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There has been continuous progress in diabetes management over the last few decades, not least due to the widespread dissemination of continuous glucose monitoring (CGM) and automated insulin delivery systems. These technological advances have radically changed the daily lives of people living with diabetes, improving the quality of life of both children and their families. Despite this, hypoglycemia remains the primary side-effect of insulin therapy. Based on a systematic review of the available scientific evidence, this paper aims to provide evidence-based recommendations for recognizing, risk stratifying, treating, and managing patients with hypoglycemia. The objective of these recommendations is to unify the behavior of pediatric diabetologists with respect to the timely recognition and prevention of hypoglycemic episodes and the correct treatment of hypoglycemia, especially in patients using CGM or advanced hybrid closed-loop systems. All authors have long experience in the specialty and are members of the Italian Society of Pediatric Endocrinology and Diabetology. The goal of treating hypoglycemia is to raise blood glucose above 70 mg/dL (3.9 mmol/L) and to prevent further decreases. Oral glucose at a dose of 0.3 g/kg (0.1 g/kg for children using “smart pumps” or hybrid closed loop systems in automated mode) is the preferred treatment for the conscious individual with blood glucose

Background/Objectives: The pediatric definition of severe obesity (OB) depends on the body mass index (BMI) references. We evaluated different BMI-derived metrics of the World Health Organization (WHO) system to define which cut-off is associated with the highest cardiometabolic risk (CMR); Methods: In this multicentric study, data were retrieved for 3727 youths (1937 boys; 2225 children, 1502 adolescents). OB was defined as BMI > 97th percentile (BMI97th), severe OB was defined as BMI > 99th percentile (BMI99th), BMI ≥ 120% of the 97th percentile (120% BMI97th), or BMI Z-score > 3 (WHO tables), or BMI ≥ the International Obesity Task Force (IOTF) value crossing a BMI of 35 kg/m2 at the age of 18 (IOTF35). The continuous CMR Z-score (sum of residual standardized for age and sex of waist-to-height ratio, systolic and diastolic blood pressure, triglycerides, and HDL-cholesterol x −1) and the cluster of at least two CMR factors (hypertension, high triglycerides, low HDL-cholesterol, and high waist-to-height ratio) were calculated. Results: Continuous CMR Z-score was significantly higher both in children or adolescents with severe OB defined by 120% BMI97th compared to BMI99th (p < 0.0001), while it was lower only in adolescents with severe OB defined by 120% BMI97th compared to BMI Z-score >3 (p < 0.0001). Compared to 120% BMI97th, BMI Z-score > 3 and IOTF35 had higher specificity, but lower sensitivity in identifying children and adolescents with clustered CMR factors. Conclusions: The definition of severe OB based on 120% BMI97th is superior to BMI99th but it is inferior to BMI Z score > 3 as far as the association between severe OB and CMR factors is concerned. Pediatricians should take into consideration the implication of the use of different BMI metrics in those countries that recommend the WHO system. WHO BMI Z-score > 3 and IOTF35 can be used interchangeably to predict cardiometabolic risk. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus (T1DM) and congenital adrenal hyperplasia (CAH) are 2 complex endocrine disorders with neighboring genetic loci. We present a case of T1DM onset in a 6-year-old child, already affected by 21-hydroxylase deficiency (salt-wasting CAH) diagnosed at 18 days of age, who was referred to our clinic because of typical symptoms of diabetes despite nondiagnostic fasting blood glucose values. Further analysis revealed elevated glycated hemoglobin (HbA1c), low C-peptide, and specific autoantibodies suggesting the diagnosis of T1DM. Although he only started with rapid-acting insulin analogue before meals, he presented spontaneous episodes of hypoglycemia just before the morning hydrocortisone dose, due to an underdosed glucocorticoid intake. Based on continuous glycemic monitoring (CGM), his morning dose was increased and given earlier; then we decided to apply an advanced hybrid closed-loop insulin pump to maintain glycemic time in range above 70%. Fasting glucose in CAH patients can be lower due to underdosed glucocorticoid replacement therapy. HbA1c and CGM can help recognize T1DM onset and evaluate the correct dosage of corticosteroid therapy in CAH patients. New studies are needed to understand the therapeutic approach for a more specific treatment in case of coexistence of these diseases. [ABSTRACT FROM AUTHOR]

Background: Reduced central sensitivity to thyroid hormones (THs) has been observed in euthyroid adults with reduced renal function. This topic is unexplored in young people with overweight or obesity (OW/OB). Objective: The aim of this study was to evaluate the association between sensitivity to TH and mild reduced estimated glomerular filtration rate (MReGFR) in euthyroid children and adolescents with OW/OB. Methods: Data of 788 euthyroid children and adolescents with OW/OB (aged 6–16 years), recruited from seven Italian centers for the care of OW/OB, were evaluated. Peripheral sensitivity to TH was estimated through the FT3/FT4 ratio, while central sensitivity was assessed by estimating TSH index (TSHI), thyrotroph T4 resistance index, thyroid feedback quantile-based index (TFQI), parametric thyroid feedback quantile-based index (PTFQI). MReGFR was defined by an eGFR value ≥60 and <90 mL/min/1.73 m2. Results: Subjects with MReGFR had significantly lower levels of FT3/FT4 ratio (0.43 ± 0.09 vs. 0.44 ± 0.10; p = 0.028) and higher levels of TSH (2.89 ± 1.00 vs. 2.68 ± 0.99; p = 0.019), TSHI (2.95 ± 0.45 vs. 2.85 ± 0.55; p = 0.031), TFQI [1.00 (0.98–1.00) versus 1.00 (0.97–1.00); p = 0.046], and PTFQI (0.66 ± 0.17 vs. 0.60 ± 0.23; p = 0.006) compared with individuals with normal eGFR. Odds ratio of MReGFR raised of 1.2–3.2-fold for each increase of 1 mIU/L in TSH, 1 unit in TSHI, and PTFQI, but not for FT3/FT4 ratio. Conclusion: MReGFR is associated with reduced indices of central sensitivity to TH in euthyroid children and adolescents with OW/OB. This preliminary observation should be confirmed in prospective studies. [ABSTRACT FROM AUTHOR]

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δ‐nitro dienes were successfully synthesized and converted to δ‐nitro alkenes with complete chemo and regioselectivity. The enantioselective organocatalytic reduction was also accomplished and afforded the product in up to 97 % e.e. The chiral nitro alkene was further elaborated and employed as starting material in a stereoselective cyclization reaction that led to an almost enantiomerically pure highly functionalised cyclopentane featuring 5 contiguous stereocenters. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD.sup.+) is a co-substrate for several enzymes, including the sirtuin family of NAD.sup.+-dependent protein deacylases. Beneficial effects of increased NAD.sup.+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that [alpha]-amino-[beta]-carboxymuconate-[epsilon]-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of [alpha]-amino-[beta]-carboxymuconate-[epsilon]-semialdehyde in the de novo NAD.sup.+ synthesis pathway, controls cellular NAD.sup.+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD.sup.+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. We also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, we identify ACMSD as a key modulator of cellular NAD.sup.+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.Genetic or pharmacological inhibition of [alpha]-amino-[beta]-carboxymuconate-[epsilon]-semialdehyde decarboxylase increases NAD.sup.+ and improves mitochondrial function in nematodes and mice, and may have therapeutic potential in kidney and liver disease., Author(s): Elena Katsyuba [sup.1] , Adrienne Mottis [sup.1] , Marika Zietak [sup.2] [sup.3] , Francesca De Franco [sup.4] , Vera van der Velpen [sup.5] , Karim Gariani [sup.1] [sup.11] , [...]