Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell–derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress–induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.

Context There is limited data available on the exact incidence of disorders of sex development (DSD) with genital ambiguity at birth. Objective To determine frequency of ambiguous genitalia in newborns. Design A prospective multicenter study. Setting Three tertiary care hospitals. Patients or Other Participants All 14,177 babies born during the study period were included. Main Outcome Measures All newborns were examined at birth; data on weeks of gestation, birth weight and length were collected. A structured questionnaire was used for data collection. Quigley and Prader scales were used for phenotypic grading. Clinical and genetic investigations were performed. Results Eighteen babies with ambiguous genitalia were found among 14,177 newborns (1.3/1,000). Fifteen newborns had 46,XY DSD, one 46,XX congenital adrenal hyperplasia and one 45,X/46,XY mixed gonadal dysgenesis. Karyotype analysis was not done in one baby who died in neonatal period. The ratio of prematurity was higher in DSD group (44% vs. 11%; p<0.001) and the ratio of small for gestational age (SGA) was also higher in DSD group (22% vs. 5%; p=0.007). Eight babies with DSD had mothers who had additional medical conditions such as preeclampsia, depression, insulin resistance and gestational diabetes mellitus. Conclusion The frequency of ambiguous genitalia was higher than the previous studies, but, as with any experiment, it should be met with caution, because this study was conducted in tertiary care hospitals. In addition, lower birth weight in DSD group supports the hypothesis that early placental dysfunction might be important in the etiology of male genital anomalies.

Increased intestinal permeability (IIP) precedes several autoimmune disorders. Although Hashimoto's thyroiditis (HT) is the most common autoimmune disorder, the role of HP in its pathogenesis had received little attention. Zonulin plays a critical role in IIP by modulating intracellular tight junctions. Rise of serum zonulin levels were shown to indicate HP in human subjects. In this case-control study, we examined the hypothesis that patients with HT have IIP. We studied 30 children and adolescents with HT, and 30 patients with congenital hypothyroidism (CH) matched for age, gender and body mass index (BMI). Serum zonulin levels, free thyroxine (fT4), thyroid stimulating hormone (TSH), anti-thyroglobulin antibody and anti-thyroid peroxidase antibody were measured. Zonulin levels were significantly higher in patients with HT than patients with CH (59.1 +/- 22.9 ng/mL vs. 43.3 +/- 32.9 ng/mL, p = 0.035). In patients with HT, zonulin levels were positively correlated with weight (r = 0.406, p= 0.03), BMI (r = 0.486, p = 0.006) and levothyroxine dose (r = 0.463, p = 0.02). In patients with CH, zonulin levels were positively correlated with age (r = 0.475, p = 0.008), weight (r = 0.707, p< 0.001), BMI (r =0.872, p <0.001) and levothyroxine dose (r =0.485, p = 0.007). After adjusting for age, weight, TSH and fT4 levels, serum zonulin was only associated with levothyroxine dose in patients with HT (R-2 =0.36, p =0.05). In patients with CH, only weight was associated with zonulin levels (R-2 =0.62, p <0.001). In conclusion, higher zonulin levels in children and adolescents with HT suggested IIP in these patients. Additionally, the association between zonulin levels and levothyroxine dose might imply a relationship between serum zonulin and disease severity.

Summary: Background: During perimenopause, the rise in serum follicle‐stimulating hormone (FSH) is associated with increased adiposity, insulin resistance (IR), and metabolic syndrome (MetS). However, data for the pubertal period, which is characterized by increasing FSH levels and changing body composition, are limited.Objectives: To investigate the relationships between FSH and anthropometric changes, IR markers, and development of MetS in the peripubertal period.Methods: Uppsala Longitudinal Study of Childhood Obesity (ULSCO) is an ongoing study that aims to understand the factors contributing to childhood obesity and the development of obesity‐related diseases. We analysed the subset of participants who were prepubertal at the first visit (n = 95, 77 with obesity). Mean follow‐up time was 3.0 ± 1.4 years.Results: Higher serum FSH levels at the first visit were associated with an increased likelihood of elevation in body mass index (BMI SDS) (p = 0.025, OR = 16.10) and having MetS (p = 0.044, OR = 4.67) at the follow‐up. We observed nonlinear relationships between varying serum FSH levels and markers of adiposity and IR, especially in girls. At the first visit, when girls were prepubertal, FSH was negatively associated with BMI (β = −0.491, p = 0.005) and positively associated with sex hormone‐binding globulin (SHBG) (β = 0.625, p = 0.002). With the progression of puberty, negative associations between BMI and SHBG disappeared while FSH became positively associated with HOMA‐IR (β = 0.678, p = 0.025) and fasting insulin (β = 0.668, p = 0.027).Conclusions: Higher serum FSH levels in prepubertal children were associated with an increased risk of MetS development during pubertal transition. Along with nonlinear associations between varying serum FSH levels and IR markers, our results might imply a relationship between FSH and IR of puberty.