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Background Sestrin2 and beclin1 are two newly found proteins that have essential roles in autophagy. This study attempted to evaluate the plasma concentrations of sestrin2 and beclin1 in women with polycystic ovary syndrome (PCOS) and healthy controls and to explore the clinical value of these proteins as novel biomarkers for PCOS. Methods In this case‐control study, plasma levels of sestrin2 and beclin1, fasting blood sugar (FBS), lipid profile, insulin, and androgens were evaluated in 63 women (31 patients and 32 controls). Sestrin2 and beclin1 levels were determined using enzyme‐linked immunosorbent assay (ELISA). Descriptive statistics, correlation coefficients, logistic regression, and ROC curve analyses were used in this study. Results Plasma sestrin2 levels of the subjects with PCOS (40.74 [24.39–257.70]) were significantly lower than those of healthy subjects (255.78 [25.46–528.66]; p‐value = 0.040). ROC curve analysis showed that a cutoff value of 420.5 ng/L had an appropriate sensitivity (83.87%) and specificity (46.88%) for discriminating individuals with and without PCOS, with the area under the curve (95% CI) of 0.648 (0.518 to 0.764), p = 0.036. There were no statistically significant differences between the two groups concerning plasma levels of beclin1, biochemical parameters, blood pressure, and anthropometric features. Conclusion Our findings highlight the dysregulation of sestrin2 as a marker of autophagy in PCOS and its potential usefulness as a novel biomarker for PCOS. Further research is needed to better understand the role of this protein in the pathophysiology of PCOS and its value as a diagnostic tool for the evaluation of PCOS patients. This study attempted to evaluate the plasma concentrations of Sestrin2 and Beclin1 in women with PCOS and healthy controls, and to explore the clinical value of these proteins as novel biomarkers for PCOS. Plasma sestrin2 levels of the subjects with PCOS (40.74 [24.39–257.70]) were significantly lower than that of healthy subjects (255.78 [25.46–528.66]; p‐value = 0.040). A cut‐off value of 420.5 ng/L had an appropriate sensitivity (83.87%) and specificity (46.88%) for discriminating individuals with and without PCOS. There were no statistically significant differences between the two groups concerning plasma levels of beclin1. Our findings highlight the dysregulation of sestrin2 as a marker of autophagy in PCOS and its usefulness as a novel biomarker for PCOS.

Introduction Neonatal diabetes mellitus (NDM) is a rare non‐immunological monogenic disorder characterized by hyperglycemic conditions primarily occurring within the first 6 months of life. The majority of cases are attributed to pathogenic variants in genes affecting beta‐cell survival, insulin regulation, and secretion. This study aims to investigate the genetic landscape of NDM in Iran. Methods We recruited a total of 135 patients who were initially diagnosed with diabetes at <12 months of age in Iran and referred to pediatric endocrinology clinics across the country. These patients underwent genetic diagnostic tests conducted by the Exeter Molecular Genetics Laboratory in the UK. The pathogenic variants identified were sorted and described based on type, pathogenicity (according to ACMG/AMP criteria), novelty, and the affected protein domain. Results Genetic defects were identified in 93 probands, presenting various pathogenic abnormalities associated with NDM and its associated syndromes. 76% of the patients were born as a result of consanguineous marriage, and a familial history of diabetes was found in 43% of the cases. A total of 58 distinct variants in 14 different genes were discovered, including 20 variants reported for the first time. Causative variants were most frequently identified in EIF2AK3, KCNJ11, and ABCC8, respectively. Notably, EIF2AK3 and ABCC8 exhibited the highest number of novel variants. Discussion These findings provide valuable insights into the genetic landscape of NDM in the Iranian population and contribute to the knowledge of novel pathogenic variants within known causative genes. Our study provides a comprehensive analysis of neonatal diabetes mellitus (NDM) in Iranian patients, revealing a diverse genetic landscape with 58 distinct variants across 14 genes.

Over the last two decades, we have extensively studied the genetics of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH) and have performed 8,290 DNA analyses of the CYP21A2 gene on members of 4,857 families at risk for CAH—the largest cohort of CAH patients reported to date. Of the families studied, 1,507 had at least one member affected with one of three known forms of CAH, namely salt wasting, simple virilizing, or nonclassical CAH. Here, we report the genotype and phenotype of each affected patient, as well as the ethnic group and country of origin for each patient. We showed that 21 of 45 genotypes yielded a phenotypic correlation in our patient cohort. In particular, contrary to what is generally reported in the literature, we found that certain mutations, for example, the P30L, I2G, and I172N mutations, yielded different CAH phenotypes. In salt wasting and nonclassical CAH, a phenotype can be attributed to a genotype; however, in simple virilizing CAH, we observe wide phenotypic variability, particularly with the exon 4 I172N mutation. Finally, there was a high frequency of homozygous I2G and V281L mutations in Middle Eastern and Ashkenazi Jewish populations, respectively. By identifying the predominant phenotype for a given genotype, these findings should assist physicians in prenatal diagnosis and genetic counseling of parents who are at risk for having a child with CAH.

Epigenetic modifications, particularly histone acetylation-deacetylation and its related enzymes, such as sirtuin 1 (SIRT1) deacetylase, may have substantial roles in the pathogenesis of obesity and its associated health issues. This study aimed to evaluate global histone acetylation status and SIRT1 gene expression in children and adolescents with obesity and their association with metabolic and anthropometric parameters. This study included 60 children and adolescents, 30 with obesity and 30 normal-weight. The evaluation consisted of the analysis of global histone acetylation levels and the expression of the SIRT1 gene in peripheral blood mononuclear cells, by specific antibody and real-time PCR, respectively. Additionally, insulin, fasting plasma glucose, lipid profile and tumor necrosis factor [alpha] (TNF-[alpha]) levels were measured. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Metabolic syndrome was determined based on the diagnostic criteria established by IDF. Individuals with obesity, particularly those with insulin resistance, had significantly higher histone acetylation levels compared to control group. Histone acetylation was positively correlated with obesity indices, TNF-[alpha], insulin, and HOMA-IR. Additionally, a significant decrease in SIRT1 gene expression was found among obese individuals, which was negatively correlated with the histone acetylation level. Furthermore, SIRT1 expression levels showed a negative correlation with various anthropometric and metabolic parameters. Histone acetylation was enhanced in children and adolescents with obesity, potentially resulting from down-regulation of SIRT1, and could play a role in the obesity-associated metabolic abnormalities and insulin resistance. Targeting global histone acetylation modulation might be considered as an epigenetic approach for early obesity management.

Abstract Objective: Obesity in childhood and adolescence is associated with metabolic syndrome and cardiovascular diseases. TRB3 (Tribbles homolog 3) and sestrin 2 are two newly found proteins that have been identified to play an important role in obesity and its complications. Aim: The purpose of this study was to evaluate concentrations of TRB3 and sestrin 2 in plasma of obese and normal-weight children and adolescents, and their association with metabolic and anthropometric parameters. Methods: Plasma levels of TRB3, sestrin 2, insulin, fasting plasma glucose (FPG), and lipid profile were evaluated in 70 children and adolescents (34 obese and 36 controls). Insulin resistance was calculated using a homeostasis model assessment of insulin resistance. Metabolic syndrome was defined according to IDF criteria. Results: Plasma TRB3 levels of the obese subjects were significantly higher than that of normal weight subjects. TRB3 levels were positively correlated with BMI, BMI z-score, waist circumference, and FPG. The concentration of sestrin 2 was significantly lower in obese subjects compared to normal-weight subjects. A statistically significant positive correlation was observed between plasma concentrations of sestrin 2 and high-density lipoprotein cholesterol. Neither TRB3 nor sestrin 2 were correlated with insulin resistance and metabolic syndrome. Conclusion: Both TRB3 and sestrin 2 may contribute to the development of obesity and its complications and can be considered interesting therapeutic target for the treatment of obesity.

Background. Angiopoietin-like protein 2 (ANGPTL2) is one of the adipocyte-derived inflammatory factors which connects obesity to insulin resistance. ANGPTL3 has a direct role in regulation of lipid metabolism. The objective of this study was to evaluate ANGPTL2 and ANGPTL3 in childhood obesity and their relationship with metabolic syndrome. Methods. 70 children and adolescents, 35 obese and 35 normal-weight subjects, were enrolled in this research after complete clinical examination and anthropometric evaluations. Serum ANGPTL2 and ANGPTL3 and insulin were measured by enzyme-linked immunosorbent assay (ELISA). Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated and used to estimate insulin resistance (IR). Colorimetric methods were used for the assessment of fasting plasma glucose (FPG), LDL-C, HDL-C, total cholesterol (TC), and triglyceride (TG). Results. The levels of ANGPTL2 and ANGPTL3 were significantly higher in obese subjects than those in controls, but they did not differ significantly in subjects with or without IR. ANGPTL3 was found to be significantly elevated in obese children with metabolic syndrome (MetS) in comparison with those without MetS. Both of the studied ANGPTLs were positively correlated with BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, and LDL-C. The correlation between ANGPTL3 and either TC or LDL-C remained significant after adjusting for BMI. Conclusion. Serum ANGPTL2 and ANGPTL3 were elevated in obesity and associated with blood pressure and indices of metabolic syndrome, suggesting that they might be involved in the advancement of obesity-related hypertension and metabolic syndrome.

Background Permanent neonatal diabetes mellitus (PNDM) presents with dehydration and hyperglycemia, which usually occurs during the first 12 months of life. Activating mutations of beta-cell adenosine triphosphate-sensitive potassium [KATP] channel subunits that cause opening of the channel are associated with PNDM. Some patients with PNDM respond to administration of a sulfonylurea derivative, which has long action on blood glucose even during hypoglycemia and has an apoptotic effect on beta cells. However, there have been no reports regarding treatment with meglitinide (repaglinide), which has rapid and short duration of action during the rise in blood glucose after meals that is more similar to beta cell function. It has no effects during hypoglycemia, so it does not cause neurological damage, and has no apoptotic effect on beta cells. We report herein the effects of repaglinide administration in the management and clinical outcome of two patients with PNDM during 9 and 10 years of follow-up. Case presentation Two Iranian infants were brought to our institution with poor general condition, dehydration, lethargy, and poor feeding. They had diabetic ketoacidosis at 52 days and 3.5 months of age, respectively. Their genetic analysis revealed mutations in the KCNJ11 gene encoding KIR6.2, so they both had PNDM. After treatment of diabetic ketoacidosis with insulin, they responded to sulfonylurea (glibenclamide) treatment, but were switched to repaglinide because of blood sugar fluctuations in terms of hyper- and hypoglycemia. Repaglinide was administered with the dosage of 0.04 mg/kg/day divided before every meal. Results The patients were 10 and 9 years old at the last visit, with normal growth parameters. The values of self-monitored blood glucose were well-controlled, and the hemoglobin A1C (HbA1C) levels ranged from 3.6 to 6.4% during the follow-up period. There was no complication of diabetes, neurological disorder, or adverse effects related to repaglinide. Conclusion In every neonate or infant < 6 months of age with diabetes mellitus, PNDM should be considered. A trial of oral repaglinide can be performed and substituted for glibenclamide for prevention of hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration.

Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycaemia from birth. Understanding the pathophysiology and genetic defects behind hyperinsulinism and its complications provides clues to timely diagnosis and management. The aim of this study was to evaluate the underlying genetic aetiology of a specific Iranian pediatric cohort with CHI. A total of 44 unrelated children, 20 girls and 24 boys, with an initial diagnosis or history of CHI from all regions of Iran were recruited between 2016 and 2019. Targeted next generation sequencing (tNGS) was performed for the genes found in about half of CHI patients. Mutations were identified in 24 cases (55%). Patients with a confirmed genetic cause were mainly diagnosed below age of one year old (p=0.01), had fewer other syndromic features, excluding seizure, (p=0.03), were less diazoxide responsive (p=0.04) and were more diazoxide unresponsive leading to pancreatectomy (p=0.007) compared to those with no identified mutations. Among 24 patients with identified genetic mutations, 17 (71%) had a mutation in , 3 (12%) in , 3 (12%) in , and 1 patient had a mutation in . These included five novel mutations in , and . This is the biggest genetic study of CHI in Iran. A high frequency of recessive forms of CHI, especially HADH mutations, in our study could be due to a high rate of consanguineous marriage. We recommend tNGS to screen for all the CHI genes.

Alkaptonuria (ALK) is a rare genetic disorder, characterized by binding of ochronotic pigment to the connective tissues in different tissues. This is the first report of a child presented with primary distal renal tubular acidosis associated with ALK. Both disorders were managed by their specific medical treatments, with no further complication.

 Type 1 diabetes (T1D) is an autoimmune disease resulting from the damage of pancreatic B-cells mediated by autoreactive CD4+ and CD8+ T cells. In recent years, follicular T helper (Tfh) cells have been recognized as a subpopulation of CD4+ T cells providing help for B cells differentiation and antibody production. In this study, we examined the frequency of circulating CD4+CXCR5+ and CD4+CXCR5+ICOS+ (representing Tfh) cells as well as serum levels of anti-glutamic acid decarboxylase 65 (GAD65) and islet cell autoantibodies (ICA) in children with type I diabetes. We analyzed the percentage of Tfh cells within peripheral blood mononuclear cells in 20 children with T1D (≤300 days from disease onset; Mean age 6.8±4.6 years) and 18 healthy individuals (Mean age 8.8±2.2 years) using flow cytometry. Anti-glutamic acid decarboxylase (GAD) and islet-cell cytoplasmic autoantibodies (ICA) levels were determined by ELISA and indirect immunofluorescence respectively. We found that the frequency of CD4+CXCR5+ and CD4+CXCR5+ICOS+ (Tfh) cells were significantly increased in the peripheral blood of patients compared with healthy controls (p<0.001). Furthermore, elevated levels of anti-GAD and ICA antibodies were detected in children with T1D (p=0.001 and p=0.02 respectively). There was no correlation between Tfh cells frequency and the autoantibody levels. The results of our study indicate an increased frequency of Tfh cells in children With T1D that could suggest a possible role of these cells in the disease pathogenesis.