centers. Medical data was derived from medical records. RESULTS: Psychiatric comorbidity was found in nearly half of the patients with insulin-manipulation (46.3%) compared to a rate of 17.5% in patients, adherent to the prescribed insulin therapy. Depression (18.3% vs 4.9%), specific phobia (21.1% vs 2.9%), social phobia (7.0% vs 0%), and eating disorders (12.7% vs 1.9%) were elevated in patients with insulin-manipulation. Females (37.7%) were more often diagnosed (P = 0.001) with psychiatric disorders than males (18.4%). In females, the percentage of psychiatric comorbidity significantly increased with the level of non-adherence to insulin therapy. Insulin-manipulation had an effect of +0.89% in HbA1c (P = <0.001) compared to patients adherent to insulin therapy, while there was no association of psychiatric comorbidity with metabolic control (HbA1c 8.16% vs 8.12% [65.68 vs 65.25 mmol/mol]). Ketoacidosis, severe hypoglycemia, and frequency of outpatient visits in a diabetes center were highest in patients with insulin-manipulation. CONCLUSIONS: This is the first study using a systematic approach to assess the prevalence of psychiatric disorders in patients who do or do not manipulate insulin in terms of intentional under- and/or overdosing. Internalizing psychiatric disorders were associated with insulin-manipulation, especially in female patients and insulin-manipulation was associated with deteriorated metabolic control and diabetes complications.

Comorbidity of attention deficit hyperactivity disorder and type 1 diabetes in children and adolescents: Analysis based on the multicentre DPV registry.

BACKGROUND: The interaction between type 1 diabetes mellitus (T1DM) and attention deficit hyperactivity disorder (ADHD) in children and adolescents has been studied rarely. We aimed to analyse metabolic control in children and adolescents with both T1DM and ADHD compared to T1DM patients without ADHD. PATIENTS AND METHODS: Auxological and treatment data from 56.722 paediatric patients (<20 years) with T1DM in the multicentre DPV (Diabetes Prospective Follow-up Initiative) registry were analysed. T1DM patients with comorbid ADHD were compared to T1DM patients without ADHD using multivariable mixed regression models adjusting for demographic confounders. RESULTS: We identified 1.608 (2.83%) patients with ADHD, 80.8% were male. Patients with comorbid ADHD suffered twice as often from diabetic ketoacidosis compared to patients without ADHD [10.2; 9.7-10.8 vs [5.4; 5.3-5.4] (P < .0001). We also found significant differences in HbA1c [8.6% (7.3-9.4); 66.7 mmol/mol (56.3-79.4) vs 7.8% (7.0-9.0); 62.1 mmol/mol (53.2-74.7)], insulin dose/kg [0.9 IU/kg (0.7-1.1) vs 0.8 IU/kg (0.7-1.0)], body mass index-standard deviation score (BMI-SDS) [0.2 (-0.5 to 0.8) vs 0.3 (-0.3 to 0.9)], body weight-SDS [0.1 (-0.5 to 0.8) vs 0.3 (0.3 - 0.9)]; (all P < 0.0001), and systolic blood pressure after adjustment [mean: 116.3 vs 117.1 mm Hg)]; (P < 0.005). CONCLUSION: Paediatric patients with ADHD and T1DM showed poor metabolic control compared to T1DM patients without ADHD. Closer cooperation between specialized paediatric diabetes teams and paediatric psychiatry/psychology seems to be necessary to improve diabetes care and metabolic control in this group of patients.

The Cross-Link between Adipokines, Insulin Resistance and Obesity in Offspring of Diabetic Pregnancies.

BACKGROUND/AIMS: Intrauterine exposure to hyperglycemia might impact the risk for future metabolic deteriorations. The aim was to characterize the association between different adipokines and neuropeptides and insulin resistance and BMI-SDS in children affected by diabetes during pregnancy. METHODS: 76 children (mean age: 6 years, male:female = 36:40) born to mothers with gestational or pregestational diabetes and nondiabetic women were consecutively included for clinical assessments comprising anthropometrics and metabolic characterization [2-hour glucose tolerance test, leptin, peptide YY (PYY), neuropeptide Y (NPY), ghrelin, growth differentiation factor 15 (GDF-15), and adiponectin]. RESULTS: The level of insulin resistance was associated with BMI-SDS (p < 0.001), leptin (p < 0.001), ghrelin (p = 0.002), age (p < 0.002) and negatively with GDF-15 (p = 0.005). BMI-SDS, leptin and GDF-15 were shown to have independent effects on insulin resistance by using a multiple regression model (additionally including age, and maternal diabetes status), whereas ghrelin lost significance (p = 0.345). No differences were present in adipokines and insulin resistance when children were evaluated by maternal glucometabolic status. However, we observed more strengthened associations between insulin resistance and covariates BMI-SDS and leptin in offspring of diabetic pregnancies. CONCLUSIONS: Young children with elevated BMI or leptin are affected by higher indices of insulin resistance, particularly those who were born to mothers with diabetes during pregnancy. The impact of this special risk constellation should be considered in future studies.

Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial.

IMPORTANCE: Exposing the oral mucosa to antigen may stimulate immune tolerance. It is unknown whether treatment with oral insulin can induce a tolerogenic immune response in children genetically susceptible to type 1 diabetes. OBJECTIVE: To assess the immune responses and adverse events associated with orally administered insulin in autoantibody-negative, genetically at-risk children. DESIGN, SETTING, AND PARTICIPANTS: The Pre-POINT study, a double-blind, placebo-controlled, dose-escalation, phase 1/2 clinical pilot study performed between 2009 and 2013 in Germany, Austria, the United States, and the United Kingdom and enrolling 25 islet autoantibody-negative children aged 2 to 7 years with a family history of type 1 diabetes and susceptible human leukocyte antigen class II genotypes. Follow-up was completed in August 2013. INTERVENTIONS: Children were randomized to receive oral insulin (n = 15) or placebo (n = 10) once daily for 3 to 18 months. Nine children received insulin with dose escalations from 2.5 to 7.5 mg (n = 3), 2.5 to 22.5 mg (n = 3), or 7.5 to 67.5 mg (n = 3) after 6 months; 6 children only received doses of 22.5 mg (n = 3) or 67.5 mg (n = 3). MAIN OUTCOMES AND MEASURES: An immune response to insulin, measured as serum IgG and saliva IgA binding to insulin, and CD4+ T-cell proliferative responses to insulin. RESULTS: Increases in IgG binding to insulin, saliva IgA binding to insulin, or CD4+ T-cell proliferative responses to insulin were observed in 2 of 10 (20% [95% CI, 0.1%-45%]) placebo-treated children and in 1 of 6 (16.7% [95% CI, 0.1%-46%]) children treated with 2.5 mg of insulin, 1 of 6 (16.7%[ 95% CI, 0.1%-46%]) treated with 7.5 mg, 2 of 6 (33.3% [95% CI, 0.1%-71%]) treated with 22.5 mg, and 5 of 6 (83.3% [ 95% CI, 53%-99.9%]) treated with 67.5 mg (P = .02). Insulin-responsive T cells displayed regulatory T-cell features after oral insulin treatment. No hypoglycemia, IgE responses to insulin, autoantibodies to glutamic acid decarboxylase or insulinoma-associated antigen 2, or diabetes were observed. Adverse events were reported in 12 insulin-treated children (67 events) and 10 placebo-treated children (35 events). CONCLUSIONS AND RELEVANCE: In this pilot study of children at high risk for type 1 diabetes, daily oral administration of 67.5 mg of insulin, compared with placebo, resulted in an immune response without hypoglycemia. These findings support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN76104595.

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

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

Gender, metabolic control and carotid intima-media-thickness in children and adolescents with type 1 diabetes mellitus.

BACKGROUND: Despite a marked improvement in the overall prognosis of patients with type 1 diabetes mellitus (T1DM), cardiovascular morbidity/mortality is still increased. Since cellular and microvascular aberrations have been demonstrated already in children with T1DM, albeit a good glycemic control (CO), we hypothesized that early macrovascular changes can be detected by common carotid artery intima-media thickness (CCA-IMT). METHODS: We included 73 children/adolescents with T1DM (34 boys, 39 girls; mean age, 14.8 ± 2 years) and 243 sex- and age-matched healthy CO. In T1DM mean HbA1c was 7.9 ± 1.1 rel.%, and duration of disease 7.5 ± 3.1 years. High-resolution ultrasonography was used to assess CCA-IMT, defined as the mean of 24 measurements of the near and far wall on both right and left CCA. RESULTS: CCA-IMT was not different in the total of children and adolescents with T1DM compared with CO (0.302 ± 0.057 vs. 0.301 ± 0.054 mm; p = 0.88). Analysis according to gender, however, revealed higher CCA-IMT values in girls than in boys in the diabetic cohort (0.315 ± 0.055 vs. 0.288 ± 0.058 mm; p = 0.047), whereas CCA-IMT was higher in boys than in girls in the CO group (0.321 ± 0.057 vs. 0.284 ± 0.045 mm; p < 0.001). Multiple stepwise backward regression showed that in the T1DM group only HbA1c remained significantly associated with CCA-IMT (Beta = - 0.307, p = 0.008). In CO, gender (Beta = - 0.302, p < 0.001), body mass index (Beta = 0.226, p < 0.001) and systolic blood pressure (Beta = 0.213, p < 0.001) were predictive of CCA-IMT. CONCLUSION: Our data suggest that in children/adolescents with T1DM the quality of metabolic CO (HbA1c) is the most important predictor of CCA-IMT and outweighs the effect of gender.

Depression, metabolic control, and antidepressant medication in young patients with type 1 diabetes.

OBJECTIVE: Recent literature suggests an association between type 1 diabetes (T1D) and depression. So far, most studies explored this link in adult populations, with few data being available on diabetes and depression from minors and young adults. This study aimed to look for associations between symptoms of depression/antidepressant treatment and metabolic outcomes of T1D. METHODS: We conducted an observational study using the German diabetes database (Diabetes-Patienten-Verlaufsdokumentation--DPV) and searched for patients up to the age of 25 yr, with depressive symptoms and/or receiving antidepressant medication. RESULTS: Of 53 986 T1D patients below the age of 25 yr, antidepressant medication and/or depressive symptoms were reported in 419 (0.78%). After adjustment for age, gender, diabetes duration and center heterogeneity, minors and young adults with depressive symptoms showed worse outcome parameters such as a higher rate of severe hypoglycemia (0.56 vs. 0.20/patient year, p = 0.005) and more episodes of diabetic ketoacidosis (0.20 vs. 0.07/patient year, p < 0.001). Hemoglobin A1c (HbA1c) was higher in the depression group (74.50 vs. 67.58 mmol/mol, p < 0.001) and young patients with T1D and depression showed longer duration of inpatient treatment (7.04 vs. 3.10 hospital days/patient year, p < 0.001) and more frequent admissions to hospital care (0.63 vs. 0.32/patient year, p < 0.001). Antidepressant medication was recorded in 52.3% of the depressed patients, with selective serotonin reuptake inhibitors (SSRIs) being the most widely described class of antidepressants (29.1%). CONCLUSIONS: Our findings demonstrate an adverse treatment outcome for young patients with T1D and comorbid depressive symptoms underlining an urgent need for collaborative mental and somatic health care for patients with T1D and depression.

Hemoglobin A1c Levels and risk of severe hypoglycemia in children and young adults with type 1 diabetes from Germany and Austria: a trend analysis in a cohort of 37,539 patients between 1995 and 2012.

BACKGROUND: Severe hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years. METHODS AND FINDINGS: We analyzed data of 37,539 patients with type 1 diabetes (mean age ± standard deviation 14.4 ± 3.8 y, range 1-20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19-1.37) to 1.05 (1.00-1.09) and from 1.39 (1.23-1.56) to 1.01 (0.93-1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6-1.7, p<0.001) and 1.9% (0.8-2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%-6.9% (RR 0.96 and 0.90 each year) and 7.0%-7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study. CONCLUSIONS: The previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near-normal glycemic control in these patients. Please see later in the article for the Editors' Summary.

Contrasting the clinical care and outcomes of 2,622 children with type 1 diabetes less than 6 years of age in the United States T1D Exchange and German/Austrian DPV registries.

AIMS/HYPOTHESIS: The study aimed to compare participant characteristics, treatment modalities and clinical outcomes in registry participants less than 6 years old. METHODS: Participant characteristics, treatment modalities and clinical outcomes (HbA1c, severe hypoglycaemia [SH] and diabetic ketoacidosis [DKA]) as well as frequencies of attaining HbA1c goals in line with the International Society for Pediatric and Adolescent Diabetes (<7.5% [<58 mmol/mol]) and ADA (<8.5% [<69 mmol/mol]) were compared. RESULTS: Insulin pump use was more frequent (74% vs 50%, p < 0.001) and HbA1c levels lower in the Prospective Diabetes Follow-up Registry (DPV) than in the T1D Exchange (T1DX) (mean 7.4% vs 8.2%, p < 0.001). A lower HbA1c level was seen in the DPV compared with the T1DX for both pump users (p < 0.001) and injection users (p < 0.001). More children from DPV were meeting the recommended HbA1c goals, compared with children from T1DX (HbA1c <7.5%: 56% vs 22%, p < 0.001; HbA1c <8.5%: 90% vs 66%, p < 0.001). The adjusted odds of having an HbA1c level <7.5% or <8.5% were 4.2 (p < 0.001) and 3.6 (p < 0.001) higher for the DPV than the T1DX, respectively. The frequency of SH did not differ between registries or by HbA1c, whereas the frequency of DKA was higher for the T1DX and greater in those with higher HbA1c levels. CONCLUSIONS/INTERPRETATION: DPV data indicate that an HbA1c of <7.5% can frequently be achieved in children with type 1 diabetes who are under 6 years old. An improved metabolic control of type 1 diabetes in young patients appears to decrease the risk of DKA without increasing SH. The greater frequency of suboptimal control in young patients in the T1DX compared with the DPV is not fully explained by a less frequent use of insulin pumps and may relate to the higher HbA1c targets that are recommended for this age group in the USA.

Predictors of increasing BMI during the course of diabetes in children and adolescents with type 1 diabetes: data from the German/Austrian DPV multicentre survey.

OBJECTIVE: Increased weight gain has been reported prior to disease onset (accelerator hypothesis) and as a side effect of intensified insulin therapy in type 1 diabetes (T1D). Paediatric studies are complicated by the age-dependency and gender-dependency of BMI, and also by a trend towards obesity in the general population. The aim of this study was to evaluate factors related to the increase in BMI during the course of diabetes in children and adolescents with T1D in a large multicentre survey. DESIGN: Within the DPV database (Diabetespatienten Verlaufsdokumentation) a standardised, prospective, computer-based documentation programme, data of 53,108 patients with T1D, aged <20 years, were recorded in 248 centres. 12,774 patients (53% male, mean age 13.4±3.9, mean diabetes duration 4.7±3.0 years and mean age at diabetes onset 8.7±4.0 years) were included in this analysis. Population-based German reference data were used to calculate BMI-SDS and define overweight and obesity. RESULTS: 12.5% of T1D patients were overweight and 2.8% were obese. Multiple longitudinal regression analysis revealed that female gender, low BMI at diabetes onset, intensified insulin therapy and higher insulin dose, as well as pubertal diabetes onset, long diabetes duration and onset in earlier calendar years among girls, were related to higher BMI-SDS increase during the course of diabetes (p<0.01; all). CONCLUSIONS: Intensified insulin regimen is associated with weight gain during T1D treatment, in addition to demographic variables. Optimisation of diabetes management, especially in females, might limit weight gain in order to reduce overweight and obesity together with comorbidities among paediatric T1D patients.

Algorithm-based cholesterol monitoring in children with type 1 diabetes.

OBJECTIVE: To facilitate child-specific and diabetes-related cholesterol control, we developed a monitoring algorithm derived from population-based reference values. STUDY DESIGN: Low-density lipoprotein (LDL)-, non-high-density lipoprotein (HDL)-, and HDL cholesterol percentile values were calculated for children with type 1 diabetes (T1D) and their peers without T1D within algorithm-based categories of sex, age: 1-10 vs >10-<18 years, body mass index: <90th vs ≥90th percentile, and hemoglobin A1c <6%, 6%-<7.5%, 7.5%-9%, >9%. Analyses included 26 147 patients sampled from a German/Austrian population-based registry for T1D (Diabetes Documentation and Quality Management System) and 14 057 peers without diabetes participating in the national Health Interview and Examination Survey for Children and Adolescents in Germany. RESULTS: Reference percentile values for cholesterol were derived as a diagnostic algorithm aimed at supporting long-term cholesterol control. Taking account of a patient's sex, age-group, weight-, and hemoglobin A1c-category, the flowcharts of the algorithm developed separately for LDL-, non-HDL-, and HDL cholesterol allow comparing his/her cholesterol levels with population-based reference percentile values of peers without T1D. CONCLUSIONS: The population-based algorithmic approach applied to LDL-, non-HDL-, and HDL cholesterol allows referencing children with T1D with regard to their peers without T1D and, if necessary, suggests corrections of glycemic control to optimize long-term cholesterol levels.

Activating AKT2 mutation: hypoinsulinemic hypoketotic hypoglycemia.

BACKGROUND: Hyperinsulinemic hypoglycemia (HH), characterized by unregulated insulin secretion, is an important cause of persistent and severe hypoglycemia. The biochemical picture of HH is hypoketotic hypo-fatty-acidemic hypoglycemia along with elevated serum insulin. Not infrequently, serum insulin might be undetectable in HH despite the presence of evidence of insulin action (suppressed ketogenesis and lipolysis). However, autonomous activity of the downstream insulin signaling pathway without the presence of the ligand (insulin) will give rise to the same clinical and biochemical picture, apart from undetectable serum insulin/C-peptide. AKT2, a serine/threonine protein kinase, is involved downstream to the insulin receptor in mediating the physiological effects of insulin. AIM: We describe the second report of an activating AKT2 mutation leading to hypoinsulinemic hypoketotic hypoglycemia. PATIENTS AND METHODS: The proband presented with hemihypertrophy and symptomatic hypoglycemia. Investigations confirmed evidence of insulin action, despite absence of detectable serum insulin on multiple occasions. Molecular genetic testing for common causes of HH (ABCC8, KCNJ11, and GLUD1) was negative. Sequencing of AKT2 identified a de novo mosaic c.49G→A (p.E17K) mutation, consistent with the clinical and biochemical phenotype. CONCLUSIONS: This is the second report of an activating AKT2 mutation leading to hypoinsulinemic hypoketotic hypo-fatty-acidemic hypoglycemia. In patients presenting a clinical and biochemical picture of HH with undetectable serum insulin, consideration of autonomous activation of the downstream insulin signaling pathway should be made.

Diabetic ketoacidosis at diagnosis in Austrian children: a population-based analysis, 1989-2011.

OBJECTIVE: To analyze the effect of a community-based, poster-focused prevention program on the frequency of diabetic ketoacidosis (DKA) at diabetes onset in Austria. STUDY DESIGN: All newly diagnosed patients with diabetes ≤ 15 years of age were registered prospectively by the Austrian Diabetes Incidence Study Group. Registered data included initial blood glucose, pH, and ketonuria. DKA was defined as pH < 7.3 and severe DKA as pH < 7.1. Data between 1989 and 2011 were available. In autumn, 2009, a community-based prevention program similar to the Parma Campaign, in which posters were dispensed broadly, was initiated. The frequency of DKA at the onset of diabetes in the years 2005-2009 and 2010-2011 was compared. RESULTS: During the study period, 4038 children were registered. A total of 37.2% presented with DKA; 26% had a mild and 11.2% a severe form. The frequency of DKA was negatively associated with age at onset. In the years before the intervention program, 26% had mild DKA compared with 27% after the intervention (not significant). The prevalence of severe DKA in the years before the campaign was 12% compared with 9.5% thereafter (not significant). No significant change in the DKA rate at onset by the prevention program could be found when we compared age groups <5, 5 to <10, and 10 to <15 years, neither for mild nor for severe DKA. CONCLUSION: The frequency of DKA in children with newly diagnosed type 1 diabetes in Austria is high and did not change despite the efforts of a community-based information program.

HLA-typing, clinical, and immunological characterization of youth with type 2 diabetes mellitus phenotype from the German/Austrian DPV database.

AIM: To characterize the clinical and immunological features of HLA-typed youth with pediatric onset of type 2 diabetes mellitus (T2DM). METHOD: One hundred and seven patients with clinically diagnosed T2DM (aged ≤20 yr at diagnosis) were examined. DNA and serum, obtained after a median diabetes duration of 2.2 (Q1-Q3: 0.8-4.6) yr, were used for centralized HLA-typing and autoantibody (GADA, IA-2A, ZnT8A) measurements. RESULTS: 64.6% of patients were female and median age at diagnosis was 13.8 (Q1-Q3: 11.6-15.4) yr. Patients were obese [median body mass index-standard deviation score (BMI-SDS): 2.6 (2.0-3.1)], 88.0% had a family history of diabetes and 40.2% a migration background. Islet autoantibodies were detected in 16 (15.0%), among which 7 (6.5%) had multiple islet autoantibodies. Autoantibody positive patients had poorer metabolic control than autoantibody negative patients [glycosylated hemoglobin A1c (HbA1c): 8.1 (6.9-10.1) % vs. 6.6 (5.9-8.0) %; p = 0.033], while patients with HLA-DR genetic risk had higher BMI-SDS than those with HLA-DRXX [2.6 (2.4-3.7) vs. 2.4 (1.7-2.9); p = 0.007]. Metabolic syndrome (61.7%), microalbuminuria (13.4%), and retinopathy (3.9%) were diagnosed. Therapies used were lifestyle only (35.5%), oral anti-diabetics (OAD) only (43.3 %), insulin + OAD (15.9%) and insulin only (5.6%). Patients with ß-cell autoimmunity or HLA-DR genetic risk more frequently used insulin than confirmed T2DM patients (50.0 vs. 22.0%; p = 0.037) and less often had diabetic relatives (61.1 vs. 86.0%; p = 0.030). CONCLUSION: T2DM was confirmed in about 90% of patients while about 10% with ß-cell autoimmunity or HLA-DR genetic risk likely had either T1.5DM or 'double diabetes' or an unknown diabetes type.

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

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

Endothelial progenitor cells are related to glycemic control in children with type 1 diabetes over time.

OBJECTIVE: The risk of cardiovascular death before the age of 40 is 20-fold higher in patients with type 1 diabetes mellitus (T1DM). Endothelial progenitor cells (EPCs) predict cardiovascular morbidity and mortality in patients without diabetes. We hypothesized that EPCs are modified in children with T1DM and are related to characteristics of T1DM such as glycemic control. RESEARCH DESIGN AND METHODS: Children (n = 190; 156 T1DM subjects and 34 control subjects) were included in an observational cohort study and matched for age and sex. EPCs were enumerated by flow cytometry at the beginning (cross-sectional) and 1 year later (longitudinal). To analyze changes of variables during the observation, Δ values were calculated. RESULTS: EPCs were significantly reduced in T1DM children versus control subjects (609 ± 359 vs. 1,165 ± 484, P < 0.001). Multivariate regression modeling revealed that glycated hemoglobin A1c (HbA1c) was the strongest independent predictor of EPCs (ß = -0.355, P < 0.001). Overall glycemic control at the beginning and end of study did not differ (7.8 ± 1.2 vs. 7.8 ± 1.2 relative %, P = NS), but we observed individual HbA1c changes of -4.30/+3.10 relative %. The strongest EPC increase was observed in the patients with the most favorable HbA1c lowering during the 1-year follow-up. Accordingly, the strongest EPC decrease was demonstrated in the patients with the strongest HbA1c worsening during the time period. CONCLUSIONS: This is the first prospective study demonstrating diminished EPCs in children with T1DM. The association of better glycemic control with an increase in EPC numbers within 1 year suggests that a reduction of the high cardiovascular disease burden might be mediated likewise.

Early-onset, coexisting autoimmunity and decreased HLA-mediated susceptibility are the characteristics of diabetes in Down syndrome.

OBJECTIVE: Down syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes. RESEARCH DESIGN AND METHODS: Clinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age- and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay. RESULTS: Age at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P < 0.0001). The frequency of the highest-risk type 1 diabetes-associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early- and later-onset DSD compared with age-matched children with type 1 diabetes (P < 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at ≤2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort. CONCLUSIONS: Early-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility.

[Diabetes in the youth]. / Diabetes mellitus im Kindes- und Jugendalter.

In contrast to adults Diabetes mellitus type 1 (DMT1) is the most frequent form of diabetes mellitus during childhood and adolescence (> 95 %). After diagnosis, the management of these DMT1-patients should take place in specialized paediatric centres, not in a primary care setting. The lifelong substitution of insulin is the cornerstone of therapy, the form of insulin-therapy should be adapted according to the age of the patient (conventional, intensified or pump therapy). Diabetes education is also an essential part in the management of diabetes patients and their families. The ISPAD (International Society for Paediatric and Adolescent Diabetes) recommends an HbA1c < 7.5 rel.%(IFCC < 58 mmol/mol) as good metabolic control, although it might be difficult to achieve this goal during different phases of life (e.g. toddlers or puberty). The aim of diabetes education and management is avoidance of acute and late diabetes related complications, as well as achievement of normal growth and psychosocial development and wellbeing.

[CGM-continuous glucose monitoring - statement of the Austrian Diabetes Association]. / Positionspapier des Insulinpumpenausschusses der OEDG zur kontinuierlichen Glukosemessung (CGM - Continuous Glucose Monitoring).

This position statement represents the recommendations of the Austrian Diabetes Association regarding the clinical diagnostic and therapeutic application, safety and benefits of continuous subcutaneous glucose monitoring systems in patients with diabetes mellitus, based on current evidence.

[Antihyperglycemic Treatment Guidelines for diabetes mellitus type 2]. / Antihyperglykämische Therapie bei Diabetes mellitus Typ 2. Grundsatz Statement.

Hyperglycemia significantly contributes to micro- and macrovascular complications in patients with diabetes mellitus. While lifestyle interventions remain cornerstones of disease prevention and treatment, most patients with type 2 diabetes will eventually require pharmacotherapy for glycemic control. The definition of individual targets in regard of optimal therapeutic efficacy and high therapeutic safety is of great importance. In this guideline we present the best and most current evidence-based clinical practice data for healthcare professionals.