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.

Role of the KCNJ Gene Variants in the Clinical Outcome of Type 1 Diabetes.

Diabetes is considered as a disease with a wide and continuous clinical spectrum, ranging from Type 1 (T1D) and Type 2 Diabetes (T2D) with complex multifactorial causes. In the last years, particular attention has been focused on the predictive value and therapeutic potential of single nucleotide polymorphisms (SNPs). SNPs can alter the seed-sequence in miRNA's loci and miRNA target sites causing changes in the structure and influencing the binding function. Only few studies have investigated the clinical influence of SNPs, in particular potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ) gene variants in T1D population. The aim of the study is to investigate the occurrence and the possible metabolic significance of KCNJ polymorphism in a group of pediatric patients with T1D. The study was performed in a cohort of 90 Caucasian children and adolescents with T1D and 93 healthy subjects. Rs5210 polymorphism has been analyzed with a prevalence of the GG genotype in the patient group suggesting its association with T1D. Therefore, a relationship was found between GG genotype and body mass index (BMI) at diagnosis and insulin requirement (IR) after 6 months. The study suggested an action for rs5210 in determining the metabolic features of T1D pediatric patients, by showing some clues of insulin resistance in patients carrying that polymorphism.

Nutrition and growth in children.

The well-balanced nourishment during "the first 1000 days," the period between conception (day 18) and the age of two years, is quite important for two main reasons. Firstly, the nutritive requirement is high due to the rapid physiological growth and functional development. Then, this period is characterized by extreme susceptibility to external stimuli such as inadequate maternal and infant nutritional status which they can interfere with the different stages of the development process leading to short and long-term consequences for health. Linear growth and brain development are particularly impaired from not sufficient nutrition. In consideration of the irreversible damage of malnutrition, especially on developing brain, an adequate nutrition during the first 1000 days of life is paramount. The aim of this review was to overview the latest scientific evidences on the relationship between nutrition and growth, focusing on nutritional requirements during the first 1000 days, and the impact of inadequate nutrition on brain development and linear growth.

Ciliopathies in pediatric endocrinology.

Ciliopathies are a group of disorders that involve many organs and systems. In this review, we consider the role of the cilium in multiorgan pathology with a focus on endocrinological aspects. Identification of new genes and mutations is the major challenge in development of a tailored and appropriate therapy. It is expected that new mutations will be identified to characterize ciliopathies and promote new therapies.

Primary prevention programs for childhood obesity: are they cost-effective?

Childhood obesity is increasing all over the world. It is associated with a reduction in quality of life and a relevant burden on society costs. This systematic review deals with the cost-effectiveness analysis (CEA) of primary prevention programs on childhood overweight/obesity, in order to benefit from cost-effective interventions.We screened and evaluated all the studies with a cost-effectiveness analysis on childhood obesity primary prevention program by PUBMED and Google Scholar, using inclusion and exclusion criteria. The quality of the studies was assessed by Drummond's checklist.Ten studies were included. Two of them examined the cost-effectiveness of community-based prevention programs, four focused only on school-based programs while four more studies examined both community-based and school-based programs. The studies were different in terms of study design, target population, health and economic outcomes. Seventy per cent of the works had positive economic results.The majority of the studies showed effective economic outcomes applying primary prevention programs on childhood obesity. It is important to increase homogeneity and consistency among different studies.

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.

Diet and Glycemic Index in Children with Type 1 Diabetes.

In children with type 1 diabetes, a healthy lifestyle is important to control postprandial glycemia and to avoid hyperglycemic peaks that worsen the inflammatory state of vessels and tissues. Glycemic index and glycemic load are two important indexes which assess the quality and quantity of foods consumed during meals. The main macronutrients of the diet have a different effect on postprandial blood glucose levels, so it is important that diabetic children consume foods which determine a slower and steadier glycemic peak. In this review, we present the results of the most recent studies carried out in the pediatric population with T1D, whose aim was to analyze the effects of low-glycemic-index foods on glycemic control. The results are promising and demonstrate that diets promoting low-glycemic-index foods guarantee a greater glycemic stability with a reduction in postprandial hyperglycemic peaks. However, one of the main limitations is represented by the poor adherence of children to a healthy diet. In order to obtain satisfactory results, a possibility might be to ensure a balanced intake of low-, moderate- and high-glycemic-index foods, preferring those with a low glycemic index and limiting the consumption of the high- and moderate-glycemic-index types.

Hypoglycemia in Children: Major Endocrine-Metabolic Causes and Novel Therapeutic Perspectives.

Hypoglycemia is due to defects in the metabolic systems involved in the transition from the fed to the fasting state or in the hormone control of these systems. In children, hypoglycemia is considered a metabolic-endocrine emergency, because it may lead to brain injury, permanent neurological sequelae and, in rare cases, death. Symptoms are nonspecific, particularly in infants and young children. Diagnosis is based on laboratory investigations during a hypoglycemic event, but it may also require biochemical tests between episodes, dynamic endocrine tests and molecular genetics. This narrative review presents the age-related definitions of hypoglycemia, its pathophysiology and main causes, and discusses the current diagnostic and modern therapeutic approaches.

Simultaneous onset and similar course of type 1 diabetes mellitus in monozygotic twins (a 4-year follow-up).

We report a rare case of monozygotic (MZ) twins who developed simultaneous onset of type 1 diabetes mellitus (T1DM). Laboratory finding showed similar values of blood sugar, pH, glycosylated hemoglobin, and C-peptide. Urinary sugar and ketones were detected in both. Endocrine and immunological assessment showed similar results. No evidence (clinical or serological) of recent viral or bacterial infection was found. In the 4 years of follow-up, the twins also showed a similar course of disease. Concordance rates for T1DM are high in MZ twins; nevertheless, a simultaneous onset and a similar course of disease are unusual, as well as the HLA allelic variants of our patients. This extraordinary concordance in a pair of MZ twins could be the consequence of a greater environmental similarity or the role of genetic factors other than HLA genes in our twins.

Peculiar characteristics of new-onset Type 1 Diabetes during COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic period is having a strong impact on the management of diabetes as well as other chronic diseases as shown by the most severe clinical presentation at onset. The aim of this study was to evaluate the severity of diabetic ketoacidosis (DKA) in youth with newly diagnosed type 1 diabetes in "Santissima Annunziata Hospital" (Chieti, Italy) during COVID-19 pandemic in comparison to the five previous years. METHODS: A retrospective population-based incidence study was performed. Data were obtained from hospital records of 172 patients with new onset type 1 diabetes divided into two groups according to the diagnosis: Group I, between January 2015 and February 2020; Group II, between March 2020 and April 2021. Data regarding anthropometric, socio-economic and laboratory test were analyzed. DKA (pH < 7.30) and different severity of the disease (severe pH < 7.10; moderate pH < 7.20, mild pH < 7.30) were evaluated. A Spearman correlation between pH values and the main variables of interest was performed. RESULTS: DKA frequency was increased by 19 percentage in Group II compared to Group I (55% vs 36%; P = 0.03) with a significant increased risk of severe DKA cases compared to the previous five years (severe DKA 22.5% vs. 8.4%, P = 0.01). pH values were significantly related with HbA1c, blood glucose and c-peptide values in all groups. In addition, in Group II but not in Group I, pH values correlated with Triglycerides and TG/HDL cholesterol ratio. CONCLUSIONS: During COVID-19 pandemic the risk of more severe clinical presentation of type 1 diabetes at onset is increased. The correlation with lipid profile might suppose an additional effect of lifestyle changes beside the delay in the diagnosis. Modifications of health care system need to be implemented during this peculiar situation in order to avoid such a relevant complication at onset.

Role of Prenatal Nutrition in the Development of Insulin Resistance in Children.

Nutrition during the prenatal period is crucial for the development of insulin resistance (IR) and its consequences in children. The relationship between intrauterine environment, fetal nutrition and the onset of IR, type 2 diabetes (T2D), obesity and metabolic syndrome later in life has been confirmed in many studies. The intake of carbohydrates, protein, fat and micronutrients during pregnancy seems to damage fetal metabolism programming; indeed, epigenetic mechanisms change glucose-insulin metabolism. Intrauterine growth restriction (IUGR) induced by unbalanced nutrient intake during prenatal life cause fetal adipose tissue and pancreatic beta-cell dysfunction. In this review we have summarized and discussed the role of maternal nutrition in preventing insulin resistance in youth.

Variables associated with severe hypoglycemia in children and adolescents with type 1 diabetes: a population-based study.

OBJECTIVE: Hypoglycemia remains a central problem in the management of type 1 diabetes mellitus (T1DM) and limits the achievement of good or normal glycemic control. The Diabetes Control and Complication Trial showed that intensive treatment of T1DM increased the risk of severe hypoglycemia (SH) when compared to conventional therapy. The aim of our study was to determine the incidence of SH and associated variables in a population of children and adolescents with T1DM. RESEARCH DESIGN AND METHODS: We performed a 7.5-yr prospective study enrolling 195 patients aged 13.9 ± 6.6 yr. The study was carried out by referring to the T1DM population-based register in the Abruzzo region of Italy. The incidence of SH, defined as blood glucose levels <50 mg/dL (<2.77 mmol/L) associated with altered states of consciousness (including confusional state, seizures, and coma) was recorded. Glycated hemoglobin (HbA1c) percentage, insulin dose, insulin regimen, time since diagnosis, and age at onset were also recorded. RESULTS: One hundred and thirty-three severe hypoglycemic events occurred during the study period; the overall incidence was 9.4 episodes per 100 patient-years. Significant predictors of hypoglycemia were diabetes duration >10 yr (p = 0.01), basal/bolus insulin ratio (ratio of daily basal insulin units to daily bolus insulin units) >0.8 (p = 0.01). No relationship was found between hypoglycemic episodes and HbA1c levels, daily insulin requirements, or insulin regimen. CONCLUSIONS: In these patients, a relatively low incidence of SH was recorded, without pronounced association with lower HbA1c or multiple daily injection insulin therapy. SH seems to be mainly related to management of diabetes. We believe that the main path to SH prevention is through patient and family education in the management of T1DM.

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.

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 oxidative stress in prepubertal children born small for gestational age.

CONTEXT: Low birth weight is associated with an increased risk of metabolic and cardiovascular diseases in adulthood. The development of insulin resistance (IR) seems to play a pivotal role; no data on the oxidant-antioxidant status are available in this risk group. OBJECTIVE: This study is an assessment of oxidant-antioxidant status in prepubertal children born small for gestational age (SGA) in comparison to healthy controls and the relationship to IR. DESIGN: This cross-sectional study compares indexes of IR and oxidant-antioxidant status in three different groups (SGA+, SGA-, controls), with analysis by post hoc and Pearson correlation. SETTING: The study was conducted in the Academic Department of Pediatrics. PARTICIPANTS: A total of 19 SGA+ and 16 SGA- children were compared with 13 controls. INTERVENTION: No intervention was used. MAIN OUTCOME MEASURES: Indexes of IR (glucose to insulin ratio, homeostasis model assessment of IR) were evaluated, and markers of oxidative stress (lag phase, malonildialdehyde, vitamin E) were measured. RESULTS: Homeostasis model assessment of IR was significantly higher in SGA+ than SGA- children (1.32+/-0.9 vs. 0.69+/-0.47; P=0.03) and controls (0.71+/-0.37; P=0.04). Glucose to insulin ratio was significantly lower in SGA+ than SGA- children (12.41+/-5.01 vs. 26.54+/-17.18; P=0.02) and controls (26.96+/-20.70; P=0.04). Lag phase was significantly shorter in SGA+ than SGA- children (24.3+/-4.38 vs. 35.59+/-11.29 min; P=0.003) and controls (45.28+/-7.69 min; P=0.0001) and in SGA- than controls (P=0.01). Malonildialdehyde was significantly higher in SGA+ than SGA- children (0.79+/-0.3 vs. 0.6+/-0.1 nmol/mg; P=0.03) and controls (0.36+/-0.04 nmol/mg; P=0.0001) and in SGA- children than controls (P=0.02). Vitamin E was significantly reduced in SGA+ children than controls (27.54+/-7.9 vs. 43.23+/-11.32 micromol/liter; P=0.002). CONCLUSION: Oxidative stress is present in both SGA+ and SGA- children, with a continuous alteration in relation to IR. Therefore, catch-up growth might exert the greatest influence in the development of future diseases.

Miller Fisher syndrome and Escherichia coli infection: is it a novel association?

Miller Fisher syndrome is characterized by ataxia, ophthalmoplegia, and reduced or absent tendon reflexes. Generally, it is considered an acute postinfectious paralytic illness caused by a wide variety of infections including Campylobacter jejuni. The authors report the case of a 10-year-old girl with Miller Fisher syndrome who had a previous infection of Escherichia coli. If confirmed by other reports, this report could disclose a new association of Miller Fisher syndrome with E coli infection.

C1858T Polymorphism of Protein Tyrosine Phosphatase Non-receptor Type 22 (PTPN22): an eligible target for prevention of type 1 diabetes?

INTRODUCTION: In type 1 diabetes (T1D), several genetic factors are associated to ß-cell autoimmunity onset and clinical progression. HLA-genes play a major role in susceptibility and initiation of ß-cell autoimmunity, whereas non-HLA genes may influence the destruction rate. Areas covered: Our review focuses on the possible role of the PTPN22 C1858 T variant as a prognostic factor, given its influence on disease variability. Moreover, we present the potential role of C1858 T as a target for tertiary prevention trials and new therapeutic strategies, such as the LYP inhibitors. We used PubMed for literature research; key words were 'PTPN22', 'C1858 T polymorphism', 'lymphoid-specific tyrosine phosphatase' and 'type 1 diabetes'. We selected publications between 2000 and 2016. Expert commentary: Current data suggest that PTPN22 can be a promising target for therapeutic interventions and identification of at-risk subjects in autoimmune diseases such as T1D.

Effects of irbesartan on intracellular antioxidant enzyme expression and activity in adolescents and young adults with early diabetic angiopathy.

OBJECTIVE: Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with diabetic nephropathy. The objective of this study was to evaluate the effects of irbesartan, an angiotensin II receptor antagonist, on IAP in adolescents and young adults with type 1 diabetes and early signs of retinopathy and nephropathy. RESEARCH DESIGN AND METHODS: This prospective, matched case-control study was conducted between November 2001 and December 2002 among 14 type 1 diabetic patients with early signs of angiopathy (ages 14-21 years), 11 type 1 diabetic patients without angiopathy (ages 12-22 years), and 10 healthy volunteers (ages 16-22 years). Skin fibroblasts were obtained by skin biopsies from the anterior part of the forearm and cultured in Dulbecco's modified Eagle's medium. The activity and mRNA expression of CuZn superoxide dismutase (CuZnSOD), Mn superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX) were measured before and after 6 months of treatment with irbesartan (150 mg/day); on both occasions, antioxidant enzyme activity was evaluated at different glucose concentrations (5 and 22 mmol/l). RESULTS: At a normal glucose concentration (5 mmol/l), the activity and mRNA expression of CuZnSOD (0.50 +/- 0.21 units/mg protein, 4.4 +/- 1.5 mRNA/glyceraldehyde-3-phosphate dehydrogenase), MnSOD (0.26 +/- 0.04 units/mg protein, 0.08 +/- 0.07 mRNA), CAT (0.32 +/- 0.08 units/mg protein, 4.8 +/- 1.3 mRNA), and GPX (0.53 +/- 0.09 units/mg protein, 2.2 +/- 0.9 mRNA) were not different among the three groups (only values of diabetic subjects with angiopathy are shown). At high glucose concentrations, the activity and mRNA expression of CuZnSOD increased similarly in all groups (diabetic subjects with angiopathy: 0.93 +/- 0.26 units/mg protein, 9.4 +/- 2.1 mRNA); that of CAT and GPX increased in only control subjects and diabetic subjects without angiopathy (diabetic subjects with angiopathy: 0.33 +/- 0.09 units/mg protein and 5.0 +/- 1.4 mRNA; 0.54 +/- 0.10 units/mg protein and 2.3 +/- 1.0 mRNA, respectively). MnSOD did not change in any group. Treatment with irbesartan in adolescents with diabetic angiopathy was able to restore CAT and GPX activity and mRNA expression after exposure to high glucose concentrations. Markers of oxidative stress (serum malondialdehyde, fluorescent products of lipid peroxidation, monocyte chemoattractant protein-1, and 8-isoprostanes prostaglandin F(2alpha)) were significantly reduced after treatment with irbesartan. CONCLUSIONS: Adolescents and young adults with early signs of diabetic angiopathy have defective intracellular antioxidant enzyme production and activity. Treatment with irbesartan can substantially improve the activity and production of these enzymes in skin fibroblasts.

Role of nutrition in preventing insulin resistance in children.

Nutrition during prenatal, early postnatal and pubertal period is crucial for the development of insulin resistance and its consequences. During prenatal period fetal environment and nutrition seems to interfere with metabolism programming later in life. The type of dietary carbohydrates, glycemic index, protein, fat and micronutrient content in maternal nutrition could influence insulin sensitivity in the newborn. The effects of lactation on metabolism and nutritional behavior later in life have been studied. Dietary habits and quality of diet during puberty could prevent the onset of a pathological insulin resistance through an adequate distribution of macro- and micronutrients, a diet rich in fibers and vegetables and poor in saturated fats, proteins and sugars. We want to overview the latest evidences on the risk of insulin resistance later in life due to both nutritional behaviors and components during the aforementioned periods of life, following a chronological outline from fetal development to adolescence.