Beate Karges

Improved Metabolic Control in Children and Adolescents With Type 1 Diabetes A trend analysis using prospective multicenter data from Germany and Austria

OBJECTIVE To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders. RESULTS Unadjusted mean HbA1c decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA1c decreased significantly by 0.038% per year (95% CI 0.032–0.043%), average odds ratio (OR) per year for HbA1c >7.5% (>9.0%) was 0.969 (95% CI 0.961–0.977) (0.948, 95% CI 0.941–0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA1c >9%; P = 0.005) but not with average HbA1c (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918–0.979; RR 0.917, 95% CI 0.885–0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time. CONCLUSIONS This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.

Ketoacidosis at Diabetes Onset Is Still Frequent in Children and Adolescents A multicenter analysis of 14,664 patients from 106 institutions

OBJECTIVE We aimed at analyzing the frequency, clinical characteristics, and trends associated with the occurrence of diabetic ketoacidosis (DKA) at the onset of type 1 diabetes on the basis of long-term follow-up data. RESEARCH DESIGN AND METHODS A total of 106 pediatric diabetes centers in Germany and Austria participated in this study. Data from14,664 patients with type 1 diabetes collected between 1995 and 2007 were suitable for evaluation. DKA was defined and classified according to the International Society for Pediatric and Adolescent Diabetes consensus guidelines. RESULTS DKA was observed in 21.1% of patients. The frequency of DKA, including the severe form, remained unchanged throughout the 13-year observation period. The frequency of DKA was particularly striking among children <5 years of age (26.5%). CONCLUSIONS Ketoacidosis occurring at diabetes onset continues to be a difficult problem. Our data show no significant change in the frequency and magnitude of DKA over the last 13 years.

Delayed pubertal onset and development in German children and adolescents with type 1 diabetes: cross-sectional analysis of recent data from the DPV diabetes documentation and quality management system

OBJECTIVE To investigate the effect of type 1 diabetes on pubertal onset and development, and to identify factors potentially affecting puberty, including glycemic control, relative diabetes duration, body mass index standard delta score (BMI SDS), insulin dose, and intensity of insulin therapy. RESEARCH DESIGN AND METHODS Initiated in 1990, the Diabetes-Patienten-Verlaufsdaten (DPV) is an ongoing, prospective longitudinal follow-up program to benchmark the quality of diabetes care provided to, predominantly, pediatric patients. Data collection for this non-interventional audit was carried out at 202 German diabetes treatment centers. Patient recruitment was done by referral, clinic/hospital ascertainment, or self-report. Data were analyzed for subcohorts of 1218-2409 boys and 579-2640 girls from a cohort of 24 385 pediatric type 1 diabetic patients. Selection was based on ethnicity and availability of data on Tanner stage 2, or higher, of genital and pubic hair development (boys) or breast and pubic hair development, and menarche (girls). RESULTS Boys showed significant (P<0.05) delay (years) in mean ages at onset of genital development (12.0 (+/-0.9) years) and pubarche (12.2 (+/-0.4) years). In girls, mean ages at thelarche (11.4 (+/-0.5) years), pubarche (11.5 (+/-0.1) years), and menarche (13.2 (+/-0.5) years) were significantly delayed compared with the general population. Sexual maturity (Tanner stage 5) was not delayed in either sex. Elevated glycohemoglobin and decreased BMI SDS were associated with significantly delayed pubertal onset, whereas relative diabetes duration and insulin dose were not. CONCLUSIONS Pubertal onset, but not sexual maturity, is delayed in children with type 1 diabetes. Delay increases with higher glycohemoglobin and lower BMI SDS.

Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.

Management of diabetes mellitus in infants

Diabetes mellitus diagnosed during the first 2 years of life differs from the disease in older children regarding its causes, clinical characteristics, treatment options and needs in terms of education and psychosocial support. Over the past decade, new genetic causes of neonatal diabetes mellitus have been elucidated, including monogenic β-cell defects and chromosome 6q24 abnormalities. In patients with KCNJ11 or ABCC8 mutations and diabetes mellitus, oral sulfonylurea offers an easy and effective treatment option. Type 1 diabetes mellitus in infants is characterized by a more rapid disease onset, poorer residual β-cell function and lower rate of partial remission than in older children. Insulin therapy in infants with type 1 diabetes mellitus or other monogenic causes of diabetes mellitus is a challenge, and novel data highlight the value of continuous subcutaneous insulin infusion in this very young patient population. Infants are entirely dependent on caregivers for insulin therapy, nutrition and glucose monitoring, which emphasizes the need for appropriate education and psychosocial support of parents. To achieve optimal long-term metabolic control with low rates of acute and chronic complications, continuous and structured diabetes care should be provided by a multidisciplinary health-care team.

Molecular Genetics of Isolated Hypogonadotropic Hypogonadism and Kallmann Syndrome

Isolated hypogonadotropic hypogonadism (IHH) is characterized by complete or partial failure of pubertal development due to impaired secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In the molecular pathogenesis of IHH, the gonadotropin-releasing hormone receptor (GnRH-R) and associated proteins have evolved as a central element. GnRH-R germline mutations were among the first genetic alterations identified in patients with IHH. These mutations are associated with impaired GnRH binding, ligand-induced signal transduction, or both, leading to various degrees of LH and FSH deficiency. As GnRH-R mutations explain several but not all cases of IHH, the search for new candidate genes continued in informative families. In 2003, mutations of the KiSS-1-derived peptide receptor GPR54 were identified in patients with IHH, opening a new pathway in the physiologic regulation of puberty and reproduction. GPR54 is putatively involved in the control of GnRH secretion. IHH associated with impaired olfactory function (Kallmann syndrome) may be caused by mutations of the X-chromosomal KAL1 (encoding anosmin) or the fibroblast growth factor receptor 1 genes (FGFR1), both leading to agenesis of olfactory and GnRH-secreting neurons. In addition to their clinical and diagnostic value, the identification of genetic and functional alterations in IHH helps to unravel the complex regulation of the gonadotropic axis.

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.

Compound Heterozygous and Homozygous Mutations of the TSHβ Gene as a Cause of Congenital Central Hypothyroidism in Europe

Background: Thyroid hormones are crucial for normal growth and central nervous system development. In recent years, germline variants of the TSHβ subunit gene have been identified as a cause of congenital TSH deficiency. Methods: We performed a genetic and clinical study in children from four European countries diagnosed with congenital isolated central hypothyroidism. Results: TSHβ gene analysis revealed compound heterozygosity for 145C→T (Q49X) and 313delT (C105Vfs114X) in 1 infant and homozygous mutation 313delT (C105Vfs114X) in 5 patients. Although all presented with typical symptoms of hypothyroidism, diagnosis and treatment was delayed until 3–5 months in 5 of 6 patients. In a longitudinal sibpair analysis, thyroxine substitution initiated immediately after birth was effective to prevent developmental delay and growth retardation. Conclusion: Clinical awareness is required to detect hypothyroidism due to TSHβ mutations, which is not identified by TSH-based newborn screening. TSHβ variants C105Vfs114X and Q49X are the most frequent cause of this severe disorder in Europe, now for the first time observed in compound heterozygous state.

Early hypoglycaemia after accidental intramuscular injection of insulin glargine

Aim  Insulin glargine is a long‐acting insulin analogue with favourable clinical characteristics. We studied a slim 24‐year‐old female with Type 1 diabetes who repeatedly experienced severe hypoglycaemia after switching from NPH insulin to insulin glargine at identical daily doses.

Association of Insulin Pump Therapy vs Insulin Injection Therapy With Severe Hypoglycemia, Ketoacidosis, and Glycemic Control Among Children, Adolescents, and Young Adults With Type 1 Diabetes

Importance Insulin pump therapy may improve metabolic control in young patients with type 1 diabetes, but the association with short-term diabetes complications is unclear. Objective To determine whether rates of severe hypoglycemia and diabetic ketoacidosis are lower with insulin pump therapy compared with insulin injection therapy in children, adolescents, and young adults with type 1 diabetes. Design, Setting, and Participants Population-based cohort study conducted between January 2011 and December 2015 in 446 diabetes centers participating in the Diabetes Prospective Follow-up Initiative in Germany, Austria, and Luxembourg. Patients with type 1 diabetes younger than 20 years and diabetes duration of more than 1 year were identified. Propensity score matching and inverse probability of treatment weighting analyses with age, sex, diabetes duration, migration background (defined as place of birth outside of Germany or Austria), body mass index, and glycated hemoglobin as covariates were used to account for relevant confounders. Exposures Type 1 diabetes treated with insulin pump therapy or with multiple (≥4) daily insulin injections. Main Outcomes and Measures Primary outcomes were rates of severe hypoglycemia and diabetic ketoacidosis during the most recent treatment year. Secondary outcomes included glycated hemoglobin levels, insulin dose, and body mass index. Results Of 30 579 patients (mean age, 14.1 years [SD, 4.0]; 53% male), 14 119 used pump therapy (median duration, 3.7 years) and 16 460 used insulin injections (median duration, 3.6 years). Patients using pump therapy (n = 9814) were matched with 9814 patients using injection therapy. Pump therapy, compared with injection therapy, was associated with lower rates of severe hypoglycemia (9.55 vs 13.97 per 100 patient-years; difference, −4.42 [95% CI, −6.15 to −2.69]; P < .001) and diabetic ketoacidosis (3.64 vs 4.26 per 100 patient-years; difference, −0.63 [95% CI, −1.24 to −0.02]; P = .04). Glycated hemoglobin levels were lower with pump therapy than with injection therapy (8.04% vs 8.22%; difference, −0.18 [95% CI, −0.22 to −0.13], P < .001). Total daily insulin doses were lower for pump therapy compared with injection therapy (0.84 U/kg vs 0.98 U/kg; difference, −0.14 [−0.15 to −0.13], P < .001). There was no significant difference in body mass index between both treatment regimens. Similar results were obtained after propensity score inverse probability of treatment weighting analyses in the entire cohort. Conclusions and Relevance Among young patients with type 1 diabetes, insulin pump therapy, compared with insulin injection therapy, was associated with lower risks of severe hypoglycemia and diabetic ketoacidosis and with better glycemic control during the most recent year of therapy. These findings provide evidence for improved clinical outcomes associated with insulin pump therapy compared with injection therapy in children, adolescents, and young adults with type 1 diabetes.