Role of glucose variability on linear growth in children with type 1 diabetes.

Objective: Linear growth is impaired in children with type 1 diabetes (T1D) and poor metabolic control. A good metabolic control is a key therapeutic goal to prevent vascular complications and also to ensure appropriate anthropometric development during childhood. In this study, we aimed to identify and characterize the effects of glycemic variability on linear growth in children with T1D. Methods: Data from 144 prepubertal children with T1D were evaluated. Anthropometric measurements (weight, weight-SDS, height, height-SDS, BMI, BMI-SDS) were collected and glycosylated hemoglobin (HbA1c) was measured at admission and every 4 months over a 2-year period. Glycemic variability indexes (glycemic coefficient of variation (CV), glycemic CV percentage (CV%), and the product between HbA1c-mean and HbA1c-SDS/100 (M*SDS-HbA1c/100)) were calculated. According to height-SDS changes after 2 years of follow-up, the study population was divided into three tertile groups and differences across groups were investigated for variables of interest. Results: The three groups were similar in terms of age, gender, and follow-up period. After 2 years, all prepubertal children showed a significant positive trend of anthropometric data. Across the three tertile groups, HbA1c-SDS, CV, CV%, and M*SDS-HbA1c significantly decreased from the first to the third tertile of height-SDS. During follow-up, children with lower Δheight-SDS values reported higher values of HbA1c-SDS, CV, CV%, and M*SDS-HbA1c than subjects with higher linear growth. Conclusions: Glycemic variability correlates with linear growth in children with T1D. Low glycemic variability indexes were reported in higher height-SDS tertiles. Δheight-SDS is inversely correlated with glycemic CV, CV%, and M*SDS-HbA1c.

Insulin resistance relates to DKA severity and affects insulin requirement in children with type 1 diabetes at onset.

BACKGROUND: Fluid and insulin treatments are the cornerstones of DKA management and indications on dosages are available. However, according to possible confounding factors, relevant data are still required to explain the different insulin dosages adopted at diabetes onset, particularly based upon insulin sensitivity. OBJECTIVE: We aimed to explore whether DKA severity is related to different insulin sensitivity states, thus resulting in different insulin requirement at diabetes onset. METHODS: Retrospective data from hospital records of 62 newly diagnosed children with type 1 diabetes with DKA were analyzed. The population was divided into three groups: severe, moderate, and mild DKA. Anthropometric, laboratory test, insulin, and glucose administration data were analyzed. The Glucose Infusion Rate (GIR), Insulin Infusion Rate (IIR), and GIR/IIR were calculated and used as indexes of insulin sensitivity. The area under the curve (AUC) for insulin and glucose infusion was calculated. RESULTS: Moving among the three groups, IIR decreased while GIR and GIR/IIR increased from severe to mild DKA group (all p < 0.01). A similar trend was documented for AUC-insulin and AUC-glucose as well as AUC-glucose/AUC-insulin ratio. The Spearman correlation showed a negative correlation between pH and both IIR and AUC-Insulin as well as a positive correlation between pH and both GIR/IIR and AUC-glucose/AUC-insulin ratio. CONCLUSIONS: Subjects with severe DKA have a higher insulin requirement compared to those with less severe DKA. Significant differences in terms of insulin sensitivity might be documented according to the severity of DKA, which might result in tailored insulin pH requirement in children with new onset type 1 diabetes.

Metabolic dysfunction-associated fatty liver disease in obese youth with insulin resistance and type 2 diabetes.

PURPOSE OF REVIEW: The aim of this review is to present the new definition of the disease, defining the epidemiology, risk factors with a particular attention to the role of insulin resistance (IR) and to define the main treatments explored. RECENT FINDINGS: Nonalcoholic fatty liver disease (NAFLD) was previously considered a primary liver disease, but it would be more correct to consider it a component of the metabolic syndrome (MetS) in which IR might play a key role. Based on these findings, it has been recently proposed to modify the classic term of NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) that better reflects the pathophysiology of this complex disease. SUMMARY: Currently, no treatments approved in childhood are available, thus the only recommended approach is the prevention and correction of the known risk factors, and particularly of IR. However, further studies are needed to better clarify the pathogenetic mechanisms of NAFLD in order to establish more tailored therapies.

The bad rainbow of COVID-19 time: effects on glucose metabolism in children and adolescents with obesity and overweight.

BACKGROUND: COVID-19 restriction measurements have enhanced the obesity status in the pediatric population which might further contribute to obesity-related glucose-insulin metabolism alterations. Therefore, we retrospectively compared anthropometric and OGTT data on children with obesity during the 13 years before and during the COVID-19 pandemic. SUBJECTS/METHODS: Data from 741 children with obesity and overweight were retrieved and clustered into seven groups starting from year 2008-2009 until 2020-2021. Differences in anthropometric measurements and glucose/insulin metabolism were evaluated between the different groups. RESULTS: Children with overweight and obesity in the COVID-19 restriction group did not present increased values of SDS-Body Mass Index (BMI). Significantly higher values for Waist Circumference (WC), SDS-WC, Waist/Height ratio (WHtR), and body mass fat were detected in these children (all P < 0.01). Fasting glycaemia, glucose, and insulin excursions were significantly higher compared to pre- pandemic children (all P < 0.01). Insulin resistance was higher while insulin secretion was lower (all P < 0.01) determining a significantly higher percentage of impaired glucose tolerance in the COVID-19 restriction group (P < 0.002). Furthermore, High-Density Lipoprotein (HDL) cholesterol was significantly lower (P < 0.01) and SDS for systolic and diastolic blood pressure values were significantly higher (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: COVID-19 restriction measurements determined profound alterations in glucose and insulin metabolism in children with obesity and overweight. Urgent strategies are needed in order to reverse COVID-19 restriction measures' effects on glucose and insulin metabolism.

Metabolic Changes across Tertiles of Delta Changes in Height SDS during Growth Hormone Therapy in Children with Growth Hormone Deficiency.

INTRODUCTION: Obesity, dyslipidemia, hypertension, and insulin resistance are components of the metabolic syndrome and in adults are positively affected by growth hormone (GH) treatment. Few data are available on youth, especially evaluating the improvement of metabolic features after starting GH treatment. The aim of this study was to evaluate changes in metabolic profile in GHD children across tertiles of h-SDS changes after at least 20 months of GH therapy. METHODS: Data from 51 normal-weight children and adolescents with GHD (age: 11.4 ± 2.3 years; h-SDS: -2.25 ± -1.94) who had performed a complete metabolic profile including IGF-1, lipid profile (total cholesterol, triglycerides, HDL cholesterol), glucose metabolism (fasting glycemia, insulin, hemoglobin A1c levels), and insulin resistance indices (HOMA, TG/HDL ratio) before and after start GH treatment were analyzed. Subjects who had received GH therapy for at least 20 months were eligible. Delta changes were calculated for each variable. Subjects were divided according to tertiles of delta changes of h-SDS (1st tertile, 2nd tertile, 3rd tertile) before and after a period of GH treatment. RESULTS: In each tertile group, a significant increase in height SDS was documented. Delta changes in glucose metabolism, lipid profile, and insulin resistance indices significantly improved across tertiles groups, showing the highest tertile a better metabolic pattern. DISCUSSION/CONCLUSIONS: GH therapy is associated with improvement of metabolic profile. Delta changes seem to be more evident in those children with a higher tertile of delta h-SDS after starting GH therapy. A tailored therapy aimed to reach a proper goal in h-SDS after GH treatment might be necessary in order to reduce cardiovascular risk in GHD children.

Gut Hormones Secretion across Clusters of Metabolic Syndrome in Prepubertal Children with Obesity.

INTRODUCTION: Metabolic Syndrome (MetS) represents a common dysmetabolic state in children with obesity. Although data in youth show a role of gut hormones (GH) in the risk of developing MetS, no data are available during the prepubertal age, especially across clusters of MetS. METHODS: We characterized components of MetS and changes in GH concentrations in 90 prepubertal children with obesity compared to 30 healthy age- and gender-matched peers. Children with obesity were divided into three groups according to the number of the components of MetS (group 1: 30 obese without components of MetS; group 2: 30 obese with 1 component of MetS; group 3: 30 obese with 2 or more components of MetS). Anthropometric parameters, blood pressure (BP), fasting insulin and glycemia, lipid profile, transaminases, and GH concentration were determined. Differences across the groups were evaluated by the Kruskal-Wallis test and post hoc analysis by Mann-Whitney test. RESULTS: Fasting glycemia and insulin, HOMA-IR, triglycerides, and BP progressively increased and high-density lipoprotein progressively decreased across the groups of children with obesity compared to controls, showing worse values in group 3. GLP-1 and ghrelin values progressively decreased and obestatin progressively increased. The more components of the MetS were present, the further GH concentrations deviated from standard values. DISCUSSION AND CONCLUSION: Components of MetS and GH concentrations are impaired in prepubertal children with obesity compared to controls. The close association between progressive alterations in GH levels and increasing number of components of the MetS might indicate a role of these hormones in the determination of metabolic risk.

Amino Acid-Related Metabolic Signature in Obese Children and Adolescents.

The growing interest in metabolomics has spread to the search for suitable predictive biomarkers for complications related to the emerging issue of pediatric obesity and its related cardiovascular risk and metabolic alteration. Indeed, several studies have investigated the association between metabolic disorders and amino acids, in particular branched-chain amino acids (BCAAs). We have performed a revision of the literature to assess the role of BCAAs in children and adolescents' metabolism, focusing on the molecular pathways involved. We searched on Pubmed/Medline, including articles published until February 2022. The results have shown that plasmatic levels of BCAAs are impaired already in obese children and adolescents. The relationship between BCAAs, obesity and the related metabolic disorders is explained on one side by the activation of the mTORC1 complex-that may promote insulin resistance-and on the other, by the accumulation of toxic metabolites, which may lead to mitochondrial dysfunction, stress kinase activation and damage of pancreatic cells. These compounds may help in the precocious identification of many complications of pediatric obesity. However, further studies are still needed to better assess if BCAAs may be used to screen these conditions and if any other metabolomic compound may be useful to achieve this goal.

Should obesogenic- effect be replaced with adipose tissue related alterations in childhood?

During the last year, primary prevention programs for childhood obesity have not obtained the goal in decreasing the prevalence of obesity in pediatric population. This phenomenon remains a crucial issue for the future translating itself in major health problems for the next young-adult generation. However ectopic adipose tissue distribution shows the same obesogenic effect also in slim people. Therefore, the use of adequate language is essential to develop consciousness of overall healthy lifestyle throughout the population. We therefore propone to replace "obesogenic effect" with adipose tissue related alterations also in childhood population.

Effects of Growth Hormone (GH) Supplementation on Dermatoscopic Evolution of Pigmentary Lesions in Children with Growth Hormone Deficiency (GHD).

Recent reports have confirmed higher levels of growth hormone (GH) receptor (GHR) transcripts in malignant melanomas (MM), yet the role of GH in the pathogenesis of MM remains controversial. Although melanocytes appear to be hormonally responsive, the effects of GH on MM cells are less clear. A direct correlation between GH administration and the development of melanoma seems possible. Our study aimed to assess whether GH supplementation in children with growth hormone deficiency (GHD) could induce changes in the melanocytic lesions both from a dimensional and dermoscopic point of view. The study population consisted of 14 patients sorted into two groups. The experimental group consisted of seven GHD pediatric patients who underwent dermatological examination with epiluminescence through the use of digital video recording of all melanocytic lesions before and after 12 months of GH supplementation, whilst the control group consisted of seven healthy pediatric patients matched for age, sex and phototype. All patients were evaluated according to auxological and dermatological features. A total of 225 melanocytic lesions were examined in the experimental group and 236 in the control group. Our study shows a significant increase in the mean size values of the lesions in the study group but not in the control group. Increases in the dermoscopic ABCD Score and in BMI correlated to an increase in the size of the melanocytic lesions and the dermoscopic parameters. The increase in SDS Height correlated with ABCD Score changes and with dermoscopic score structures. No differences were found compared to the control group. Dimensional/structural modifications in melanocytic lesions of patients treated with GH were closely related to weight and statural growth and can be considered a normal physiological process induced by GH supplementation.

Early Insulin Resistance, Type 2 Diabetes, and Treatment Options in Childhood.

BACKGROUND: Type 2 diabetes (T2D) represents just the tip of the iceberg of the complex metabolic alterations associated with obesity and other clinical conditions associated to impaired adipose tissue storage. SUMMARY: Available data have suggested the presence of a continuous spectrum of metabolic alterations developed in the progression from insulin resistance (IR) to T2D, most of which are likely preventable through the early characterization of all the multiple risk factors involved. Therefore, the complete characterization of the natural history of the disease and the major modifiable factors represents a milestone in the daily care of young subject at risk for the development of impaired glucose metabolism early in life. This review will focus on the main components defining the risk of IR and T2D in childhood with a specific focus on the main aspects of treatment options available in children and adolescents. KEY MESSAGES: Impaired adipose tissue storage documented in obesity results in a continuous spectrum of metabolic alterations ranging from IR to T2DM. These metabolic alterations are mostly likely preventable through the early characterization of all the multiple risk factors involved. The complete characterization of the disease and of the major modifiable factors represent a milestone in the daily care of young subject at risk for the development of impaired glucose metabolism early in life.

Increased hepcidin levels and non-alcoholic fatty liver disease in obese prepubertal children: a further piece to the complex puzzle of metabolic derangements.

INTRODUCTION: Several studies on obese youths and adults have reported increased hepcidin levels, which seems to be related to metabolic and iron metabolism alterations. The complete mechanisms involved in hepcidin increase remain to be elucidated, and particularly its role in the development of other known complications such as Nonalcoholic Fatty Liver Disease (NAFLD). NAFLD in prepubertal children might be of special interest in understanding the underlying mechanisms. METHODS: Anthropometric measurements, liver ultrasonography, lipid profile, liver function, oxidative stress, inflammatory state, and iron metabolism were studied in 42 obese prepubertal children and 33 healthy controls. We, therefore, evaluated the presence of possible correlations between Hepcidin and the other metabolic variables, and the possible association between NAFLD and iron metabolism. RESULTS: Hepcidin levels were significantly increased in the obese prepubertal children (p=0.001) with significant differences between obese children with and without NAFLD (p=0.01). Blood iron was lower in obese children (p=0.009). In the obese group, a negative correlation between hepcidin and both blood iron levels (p=0.01) and LagPHASE (p=0.02) was found. In addition, a positive association between hepcidin and NAFLD (p=0.03) was detected. CONCLUSIONS: We suggest that an increase in hepcidin levels may represent an early step in iron metabolism derangements and metabolic alterations, including NAFLD, in prepubertal obese children.

ABCD1 gene mutation in an Italian family with X-linkedadrenoleukodystrophy: case series.

SUMMARY: Adrenoleukodystrophy is a peroxisomal X-linked recessive disease caused by mutations in the ABCD1 gene, located on the X-chromosome (Xq28). Gene mutations in patient with adrenoleukodystrophy induce metabolic alterations characterized by impaired peroxisomal beta-oxidation and accumulation of very long chain fatty acid (VLCFA) in plasma and in all tissues. Although nutritional intervention associated with a various mixture of oil prevents the accumulation of VLCFA, to date no causal treatment is available. Therefore, haematopoietic stem cell transplantation (HSCT) and gene therapy are allowed only for very early stages of cerebral forms diagnosed during childhood.We reported a case series describing five family members affected by X-linked adrenoleukodystrophy caused by a novel mutation of the ABCD1 gene. Particularly, three brothers were affected while the sister and mother carried the mutation of the ABCD1 gene. In this family, the disease was diagnosed at different ages and with different clinical pictures highlighting the wide range of phenotypes related to this novel mutation. In addition, these characteristics stress the relevant role of early diagnosis to properly set a patient-based follow-up. LEARNING POINTS: We report a novel mutation in the ABCD1 gene documented in a family group associated to an X-ALD possible Addison only phenotype. All patients present just Addison disease but with different phenotypes despite the presence of the same mutations. Further follow-up is necessary to complete discuss the clinical development. The diagnosis of ALD needs to be included in the differential diagnosis in all patients with idiopathic PAI through accurate evaluation of VLCFA concentrations and genetic confirmation testing. Early diagnosis of neurological manifestation is important in order to refer timely to HSCT. Further follow-up of these family members is necessary to characterize the final phenotype associated with this new mutation.

Hyperglycaemic hyperosmolar state in an obese prepubertal girl with type 2 diabetes: case report and critical approach to diagnosis and therapy.

INTRODUCTION: Isolated Hyperosmolar Hyperglycaemic Syndrome (HHS) is a life-threatening condition characterized by elevated serum glucose concentrations and hyperosmolality without significant ketosis. It is often described in obese adults with unknown Type 2 Diabetes (T2D), rarely in youth. In childhood the most common cause of metabolic glucose related derangement is Diabetic Ketoacidosis (DKA) in Type 1 Diabetes (T1D). Interestingly, both components can be combined with each other, thus the prevalent condition needs to be recognised implying a different therapeutic approach. CASE PRESENTATION: In this case, we report a prepubertal Caucasian obese girl admitted for two episodes of combined HHS/DKA in order to elucidate her clinical course taking into account the current pediatric recommendations based on adult guidelines for HHS. CONCLUSIONS: The treatment of HHS and even more of HHS/DKA in youth is still controversial as no specific guidelines for children are available especially during the prepubertal age. The description of our case might be helpful and offer relevant points for future consensus.

Effects of Gluten-free Diet on Lipid Profile Risk Factors in Celiac Children.

Many studies raise concerns about the nutritional consequences of gluten-free diet. It has been documented that gluten-free (GF) foods have a higher glycemic index, saturated fats, and lower content of micronutrients determining important health implications. In this retrospective study, we evaluated the change in cardiometabolic risk factors in prepubertal celiac children in remission following different gluten-free diet regimes. Patients using processed GF foods showed a significant increase over time for standard deviation score-total cholesterol, standard deviation score-low density lipoprotein cholesterol, and fasting glycemia. These alterations were not confirmed in patients using naturally GF foods. Therefore, processed GF foods might promote unfavorable alterations of metabolic parameters, especially those associated with increased risk of cardiovascular diseases. Supervision of a dietitian and medical practitioner is recommended to ensure nutritional adequacy and monitoring of cardiovascular risk factors in this population.

Role of urinary NGAL and KIM-1 as biomarkers of early kidney injury in obese prepubertal children.

Objectives Childhood obesity is an important cause of end-stage renal disease. To date, available markers do not characterize kidney changes, especially in the early stages. kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are already detected before the onset of proteinuria or alterations of glomerular filtration rate and thus might represent biomarkers that directly reflect kidney injury. Methods We characterize kidney injury in a group of 40 obese-prepubertal children compared to 29-healthy age- and gender matched-peers. Anthropometric measurements and body composition were determined. Fasting blood samples were collected for measurement of insulin, glucose, lipid profile, transaminases, cystatin C and creatinine. Urine samples were collected to assess urinary NGAL, KIM-1 and urinary isoprostanes. Kidney length was measured with ultrasound evaluation. Differences between the two groups were evaluated by Mann-Whitney U test, and Spearman correlation analysis was used to explore relationship between variables. Results Triglycerides, alanine transaminase (ALT), glucose, insulin, homeostasis model assessment insulin resistance, triglycerides/high-density lipoprotein (HDL)-cholesterol ratio and cystatin C values were significantly higher in obese children than normal weight peers. Creatinine values were normal and similar between the two groups, while isoprostanes were higher in obese. Obese children had larger kidney sizes, indicating organ hypertrophy. NGAL and KIM-1 were increased in obese children compared to controls. A significant association between NGAL and KIM-1 with adiposity indices, insulin status and markers of oxidative stress postulated a possible effect of obesity in inducing kidney abnormalities. KIM-1 and NGAL are directly related respectively to cystatin C and isoprostanes, supporting the ability of these biomarkers in reflecting early kidney damages in obese subjects. Conclusions These findings suggest that obese subjects exhibit a certain degree of renal damage before kidney function loss.

Deciphering short stature in children.

Short stature is a common reason for referral to pediatric endocrinologists. Multiple factors, including genetic, prenatal, postnatal, and local environmental factors, can impair growth. The majority of children with short stature, which can be defined as a height less than 2 standard deviation score below the mean, are healthy. However, in some cases, they may have an underlying relevant disease; thus, the aim of clinical evaluation is to identify the subset of children with pathologic conditions, for example growth hormone deficiency or other hormonal abnormalities, Turner syndrome, inflammatory bowel disease, or celiac disease. Prompt identification and management of these children can prevent excessive short stature in adulthood. In addition, a thorough clinical assessment may allow evaluation of the severity of short stature and likely growth trajectory to identify the most effective interventions. Consequently, appropriate diagnosis of short stature should be performed as early as possible and personalized treatment should be started in a timely manner. An increase in knowledge and widespread availability of genetic and epigenetic testing in clinical practice in recent years has empowered the diagnostic process and appropriate treatment for short stature. Furthermore, novel treatment approaches that can be used both as diagnostic tools and as therapeutic agents have been developed. This article reviews the diagnostic approach to children with short stature, discusses the main causes of short stature in children, and reports current therapeutic approaches and possible future treatments.

Insulin resistance and type 2 diabetes in children.

Type 2 diabetes (T2D) is an emerging health risk in obese children and adolescents. Both environmental (lack of physical activity, excess nutritional intake, sedentary lifestyle) and genetic factors contribute to this global epidemic. The growing prevalence of T2D in youth is also associated with a consistently increased incidence of metabolic and cardiovascular complications. Insulin resistance (IR), i.e., whole-body decreased glucose uptake in response to physiological insulin levels, determines impaired glucose homeostasis and it is recognized as cardinal trigger of T2D and cardiovascular disease in both adults and children. In particular, IR and beta-cell dysfunction lead to the persistent hyperglycemia which characterizes T2D. Indeed, both pathological states influence each other and presumably play a crucial, synergistic role in the pathogenesis of T2D, although the precise mechanisms are not completely understood. However, beta-cell dysfunction and IR induce impaired glucose metabolism, thus leading to the progression to T2D. Therefore, understanding the mechanisms correlated with the decline of beta-cell function and IR is crucial in order to control, prevent, and treat T2D in youth. This review focuses on the current knowledge regarding IR and T2D in children and adolescents and showcases interesting opportunities and stimulating challenges for the development of new preventative approaches and therapeutic strategies for young patients with T2D.

Increased GLP-1 response to oral glucose in pre-pubertal obese children.

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.