Search

BACKGROUND: The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. METHODS: In this context, we have developed a Master Protocol, based on the "backbone" of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. DISCUSSION: The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

The aim of this study was to investigate the association between uric acid (UA) and cardiometabolic risk factors (CMRFs) by sex in youth with type 1 diabetes (T1D). Retrospective data collected from 1323 children and adolescents (5–18 years; 716 boys) with T1D recruited in 9 Italian Pediatric Diabetes Centers were analyzed. CMRFs included UA, HbA1c, blood pressure (BP), cholesterol (TC), HDL, triglycerides (TG), neutrophils (N) and lymphocytes (L) count, glomerular filtration rate (eGFR) (calculated using Schwartz-Lyon equation). In boys, we found a higher age, daily insulin dose, TG, TG/HDL ratio, TC/HDL ratio, systolic BP, N/L ratio and lower HDL, and eGFR across UA tertiles (p = 0.01–0.0001). Similar results were found in girls but not for TG and systolic BP. In boys, the odds ratio (OR) of high levels of TG/HDL ratio, TC/HDL ratio, BP and mildly reduced eGFR (MRGFR) increased for 0.5 mg/dL of UA. Instead, in girls an increased levels of 0.5 mg/dL of UA were associated with high OR of TC/HDL ratio, N/L ratio and MRGFR. Uric acid may represent a useful marker for identifying youth with T1D at high cardiometabolic risk, and this association appears to vary by sex.

Spirit checklist

Additional materials that support paper

Level of evidence and grade of recommendations according to the National Guidelines System [4]. (DOCX 15Â kb)

AIM: To systematically assess the impact of commercially available hybrid closed loop (HCL) systems on psychological outcomes in youths with type 1 diabetes and their parents. METHODS: We performed a systematic review including studies published in the last 10 years. PICOS framework was used in the selection process, and evidence was assessed using the GRADE system. RESULTS: A total of 215 studies were identified after duplicate removal, and 31 studies were included in this systematic review: 20 on first-generation HCL and 11 on second-generation HCL systems. According to studies with moderate- to high-level quality of evidence, HCL systems led to better, or in some studies, unchanged psychological outcomes such as distress and burden related to diabetes management, fear of hypoglycemia, quality of life, satisfaction; instead, quality of sleep was perceived as improved, although results were not confirmed in studies using actigraphy. From semi-structured interviews, answers were more homogeneous, and participants reported a positive experience and attitude towards HCL technology, which was felt to be easy to use and apt to achieve glycemic targets. CONCLUSIONS: Evidence confirms the importance of evaluating the psychosocial needs of youths with diabetes and their families when starting HCL systems and during follow-up, and to set realistic expectations of what can be achieved along with awareness of the limitations of the systems, and educate and motivate families to overcome barriers.

Juvenile idiopathic arthritis (JIA) is a common pediatric rheumatic disease. Renal manifestations have been rarely observed in JIA, although amyloidosis could be a renal complication in systemic JIA (sJIA). To investigate renal damage in JIA children and to establish the relationship with treatment. Blood urea nitrogen (BUN), creatinine, cystatin C (CysC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinary albumin excretion (UAE), estimated glomerular filtration rate (eGFR), and renal resistive index (RRI) were assessed in 49 JIA children (9 boys/40 girls, mean age 10.3 ± 3.8 years) and in 49 healthy controls (24 boys/25 girls, mean age 11.3 ± 3.4 years). Twenty-two JIA patients were on methotrexate (MTX) therapy (group A) and 27 on biologic drugs (group B). CysC and BUN (respectively, 0.8 ± 0.1 vs. 0.7 ± 0.1 mg/dl; 13.3 ± 2.9 vs. 11.7 ± 1.4 mg/dl) were higher (p ≤ 0.001) whereas creatinine and eGFR (respectively, 0.5 ± 0.1 vs. 0.6 ± 0.1 mg/dl; 99.2 ± 10.5 vs. 122.5 ± 19.8 ml/min/1.73 m2) were lower in JIA children as compared to controls (p p = 0.003). Mean RRI was higher in JIA children than controls (0.7 ± 0.04 vs. 0.6 ± 0.04; p p p p = 0.003) and eGFR (p = 0.001). JIA children had reduced eGFR, increased UAE and higher RRI values, than controls. RRIs were higher in patients on biologic drugs than MTX group and were associated with inflammation indexes and disease state, suggesting a direct effect of the disease.

Background: The INNODIA consortium has established a pan-European infrastructure using validated centres to evaluate prospectively clinical data from individuals with newly diagnosed Type 1 diabetes combined with centralized collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of Phase 2 clinical trials. Methods: In this context we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of Phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed Type 1 diabetes. Although many IMPs have demonstrated potential efficacy in Phase 2 studies, few subsequent Phase 3 studies have confirmed these benefits. Currently Phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion: The Master Protocol provides: 1) standardized assessment of efficacy and safety; 2) comparable collection of mechanistic data; 3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies; 4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

• 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

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.

Over the last decades the diagnosis and management of pediatric endocrine disorders has substantially improved. However, clinicians still face some key challenges, without straightforward solutions, during their daily clinical practice. This Research Topic includes a collection of papers on relevant topics in Pediatric Endocrinology and Diabetes, which can support clinicians in better understanding endocrine conditions and their management. The global obesity epidemic has brought to light that metabolic complications, previously thought to affect only obese adults, can manifest at a younger age. The true incidence of pediatric type 2 diabetes (T2D) is still debated (1), and North American and European studies show contrasting results. Indeed, the exponential increase in the incidence of T2D reported among North American obese children and adolescents is not confirmed among European youth. Data from different populations and Countries are essential to better understand the epidemiology of T2D. In this issue, Al-Kandari et al. report the incidence of T2D in Kuwait, providing some Country-specific unique epidemiological data. The prevalence of glucokinase (GKC) deficit in pregnant women with diabetes is the focus of Bitterman et al.’s paper. Although maturity onset diabetes of the young (MODY) due to GCK deficit is a benign condition, a prompt diagnosis is essential for the optimal course of pregnancy and planning of appropriate newborn care. Available data indicate that the prevalence of GKC deficit varies between 0-80% among pregnant women, dependent on the screening criteria and the populations’ characteristics (2, 3). In this retrospective study, the authors show that even the recent “new-pregnancy-specific criteria,” based on BMI 99 mg/dl, do not reach optimal sensitivity and specificity thresholds. Therefore, better criteria applicable to different populations, are required for a tailored selection of pregnant women eligible for genetic tests. This issue also includes a systematic review and meta-analysis addressing the potential association between type 1 diabetes (T1D) and periodontal disease in children (4). Previous studies reported a three- to four-fold increased risk of periodontal disease in adults with T2D and suggested a bidirectional relationship between these two conditions. Rapone et al. highlight lack of strong evidence for similar associations in children with T1D. Current evidence is primarily based on cross-sectional studies, which show a higher prevalence of periodontal disease in children with diabetes. However, pediatric studies do not support a role of periodontal disease in the pathogenesis of T1D and its complications and exclude an effect on glycemic control. The hypothalamic-pituitary-gonadal axis is discussed in two comprehensive reviews. Bizzarri and Cappa offer an interesting description of the transient sex-specific activation of hypothalamic-pituitary-gonadal axis during the first 6 months of life in boys, and the first 2 years in girls. This phenomenon, known as “mini-puberty,” is fascinating and provides insights into the understanding of the mechanisms of pubertal development later in life. Festa et al. review genetic causes of pubertal delay and propose a diagnostic algorithm to distinguish between self-limited delayed puberty and other forms of hypogonadotropic hypogonadism. Self-limited delayed puberty is a frequent condition in endocrine clinical practice, whereas congenital hypogonadotropic hypogonadism accounts for 4% and 5.7% cases of delayed puberty in boys and girls, respectively. The authors offer an in-depth discussion of the benefits and limitations of genetic testing in the clinical setting, underling its potential role for a better classification and management of delayed puberty. Assessment of bone maturation (BM) in children and adolescents is relevant in medical and non-medical fields (5). Despite a few issues related to the use of different methods, bone age is a unique tool to assess the maturational changes during childhood and adolescence, and to aid the diagnostic workout of growth disorders. In this Research Topic, Cavallo et al. provide an overview of the main methods to assess bone age and discuss their advantages and disadvantages. In a second paper, Pepe et al. report the results of a prospective study assessing the link between BM and postnatal growth during the first year of life in a population of children born small for gestational age (SGA). Although most SGA children show spontaneous catch-up growth during the first two years of life, a percentage of them remains short during childhood (6). In the present study, SGA newborns with delayed BM showed greater growth velocities and height gains at 12 months of age compared to those with adequate BM at birth. Besides, the study shows that ultrasonographic evaluation of the Beclard’s nucleus could be a useful noninvasive technique to identify intrauterine BM delay. Another key topic discussed in this issue is the reason for and appropriateness of pediatric endocrinology referrals. A clear understanding of referral pathways is essential to optimize resource use and plan continuous medical education and public health interventions. Bellotto et al. report data on endocrine referrals to a single Italian tertiary center for pediatric endocrinology. The study highlights that growth and puberty represent nearly half of all reasons for endocrine referrals, and that timing for referral (i.e. urgent vs deferrable priority) is often inappropriate. The authors suggest that medical education of primary care can be better tailored to improve the timing of referral and the ability to recognize subclinical and para-physiological conditions. These steps are paramount to better define windows of intervention and optimize clinical outcomes. We hope that this Research Topic will provide a valuable resource for the management of clinical endocrine issues in daily practice and we encourage the readers to submit their General Commentary articles on these articles.

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

An increased albumin-creatinine ratio (ACR) 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 inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation; FMD and reactive hyperemia index; RHI) and arterial stiffness (carotid-femoral pulse wave velocity; PWV) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2x2 factorial trial (RCT) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the RCT, high-risk patients randomized to ACE inhibitors had improved FMD after 2-4 years of follow-up (mean [95%CI]: 6.6%[6.0,7.2] vs. 5.3%[4.7,5.9]; p=0.005), whereas no effect was observed following statin use (6.2%[5.5,6.8] vs. 5.8%[5.1,6.4]; p=0.358). In the observational study, high-risk ACR patients showed evidence of endothelial dysfunction at the end of follow-up (FMD= 4.8%[3.8,5.9] vs. 6.3% [5.8,6.7] for high-risk vs. low-risk groups; p=0.015). Neither RHI nor PWV 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 0.5m/s[0.4,0.6]; p

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 which have been implemented into clinical practice. This highlights the need of further work in this area to move towards better diagnostic and prognostic approaches.

Objectives: To determine differences in body composition and glucose metabolism according to childhood growth outcomes, in a population-based sample of children born small for gestational age (SGA). Methods: Single-centre study of 259 children born SGA identified through hospital records and contacted when aged 4-7years. Questionnaire data on pre/perinatal history and growth parameters during childhood were collected from the parents and, in a subgroup of 150 children, face-to-face assessments were performed, including anthropometric parameters, lean and fat mass, blood pressure, fasting glucose and C-peptide. Results: Based on the questionnaires few children had formal clinic follow-up of growth, but 7% of the cohort showed height and weight

Purpose of review: Individuals with type 1 diabetes (T1D) have excess cardiovascular risk and reduced life expectancy. Adolescence is the time when the first signs of vascular complications appear and a critical window for interventions. This article reviews recent evidence on cardiometabolic risk factors and their management in youth with T1D. Recent findings: Adolescents with T1D show early signs of vascular complications, as a result of several cardiometabolic risk factors. Poor glycemic control is one of the main risk factors and the main target of treatment. However, only a minority of adolescents with T1D reaches recommended targets for glycemic control. Hypertension, dyslipidemia, smoking, alcohol use, obesity and insulin resistance are other common cardiometabolic risk factors in this age group. Recent data confirm that screening for these risk factors is suboptimal and use of pharmacological interventions for hypertension and dyslipidemia remains low. Data on adjunctive non-insulin agents to improve glycemic control and other cardiometabolic risk factors are still lacking in this age group. Summary: Vascular complications and the associated mortality remain a major issue for youth with T1D. Better screening strategies for cardiometabolic risk factors and interventions are required to improve the longterm prognosis of youth with T1D.

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.

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.

PURPOSE: Obese adults with normal glucose tolerance (NGT) but with 1-hour post-load plasma glucose (1hPG) ≥ 155 mg/dl are at higher risk of developing type 2 diabetes (T2D) and cardiometabolic complications. Little information is available for the pediatric population, where recently, a lower cutoff, 132.5 mg/dl, has been suggested as being more sensitive to identify subjects at risk of T2D. Our aim was to assess whether obese Caucasian youth with 1hPG ≥ 132.5 mg/dl have worse insulin sensitivity and secretion and a worse cardiometabolic profile compared to obese youth with 1hPG < 132.5 mg/dl. METHODS: Medical records of 244 (43% male; age: 11.1 ± 2.7years) overweight/obese children and adolescents, who had undergone an oral glucose tolerance test (OGTT), were retrieved. Anthropometric and biochemical data were collected from the hard copy archive. Indexes of insulin resistance (HOMA-IR), insulin sensitivity (WBISI), and insulin secretion (Insulinogenic Index, Disposition Index) were calculated. RESULTS: Of the 244 records analyzed, 215 fulfilled criteria for NGT and had complete biochemical data. Among NGT patients, 42 (19.5%) showed 1hPG ≥ 132.5 mg/dL (high-NGT), while the remaining had 1hPG < 132.5 mg/dL (low-NGT). The high-NGT group showed a higher male prevalence (59.5 vs 37%), lower Disposition Index (0.54 [0.39-0.71] vs 0.79 [0.47-1.43]), and WBISI (0.24 [0.18-0.35] vs 0.33 [0.23-0.50]) than the low-NGT group. High-NGT subjects also showed a trend towards lower HDL-cholesterol and higher triglycerides/HDL-cholesterol ratio (2.13 [1.49-3.41] vs 1.66 [1.24-2.49]). CONCLUSIONS: In overweight/obese NGT Caucasian youth a 1hPG ≥ 132.5 mg/dL was able to identify those with impaired insulin sensitivity and secretion and a trend towards a worse cardio-metabolic profile, a group likely at risk for future T2D.

Background: Gastrointestinal hormones, such as glucagon-like peptide (GLP-1), have been hypothesized to play a role in the pathogenesis of obesity-related complications. However, few data are available in youth. The objective of this study was to investigate the GLP-1 response to oral glucose load in obese pre-pubertal children and its relationship with insulin secretion. Methods: Ten pre-pubertal obese children [five boys; 10.5±1.6 years; body mass index-standard deviation score (BMI-SDS): 2.2±0.5] and 10 controls (eight boys; 9.9±1.2 years; BMI-SDS: –0.7±0.5) underwent a modified oral glucose tolerance test (OGTT) to evaluate post-load glucose, insulin and GLP-1 responses. Insulin sensitivity [homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and secretion [HOMA-beta, insulinogenic index (IGI)] indexes, area under the curve (AUC) for glucose, insulin and GLP-1 were calculated. Results: In obese children GLP-1 AUC values were higher and correlated with BMI-SDS (r=0.45; p=0.04), HOMA-IR (r=0.53; p=0.01) and fasting glucose (r=0.68; p=0.001). Conclusions: Obese children showed an increased GLP-1 response to oral glucose. These changes might likely represent a compensatory mechanism to avoid post-prandial hyperglycemia and allow a normal glucose tolerance.

NA

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.

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.

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.

Hyperglycemia is due to a dysregulation in the complex mechanisms implicated in glucose homeostasis. Chronic hyperglycemia, as measured by hemoglobin A1c (HbA1c), is a key risk factor for the development of microvascular and macrovascular complications, which in turn negatively influence the prognosis of patients with diabetes. Several studies have shown that acute hyperglycemia can add to the effect of chronic hyperglycemia in inducing tissue damage. Acute hyperglycemia can manifest as high fasting plasma glucose (FPG) or high postprandial plasma glucose (PPG) and can activate the same metabolic and hemodynamic pathways as chronic hyperglycemia. Glucose variability, as expressed by the intraday glucose fluctuations from peaks to nadirs, is another important parameter, which has emerged as an HbA1c-independent risk factor for the development of vascular complications, mainly in the context of type 2 diabetes. Treatments able to decrease HbA1c have been associated with positive effects in terms of reducing risk for the development and progression of complications. Further studies are required to clarify the impact of strategies more specifically targeting components of acute hyperglycemia, to improve outcomes in patients with diabetes.

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.