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Aims/hypothesis We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. Methods This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as ‘high ACR’ or ‘low ACR’ (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. Results At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. Conclusions/interpretation High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. Trial registration isrctn.org ISRCTN91419926. Graphical abstract

Peer reviewed: True, The aim of this systematic review was to report the evidence on optimal prandial timing of insulin bolus in youths with type 1 diabetes. A systematic search was performed including studies published in the last 20 years (2002-2022). A PICOS framework was used in the selection process and evidence was assessed using the GRADE system. Up to one third of children and adolescents with type 1 diabetes injected rapid-acting insulin analogues after a meal. Moderate-high level quality studies showed that a pre-meal bolus compared with a bolus given at the start or after the meal was associated with a lower peak blood glucose after one to two hours, particularly after breakfast, as well as with reduced HbA1c, without any difference in the frequency of hypoglycemia. There were no differences related to the timing of bolus in total daily insulin and BMI, although these results were based on a single study. Data on individuals' treatment satisfaction were limited but did not show any effect of timing of bolus on quality of life. In addition, post-prandial administration of fast-acting analogues was superior to rapid-acting analogues on post-prandial glycemia. There was no evidence for any difference in outcomes related to the timing of insulin bolus across age groups in the two studies. In conclusion, prandial insulin injected before a meal, particularly at breakfast, provides better post-prandial glycemia and HbA1c without increasing the risk of hypoglycemia, and without affecting total daily insulin dose and BMI. For young children who often have variable eating behaviors, fast-acting analogues administered at mealtime or post-meal could provide an additional advantage.

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0–7.2] versus 5.3% [4.7–5.9]; P =0.005), whereas no effect was observed following statin use (6.2% [5.5–6.8] versus 5.8% [5.1–6.4]; P =0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8–5.9] versus 6.3% [5.8–6.7] for high-risk versus low-risk groups; P =0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment ( P >0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03–0.12]; P =0.001 and 0.5 m/s [0.4–0.6]; P Registration— URL: https://www.clinicaltrials.gov ; Unique identifier NCT01581476.

Long-term complications of type 1 diabetes (T1D) include microvascular complications and macrovascular disease. Despite the important advances in the treatment of T1D of the last decades, these complications still represent the leading cause of morbidity and mortality in patients with T1D. Extensive evidence indicates that structural and functional alterations of the kidney, retina, nerves and large arteries occur already in the first years after the onset of diabetes. We performed a comprehensive review of the available evidence on screening, diagnosis, prevention and treatment of vascular complications of T1D. In particular, we focused on three major challenges related to long-term complications of T1D: 1) finding of new biomarkers and diagnostic methods able to identify early signs of complications; 2) identifying specific risk factors for the development of these complications; 3) identifying and implementing new therapeutic strategies able to prevent the development and progression of vascular complications.

• Introduction: Type 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing β cells of the pancreas. One immunosuppressive agent that has recently shown promise in the treatment of new-onset T1D subjects aged 12-45 years is ATG, Thymoglobuline®, encouraging further exploration in lower age groups. Methods and analysis: MELD-ATG is a phase 2, multi-centre, randomised, double-blind, placebo-controlled, multi-arm parallel-group trial in participants 5-25 years diagnosed with T1D within 3–9 weeks of planned treatment day 1. A total of 114 participants will be recruited sequentially into seven different cohorts with the first cohort of 30 participants being randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg ATG total dose in a 1:1:1:1:1 allocation ratio. The next six cohorts of 12-15 participants will be randomised to placebo, 2.5 mg/kg, and one or two selected middle ATG total doses in a 1:1:1:1 or 1:1:1 allocation ratio, as dependent on the number of middle doses, given intravenously over 2 consecutive days. The primary objective will be to determine the changes in stimulated C-peptide response over the first 2 hours of a mixed meal tolerance test (MMTT) at 12 months for 2.5mg/kg ATG arm versus the placebo. Conditional on finding a significant difference at 2.5 mg/kg, a minimally effective dose will be sought. Secondary objectives include the determination of the effects of a particular ATG treatment dose on 1) stimulated C-peptide, 2) HbA1c, 3) daily insulin dose, 4) time in range by intermittent continuous glucose monitoring (CGM) measures, 5) fasting and stimulated dry blood spot (DBS) C-peptide measurements. Ethics and dissemination: MELD-ATG received first regulatory and ethical approvals in Belgium in September 2020 and from the German and UK regulators as of February 2021. The publication policy is set in the INNODIA grant agreement (www.innodia.eu)., Union’s Horizon 2020 research and innovation program EFPIA JDRF The Leona M. and Harry B. Helmsley Charitable Trust

Diabetes vascular complications, including cardiovascular disease, diabetic nephropathy and retinopathy, have a negative effect on the long-term prognosis of young people with type 1 diabetes mellitus (T1DM). Poor glycaemic control and consequent increased HbA1c levels are major risk factors for the development of vascular complications. HbA1c levels are the main focus of current management strategies; however, the recommended target is rarely achieved in adolescents. Thus, a clear need exists for improved biomarkers to identify high-risk young people early and to develop new intervention strategies. Evidence is accumulating that early increases in urinary albumin excretion could be predictive of adolescents with T1DM who are at an increased risk of developing vascular complications, independent of HbA1c levels. These findings present an opportunity to move towards the personalized care of adolescents with T1DM, which takes into consideration changes in albumin excretion and other risk factors in addition to HbA1c levels.

Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in individuals with type 1 diabetes (T1D). Adolescence appears to be a critical time for the development of early subclinical manifestations of CVD, with these changes likely driven by a deterioration in glycemic control during the progression through puberty, combined with the emergence of numerous other traditional cardiometabolic risk factors (e.g., hypertension, dyslipidemia, smoking, alcohol use, obesity, etc.) which emerge at this age. Although hemoglobin A1C has long been the primary focus of screening and treatment strategies, glycemic control remains poor in youth with T1D. Furthermore, screening for cardiovascular risk factors—which are often elevated in youth with T1D—is suboptimal, and use of pharmacological interventions for hypertension and dyslipidemia remains low. As such, there is a clear need not only for better screening strategies for CVD risk factors in youth, but also early interventions to reduce these, if future CVD events have to be prevented. Accumulating evidence has recently suggested that early increases in urinary albumin excretion, even within the normal range, may identify adolescents with T1D who are at an increased risk of complications, and results from pharmacological intervention with statins and ACE inhibitors in these individuals have been encouraging. These data join a growing evidence highlighting the need for a whole-life approach to prevention starting from childhood if efforts to improve CVD outcomes and related mortality in T1D are to be maintained.

IntroductionThe Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration of Bifidobacterium infantis from age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.Methods and analysisInfants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration of B. infantis EVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin.Ethics and disseminationThe study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universität Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study.Trial registration numberNCT04769037.

Microvascular complications of type 1 diabetes, which primarily include diabetic kidney disease, retinopathy, and neuropathy, are characterized by damage to the microvasculature of the kidney, retina, and neurons. The pathogenesis of these complications is multifactorial, and several pathways are implicated. These complications are often silent during their early stages, and once symptoms develop, there might be little to be done to cure them. Thus, there is a strong need for novel biomarkers to identify individuals at risk of microvascular complications at an early stage and guide the implementation of new therapeutic options for preventing their development and progression. Recent advancements in proteomics, metabolomics, and other 'omics' have led to the identification of several potential biomarkers of microvascular complications. However, biomarker discovery has met several challenges and, up to now, there are no new biomarkers that have been implemented into clinical practice. This highlights the need for further work in this area to move towards better diagnostic and prognostic approaches.

Objective To determine the potential role of cardiovascular autonomic dysfunction in the development of renal complications in young people with type 1 diabetes (T1D). Methods In this prospective study, 199 children and adolescents recruited to the Oxford Regional Prospective Study underwent assessment of autonomic function ~5 years after diagnosis, and were subsequently followed with longitudinal assessments of HbA1c and urine albumin-creatinine ratio (ACR) over 8.6 ± 3.4 years. Autonomic function was assessed with 4 standardized tests of cardiovascular reflexes: heart rate (HR) response to (1) Valsalva Maneuver, (2) deep breathing, (3) standing, and (4) blood pressure (BP) response to standing. Linear mixed models were used to assess the association between autonomic parameters and future changes in ACR. Results Independent of HbA1c , each SD increase in HR response to Valsalva Maneuver predicted an ACR increase of 2.16% [95% CI: 0.08; 4.28] per year (P = .04), while each SD increase in diastolic BP response to standing predicted an ACR increase of 2.55% [95% CI: 0.37; 4.77] per year (P = .02). The effect of HR response to standing on ACR reached borderline significance (-2.07% [95% CI: -4.11; 0.01] per year per SD increase, P = .051). Conclusions In this cohort of young people with T1D, enhanced cardiovascular reflexes at baseline predicted future increases in ACR. These results support a potential role for autonomic dysfunction in the pathogenesis of diabetic nephropathy.

Childhood obesity is commonly associated with early signs of endothelial dysfunction, characterized by impairment of insulin signaling and vascular Nitric Oxide (NO) availability. However, the underlying mechanisms remain to be established. Hence, we tested the hypothesis that endothelial insulin-stimulated NO production and availability was impaired and related to Endoplasmic Reticulum (ER) in human umbilical vein endothelial cells (HUVECs) cultured with plasma obtained from pre-pubertal obese (OB) children. OB children (N = 28, age: 8.8 ± 2.2; BMI z-score: 2.15 ± 0.39) showed impaired fasting glucose, insulin and HOMA-IR than normal weight children (CTRL; N = 28, age: 8.8 ± 1.7; BMI z-score: 0.17 ± 0.96). The in vitro experiments showed that OB-plasma significantly impaired endothelial insulin-stimulated NO production and bioavailability compared to CTRL-plasma. In parallel, in HUVECs OB-plasma increased GRP78 and activated PERK, eIF2α, IkBα and ATF6 (all ER stress markers). Moreover, OB-plasma increased NF-κB activation and its nuclear translocation. Notably, all these effects proved to be significantly restored by using PBA and TUDCA, known ER stress inhibitors. Our study demonstrate for the first time that plasma from obese children is able to induce in vitro endothelial insulin resistance, which is characterized by reduced insulin-stimulated NO production and bioavailability, endothelial ER stress and increased NF-κB activation., Graphical abstract Image 1, Highlights • Plasma from obese children induce in vitro endothelial insulin resistance (IR). • The mechanism involved is the reduced insulin-stimulated NO bioavailability. • In this experimental condition ER stress is associated to endothelial IR. • The additional effect is the increased endothelial inflammation.

OBJECTIVE Suboptimal adherence to insulin treatment is a main issue in adolescents with type 1 diabetes. However, to date, there are no available data on adherence to adjunct noninsulin medications in this population. Our aim was to assess adherence to ACE inhibitors and statins and explore potential determinants in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS There were 443 adolescents with type 1 diabetes recruited into the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and exposed to treatment with two oral drugs—an ACE inhibitor and a statin—as well as combinations of both or placebo for 2–4 years. Adherence was assessed every 3 months with the Medication Event Monitoring System (MEMS) and pill count. RESULTS Median adherence during the trial was 80.2% (interquartile range 63.6–91.8) based on MEMS and 85.7% (72.4–92.9) for pill count. Adherence based on MEMS and pill count dropped from 92.9% and 96.3%, respectively, at the first visit to 76.3% and 79.0% at the end of the trial. The percentage of study participants with adherence ≥75% declined from 84% to 53%. A good correlation was found between adherence based on MEMS and pill count (r = 0.82, P < 0.001). Factors associated with adherence were age, glycemic control, and country. CONCLUSIONS We report an overall good adherence to ACE inhibitors and statins during a clinical trial, although there was a clear decline in adherence over time. Older age and suboptimal glycemic control at baseline predicted lower adherence during the trial, and, predictably, reduced adherence was more prevalent in subjects who subsequently dropped out.

Copyright © 2016 Termedia & Banach Introduction: Egg allergy is one of the most common food allergies in children. Egg white, including ovomucoid (OVM or Gal d 1) and ovalbumin (OVA or Gal d 2), is the major source of allergens. The aim of this study was to assess the role of Gal d 1 and Gal d 2 in predicting the risk of anaphylaxis caused by eggs in children, and to compare this new diagnostic tool with established methods of allergen-specific IgE detection. Material and methods: One hundred and forty-eight children were divided into 2 groups according to a positive (group A, 33 children) or negative (group B, 115 children) history of anaphylaxis after ingestion/contact with eggs. All patients underwent an allergological evaluation by measurements of specific IgE against egg white: Gal d 1 and Gal d 2. Results: Higher levels of Gal d 1, Gal d 2 and IgE against egg white were detected in group A compared to group B (p < 0.001). Although the area under the curve was similar for Gal d 1 and Gal d 2, egg white specific IgE showed a better sensitivity (85%) for a cut-off value ≥ 0.975 kUA/l, while Gal d 1 and Gal d 2 demonstrated a better specificity (90% and 80%, respectively) for cut-off values ≥ 1.460 kUA/l and ≥ 2.310 kUA/l, respectively. Conclusions: Egg white specific IgE showed a similar ability as Gal d 1 and Gal d 2 in differentiating children at risk for egg anaphylaxis, although Gal d 1 and Gal d 2 showed a better specificity.

Aims High-density lipoprotein (HDL) function may be altered in patients with chronic disease, transforming the particle from a beneficial vasoprotective molecule to a noxious pro-inflammatory equivalent. Adolescents with Type 1 diabetes often have elevated HDL, but its vasoprotective properties and relationship to endothelial function have not been assessed. Methods and results Seventy adolescents with Type 1 diabetes (age 10-17 years) and 30 age-matched healthy controls supplied urine samples for the measurement of early renal dysfunction (albumin:creatinine ratio; ACR), blood samples for the assessment of cardiovascular risk factors (lipid profiles, HDL functionality, glycaemic control, and inflammatory risk score), and had their conduit artery endothelial function tested using flow-mediated dilation (FMD). HDL-c levels (1.69 ± 0.41 vs. 1.44 ± 0.29mmol/L; P < 0.001), and glycated haemoglobin (HbA1c) (8.4 ± 1.2 vs. 5.4 ± 0.2%; P < 0.001) were increased in all patients compared with controls. However, increased inflammation and HDL dysfunction were evident only in patients who also had evidence of early renal dysfunction (mean ± standard deviation for high-ACR vs. low-ACR and healthy controls: inflammatory risk score 11.3 ± 2.5 vs. 9.5 ± 2.4 and 9.2 ± 2.4, P < 0.01; HDL-mediated nitric-oxide bioavailability 38.0 ± 8.9 vs. 33.3 ± 7.3 and 25.0 ± 7.7%, P < 0.001; HDL-mediated superoxide production 3.71 ± 3.57 vs. 2.11 ± 3.49 and 1.91 ± 2.47nmol O2 per 250 000 cells, P < 0.05). Endothelial function (FMD) was impaired only in those who had both a high inflammatory risk score and high levels of HDL-c (P < 0.05). Conclusion Increased levels of HDL-c commonly observed in individuals with Type 1 diabetes may be detrimental to endothelial function when accompanied by renal dysfunction and chronic inflammation. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

High-density lipoprotein (HDL) function may be altered in patients with chronic disease, transforming the particle from a beneficial vasoprotective molecule to a noxious pro-inflammatory equivalent. Adolescents with Type 1 diabetes often have elevated HDL, but its vasoprotective properties and relationship to endothelial function have not been assessed.Seventy adolescents with Type 1 diabetes (age 10-17 years) and 30 age-matched healthy controls supplied urine samples for the measurement of early renal dysfunction (albumin:creatinine ratio; ACR), blood samples for the assessment of cardiovascular risk factors (lipid profiles, HDL functionality, glycaemic control, and inflammatory risk score), and had their conduit artery endothelial function tested using flow-mediated dilation (FMD). HDL-c levels (1.69 ± 0.41 vs. 1.44 ± 0.29mmol/L; P 0.001), and glycated haemoglobin (HbA1c) (8.4 ± 1.2 vs. 5.4 ± 0.2%; P 0.001) were increased in all patients compared with controls. However, increased inflammation and HDL dysfunction were evident only in patients who also had evidence of early renal dysfunction (mean ± standard deviation for high-ACR vs. low-ACR and healthy controls: inflammatory risk score 11.3 ± 2.5 vs. 9.5 ± 2.4 and 9.2 ± 2.4, P 0.01; HDL-mediated nitric-oxide bioavailability 38.0 ± 8.9 vs. 33.3 ± 7.3 and 25.0 ± 7.7%, P 0.001; HDL-mediated superoxide production 3.71 ± 3.57 vs. 2.11 ± 3.49 and 1.91 ± 2.47nmol O2 per 250 000 cells, P 0.05). Endothelial function (FMD) was impaired only in those who had both a high inflammatory risk score and high levels of HDL-c (P 0.05).Increased levels of HDL-c commonly observed in individuals with Type 1 diabetes may be detrimental to endothelial function when accompanied by renal dysfunction and chronic inflammation.

Diabetic kidney disease (DKD) remains one of the leading causes of reduced lifespan in diabetes. The quest for both prognostic and surrogate endpoint biomarkers for advanced DKD and end-stage renal disease has received major investment and interest in recent years. However, at present no novel biomarkers are in routine use in the clinic or in trials. This review focuses on the current status of prognostic biomarkers. First, we emphasise that albuminuria and eGFR, with other routine clinical data, show at least modest prediction of future renal status if properly used. Indeed, a major limitation of many current biomarker studies is that they do not properly evaluate the marginal increase in prediction on top of these routinely available clinical data. Second, we emphasise that many of the candidate biomarkers for which there are numerous sporadic reports in the literature are tightly correlated with each other. Despite this, few studies have attempted to evaluate a wide range of biomarkers simultaneously to define the most useful among these correlated biomarkers. We also review the potential of high-dimensional panels of lipids, metabolites and proteins to advance the field, and point to some of the analytical and post-analytical challenges of taking initial studies using these and candidate approaches through to actual clinical biomarker use. Electronic supplementary material The online version of this article (10.1007/s00125-018-4567-5) contains a slideset of the figures for download, which is available to authorised users.

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention. The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase. Electronic supplementary material The online version of this article (10.1186/s13052-018-0525-6) contains supplementary material, which is available to authorized users.

Diabetes mellitus is een endocriene ziekte die veel voorkomt onder kinderen en adolescenten. Van zeer groot belang is een goede glucose-instelling ter voorkoming van lange- en kortetermijncomplicaties en om een normale groei en kwaliteit van leven mogelijk te maken. Deze review geeft een update van de momenteel beschikbare behandelstrategieen bij type 1 en type 2 diabetes, toegelaten voor gebruik bij kinderen en adolescenten. Hoewel er veel vooruitgang is geboekt in de behandeling van diabetes bij kinderen en adolescenten, vallen er nog steeds ook veel problemen te verhelpen. Bij type 1 diabetes is insulinetoediening nog steeds de belangrijkste en essentiele therapeutische strategie. Het grootste probleem is echter dat er een systeem ontwikkeld moet worden dat een betere fysiologische substitutie van insuline geeft en het risico op hypoglycemie en gewichtstoename verlaagt. Een adjuvante therapie zou van onschatbare waarde zijn voor patienten die veel moeite hebben hun glucose-instelling op een acceptabel niveau te krijgen. De behandeling van type 2 diabetes gebaseerd op leefstijlinterventies en metformine is de farmacologische behandeling van eerste keus bij kinderen ouder dan 10 jaar. Voor type 1 diabetes geldt dat er grote behoefte is aan de ontwikkeling van nieuwe geneesmiddelen die op zichzelf of in combinaties kunnen worden toegepast.

Low serum IGF-1 levels have been linked to increased risk for development of type 2 diabetes. However, the physiological role of IGF-1 in glucose metabolism is not well characterized.Our objective was to explore glucose and lipid metabolism associated with variations in serum IGF-1 levels.IGF-1 levels were measured in healthy, nonobese male volunteers aged 18 to 50 years from a biobank (n = 275) to select 24 subjects (age 34.8 ± 8.9 years), 12 each in the lowest (low-IGF) and highest (high-IGF) quartiles of age-specific IGF-1 SD scores. Evaluations were undertaken after a 24-hour fast and included glucose and glycerol turnover rates using tracers, iv glucose tolerance test to estimate peripheral insulin sensitivity (IS) and acute insulin and C-peptide responses (indices of insulin secretion), magnetic resonance spectroscopy to measure intramyocellular lipids (IMCLs), calorimetry, and gene expression studies in a muscle biopsy.Acute insulin and C-peptide responses, IS, and glucose and glycerol rate of appearance (Ra) were evaluated.Fasting insulin and C-peptide levels and glucose Ra were reduced (all P.05) in low-IGF compared with high-IGF subjects, indicating increased hepatic IS. Acute insulin and C-peptide responses were lower (both P.05), but similar peripheral IS resulted in reduced insulin secretion adjusted for IS in low-IGF subjects (P = 0.044). Low-IGF subjects had higher overnight levels of free fatty acids (P = .028) and β-hydroxybutyrate (P = .014), increased accumulation of IMCLs in tibialis anterior muscle (P = .008), and a tendency for elevated fat oxidation rates (P = .058); however, glycerol Ra values were similar. Gene expression of the fatty acid metabolism pathway (P = .0014) was upregulated, whereas the GLUT1 gene was downregulated (P = .005) in the skeletal muscle in low-IGF subjects.These data suggest that serum IGF-1 levels could be an important marker of β-cell function and glucose as well as lipid metabolic responses during fasting.

AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes.METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

OBJECTIVE We assessed the association between early increases in albumin excretion and cardiovascular (CV) and renal markers in a large cohort of young people with type 1 diabetes. RESEARCH DESIGN AND METHODS As part of preliminary screening for a multicenter, randomized controlled trial of statins/ACE inhibitors, we measured albumin–creatinine ratio (ACR) in six early morning urine samples from 3,353 adolescents (10–16 years of age) and calculated tertiles based on an established algorithm. From those subjects deemed to be at higher risk (upper ACR tertile), we recruited 400 into the intervention study (trial cohort). From those subjects deemed to be at lower risk (middle–lower ACR tertiles), we recruited 329 to the observation cohort. At baseline, vascular measurements (carotid intima-media thickness, pulse wave velocity [PWV], flow-mediated dilatation, digital pulse amplitude tonometry), renal markers (symmetric dimethylarginine, cystatin C, creatinine), and CV disease markers (lipids and apolipoproteins [Apo] A-1 and B, C-reactive protein, asymmetric dimethylarginine) were assessed. RESULTS Age- and sex-adjusted PWV was higher in the trial than in the observational cohort (5.00 ± 0.84 vs. 4.86 ± 0.70 m/s; P = 0.021). Similarly, non-HDL cholesterol (2.95 ± 0.83 vs. 2.81 ± 0.78 mmol/L; P = 0.02) and ApoB–ApoA-1 ratio (0.50 ± 0.14 vs. 0.47 ± 0.11; P = 0.04) were higher in the trial cohort. Cystatin C and creatinine were decreased (0.88 ± 0.13 vs. 0.90 ± 0.13 mg/L, P = 0.04; 51.81 ± 10.45 vs. 55.35 ± 11.05 μmol/L, P < 0.001; respectively) and estimated glomerular filtration rate (137.05 ± 23.89 vs. 129.31 ± 22.41 mL/min/1.73 m2; P < 0.001) increased in the trial compared with the observational cohort. CONCLUSIONS Our data demonstrate that in adolescents with type 1 diabetes, the group with the highest tertile of albumin excretion showed more evidence of early renal and CV disease than those in the lower tertiles.

ObjectiveTo investigate whether there is an association of the triglyceride-to-HDL cholesterol (TG:HDL-C) ratio with cardiovascular risk factors and early signs of vascular damage in obese prepubertal children.Design and methodsIn 50 obese (27 boys, 7.8±1.4 years) and 37 normal-weight (20 boys; 7.3±1.5 years) prepubertal children, anthropometric measurements, oxidative stress markers (urinary isoprostanes (PGF2α (prostaglandin F2α)), soluble receptor for advanced glycation end-products (sRAGE)) and insulin sensitivity (homeostasis model assessment of insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI)) were evaluated. Lipids profile was assessed and the TG:HDL-C ratio was calculated. In addition, high-resolution ultrasound was performed to assess carotid intima-media thickness (cIMT).ResultsObese children showed significantly higher values of the TG:HDL-C ratio (1.9±1.1 vs 1.2±0.6, P=0.002) compared with controls. After dividing the population in tertiles of the TG:HDL-C ratio (1.67), cIMT (P=0.0003), and HOMA-IR (P=0.0001) progressively increased from the lower to the upper tertile, whereas WBISI (P=0.0003) and sRAGE (P=0.05) progressively decreased. In a regression model, the TG:HDL ratio was significantly and positively associated with cIMT (r=0.493; P=0.0005). A cutoff point for TG:HDL-C ratio of 1.12 had 81% sensitivity and 49% specificity in the identification of children with cIMT values in the upper quartile (Area under the curve values from receiver operating characteristic curves=0.633±0.065, P=0.045).ConclusionThis study confirms the reliability of the TG:HDL-C ratio as a useful marker of cardiovascular risk. Interestingly, our results underline that the TG:HDL-C ratio is directly related with early signs of vascular damage already present in prepubertal children.

Diabetes is the leading cause of end stage renal disease. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2,843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (p=6x10-3 7 ). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (p=2.2×10-5) and the risk of type 2 diabetes (p=6.1x10-4 11 ) were associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (p=1.1×10-4 13 ). Pathway analysis implicated ascorbate and aldarate metabolism (p=9×10-6), and pentose and glucuronate interconversions (p=3×10-6 14 ) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.

Objective: To evaluate the association between a clustering of cardio‐metabolic risk factors in parents and the development of microalbuminuria (MA) in their offspring with childhood‐onset type 1 diabetes (T1D). Methods: The study population comprised 53 parents (mean age [±SD]: 56.7±6.2 years) of 35 T1D young people with MA (MA+) and 86 parents (age: 56.1±6.3 years) of 50 matched offspring with normoalbuminuria (MA–), who underwent clinical, biochemical and cardiovascular imaging assessments. The primary study endpoint was the difference between parents from the MA+ and MA− groups in a cardio‐metabolic risk score, calculated as the average value of the standardized measures (z‐scores) for waist circumference, blood pressure, fasting glucose, insulin, HDL‐cholesterol and triglycerides levels. Cardiovascular parameters, including carotid intima‐media thickness (cIMT), flow‐mediated dilatation (FMD) and pulse wave velocity (PWV), were also assessed. A DXA scan was performed to assess body composition. Results: The cardio‐metabolic risk score was significantly higher in parents of MA+ compared to parents of MA− offspring (mean [95% CI]: 1.066[0.076; 2.056] vs −0.268[−0.997; 0.460], P = .03). Parents of MA+ offspring had slightly higher values of waist circumference, lipids, insulin and blood pressure, although only diastolic blood pressure was statistically different between the 2 groups (P = .0085). FMD, cIMT, PWV (all P > .3), and DXA parameters (all P > .2) were not significantly different between the 2 groups. Conclusions: Parents of young offspring with childhood‐onset T1D and MA showed an abnormal metabolic profile, reflected by a calculated risk score. The finding supports the role of a familial predisposition to risk of developing diabetic nephropathy.

SUMMARY Progressive increases in albumin excretion and microalbuminuria can be detected in young people with childhood-onset Type 1 diabetes during puberty. Risk factors for microalbuminuria during puberty include hyperglycemia, diabetes duration, female gender, high blood pressure and lipid levels, changes in sex hormones, reduced IGF-I levels, together with other, as yet unidentified, genetic and environmental factors. Annual screening for microalbuminuria during puberty is recommended for the early detection of this marker of later diabetes complications. When microalbuminuria is detected, the first treatment strategy is to improve glycemic control, a known modifiable risk factor, whereas the efficacy and safety of additional interventions, such as angiotensin-converting enzyme inhibitors or statins, is not yet established, and are currently being evaluated.

SUMMARY Increases in urinary albumin excretion (microalbuminuria) can be detected in young people with Type 1 diabetes (T1D) during puberty, and they may indicate a risk for the development of overt diabetic nephropathy (DN) and cardiovascular disease. During adolescence, poor glycemic control, dyslipidemia, increases in blood pressure and inflammatory markers, female gender, and hormonal changes all contribute to the risk of microalbuminuria. Currently, interventions to reduce the long-term risk for DN in adolescents with T1D are mainly based on improving glycemic control, while there is no clear guidance on other potential cardio–renal protection strategies. The efficacy of angiotensin-converting enzyme inhibitors and statins is currently being investigated in adolescents with T1D at high risk of developing DN. In addition, there is growing interest in the development of new interventions targeting specific pathways implicated in DN.

Objective: To determine whether in obese prepubertal children insulin resistance (IR) is associated with the development of liver steatosis. Methods and Procedures: Cross-sectional study evaluating the prevalence of liver steatosis in 100 severely obese prepubertal children and comparing IR indexes between children with (group 1) and without steatosis (group 2). Furthermore, IR indexes were compared to values of 50 normal weight children. Fasting blood samples were collected for the evaluation of liver function tests, lipid profile, plasma glucose, and insulin levels. All children underwent an oral glucose tolerance test and anthropometric measurements. Hepatic ultrasound was performed according to international criteria and by one single operator. Analysis was performed by Mann–Whitney U-test, Pearson correlation, and logistic regression. Results: Liver steatosis was found in 52% obese children and was equally distributed between the two sexes. Obese children were more insulin resistant when compared to controls (homeostasis model assessment of IR (HOMA-IR): P = 0.0001; whole body insulin sensitivity index (WBISI): P = 0.0005; fasting glucose/fasting insulin ratio (G/I): P = 0.0001), and group 1 presented an even higher degree of IR when compared to group 2 (HOMA-IR P = 0.0001; WBISI P = 0.0004; G/I P = 0.0001). The area under the curve (AUC) for insulin was significantly higher in group 1 when compared to group 2, while no difference was found in the AUC for glucose. There was no association between IR and adiposity indexes (P >0.05). The role of IR as a predictor for the development of steatosis was analyzed by multiple logistic regression, which documented that IR indexes were significantly related to steatosis independently of BMI-SDS. Discussion: Liver steatosis is an emerging problem in prepubertal severely obese children, and it appears to be an association between liver steatosis and IR in these subjects.

The needs of pediatric patients with diabetes differ from those of adults. Challenges include growth and development, and care outside of the home, such as in the school setting. In addition, in type 2 diabetes, there are fewer treatment options for pediatric patients; while recent years have seen the approval of many glucose-lowering drugs for adults, only metformin and insulin are approved in patients aged under 18 years. In an expert interview, M Loredana Marcovecchio, of the University of Cambridge, UK, discusses recent advances and remaining challenges in the treatment of pediatric patients with both type 1 and type 2 diabetes.

OBJECTIVE To assess the potential association between A1C variability (A1C-SD) and microalbuminuria in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS Serially collected samples for A1C measurement were available for 1,232 subjects with childhood-onset type 1 diabetes recruited to the Oxford Regional Prospective Study and the Nephropathy Family Study. RESULTS The median (range) number of A1C assessments was 4 (2–16). Mean intrapersonal A1C was 9.5% and A1C-SD was 0.91. Mean A1C and A1C-SD values were higher in subjects with microalbuminuria (n = 227) than in those with normoalbuminuria (10.3 vs. 9.4%; 1.12 vs. 0.86, P < 0.001). In a Cox regression model, A1C-SD was independently associated with microalbuminuria (hazard ratio 1.31 [95% CI 1.01–1.35]). CONCLUSIONS In the current study, A1C variability was an independent variable that added to the effect of A1C on the risk for microalbuminuria in youth with type 1 diabetes, a population highly vulnerable to vascular complications.

A 7-year-old boy was admitted to the pediatric ward (University of Chieti) for the onset of multiple erythematous target lesions, some with vesicles in the middle, located on the ears, face (Figure 1 A), in the oral cavity (Figure 1 B), on both hands, feet and lower limbs. Four days prior to admission the patient presented prodromal symptoms, such as fever (maximum temperature 38°C), sore throat and asthenia. All these features supported a diagnosis of erythema multiforme (EM) secondary to an infection. Blood examination revealed lymphopenia (1.28 × 10,000/µl), neutrophilia (6.10 × 10,000/µl), erythrocyte sedimentation rate of 15 mm/h (normal range: 1–12 mm/h) and alanine aminotransferase of 80 U/l (normal range: 11–66). Serum antibodies against Mycoplasma pneumoniae, Adenovirus, Varicella Zoster, Epstein-Barr virus and Herpes Simplex Virus (HSV) 1 and 2 were negative. In contrast, cytomegalovirus (CMV) IgM antibody titers were positive (23.6 U/ml; normal range: 0 to 18), whereas IgG antibody values were normal (< 5 U/ml; normal range: 0 to 12). Four weeks later, the levels of anti-CMV IgG antibodies rose (190 U/ml) with normalization of anti-CMV IgM levels. During hospitalization, management included intravenous fluids and electrolyte infusion for skin and mucosae dehydration and for the poor oral intake due to an intense oral burning sensation; methylprednisolone (0.8 mg/kg/day); intravenous antibiotic therapy (ceftriaxone) to prevent skin bacterial infection, because the patient (unable to take oral drugs for the several lesions in the oral cavity) presented fever and neutrophilia (6.10 × 10,000/µl) and mild elevation of erythrocyte sedimentation rate (15 mm/h). Figure 1 The erythematous and vesiculo-bullous lesions on the face (A), numerous injuries in the oral cavity (B) and lesions on the hands (C) The erythematous vesicular lesions gradually improved. Erythema multiforme is a rare, acute, self-limiting, immune-mediated hypersensitivity reaction [1] in children and it is exceptional in newborns [2]. Erythema multiforme presents over a period of 12 to 24 h. A relatively mild prodromal phase that resembles an upper respiratory infection usually occurs before the skin eruption. The papular lesions appear symmetrically on the extremities and are target-shaped, with 3 different-colored zones and a blister in the center clearly demarcated from the surrounding skin. Mucosal disease is typically restricted to the oral mucosa [3]. The precise incidence of EM is unknown, but it has been postulated to be less than 1% but probably greater than 0.01% [4]. Several factors have been suggested to be associated with the development of EM, such as infections (90%, particularly HSV and Mycoplasma pneumoniae), medication use, autoimmune disease, malignancy, immunization, radiation, and menstruation [4]. Erythema multiforme can also be an early cutaneous manifestation of a particular disease, such as Lyme disease [5], a multi-organ animal-borne disease, caused by spirochetes of Borrelia burgdorferi, which typically affect the skin, nervous system, musculoskeletal system and heart [6]. In our patient, a role of CMV infection seemed highly plausible, due to the temporal relationship between the skin and mucosa lesions and the changes in the antibodies against CMV. Furthermore, our patient did not have any history of other past infectious diseases or drug use, therefore ruling out the possibility of EM related to drugs or other infections. To our knowledge only some cases of EM associated with CMV infection are reported in children and in adults [7] and one case in a newborn [2]. In HSV-associated EM, the findings are thought to result from a cell-mediated immune reaction against viral antigen-positive cells that contain the HSV DNA polymerase gene. A number of subjects with EM is genetically predisposed to develop EM. A study [8] revealed the role of the HLADQB1*0301 allele, which is important particularly for patients with HSV-associated EM. However, the diagnosis of EM is a clinical one [9]. The severity of EM and mucosal disease varies between patients. For this reason, management should be personalized for each patient. Mild cutaneous EM can be treated primarily with a goal of achieving symptomatic improvement. Hospitalization is necessary in the presence of severe mucosal disease that produces poor oral intake and subsequent fluid and electrolyte imbalance [4]. Some clinical evidence suggest treating minor EM with topical steroids. The use of systemic steroids for EM major remains controversial, as there is evidence both for and against treatment, and no randomized controlled trials have been performed [10]. Other studies are necessary to determine the effectiveness of these therapeutic approaches. This case report provides a rare clinicopathological correlation in pediatric age, because although already but rarely reported in the literature, it highlights the need to consider CMV infection as a potential cause of EM in patients without a history of other infections (particularly HSV and Mycoplasma pneumoniae), drug intake or other causes (autoimmune disease, malignancy, immunization, radiation). It can be useful in the future to estimate the incidence of the various pathogenic agents that can cause EM, and it also provides significant images of this serious disease that can help clinicians in diagnosis. On the other hand, it provides another experience in the use of corticosteroids in these patients, supporting the usefulness of these drugs in children with EM.

OBJECTIVES—To perform a longitudinal evaluation of high-sensitivity C-reactive protein (hs-CRP) in young people with type 1 diabetes in relation to the development of microalbuminuria (MA). RESEARCH DESIGN AND METHODS—hs-CRP was measured in 329 blood samples collected from 49 subjects with type 1 diabetes with MA and 49 normoalbuminuric subjects matched for age, sex, and duration of diabetes. RESULTS—In subjects developing MA, a progressive rise in hs-CRP was detected with levels significantly higher in the years after the onset of MA when compared with levels before MA onset (P = 0.003; age-adjusted P = 0.06). After the onset of MA, hs-CRP levels were significantly higher in subjects with MA when compared with normoalbuminuric subjects (median 1.9 mg/l [range 0.2–9.8] vs. 1.1 mg/l [0.2–6.4]; P = 0.02; adjusted P = 0.036). CONCLUSIONS—In this population of young subjects with type 1 diabetes, there was a significant increase in hs-CRP levels after the onset of MA, likely reflecting a general state of inflammation.