Characterization of newly diagnosed type 1 diabetes in children and adolescents from 2017 to 2022 in China: a single-center analysis.

OBJECTIVE: This study investigated the characteristics of newly diagnosed type 1 diabetes mellitus (T1DM) related to autoimmunity and the frequency of diabetic ketoacidosis (DKA) in children and adolescents from 2017-2022 in China. RESEARCH DESIGN AND METHODS: Single-center regional data from the Department of Pediatric Endocrinology, Tongji Hospital, were used to compare 88 children and adolescents newly diagnosed with T1DM from 2020 to 2022 (i.e. during the COVID-19 pandemic in China) and 76 children and adolescents diagnosed with T1DM from 2017 to 2019. Auto-antibodies, including glutamic acid decarboxylase-65 and insulin auto-antibodies, were detected by enzyme-linked immunoassays. DKA was defined as a pH < 7.3 and/or a bicarbonate level < 15 mmol/L. RESULTS: The median age of the 164 children and adolescents newly diagnosed with T1DM from 2017 to 2022 was 7.0 years (interquartile range [IQR]: 3.8-10.0 years; 51.83% male). The mean annual incidence of T1DM was 2.98 per 1,000,000 child years. The estimated frequency of auto-antibody positivity was 51.22% (n = 84), and there was no difference between the 2020-2022 group and 2017-2019 group (55.68% [n = 49] vs. 46.5% [n = 35]; p = 0.219). The frequency of DKA among the entire cohort was 57.93% (n = 95), and peaked in 2020 at 78.9% (15/19 patients). The frequency of DKA was not significantly higher in the 2020-2022 group compared with the 2017-2019 group (60.23% [n = 53] vs. 55.26% [n = 42]; p = 0.521). We found no significant difference in the frequency of DKA between patients who were negative vs. positive for auto-antibodies in the 2020-2022 group (64.10% [n = 25] vs. 57.14% [n = 28], p > 0.05). The C-peptide level and HbA1c (%) were positively correlated with onset age (R1 = 0.389, p < 0.01; R2 = 0.371, p < 0.01), and the estimated mean C-peptide level was 0.26 ng/ml (IQR: 0.2-0.4 ng/ml) in patients with DKA and 0.370 ng/ml (IQR: 0.2-0.6 ng/ml) in patients without DKA (p = 0.044). CONCLUSIONS: This study showed the annual incidence of T1DM was 2.98 per 1,000,000 child years, gradually increased over the study period, and there was no significant increase in T1DM with auto-antibody positivity in children and adolescents newly diagnosed from 2020-2022 in China compared with the previous 3 years. Furthermore, the frequency of DKA was peaked in 2020, and were not significantly different between patients who were negative vs. positive for auto-antibodies.

Endothelin receptors promote schistosomiasis-induced hepatic fibrosis via splenic B cells.

Endothelin receptors (ETRs) are activated by vasoactive peptide endothelins and involved in the pathogenesis of hepatic fibrosis. However, less is known about the role of ETRs in Schistosoma (S.) japonicum-induced hepatic fibrosis. Here, we show that the expression of ETRs is markedly enhanced in the liver and spleen tissues of patients with schistosome-induced fibrosis, as well as in murine models. Additional analyses have indicated that the expression levels of ETRs in schistosomiasis patients are highly correlated with the portal vein and spleen thickness diameter, both of which represent the severity of fibrosis. Splenomegaly is a characteristic symptom of schistosome infection, and splenic abnormality may promote the progression of hepatic fibrosis. We further demonstrate that elevated levels of ETRs are predominantly expressed on splenic B cells in spleen tissues during infection. Importantly, using a well-studied model of human schistosomiasis, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells characterized by interleukin-10 (IL-10) secretion and regulatory T (Treg) cell-inducing capacity. Our study provides insights into the mechanisms by which ETRs regulate schistosomiasis hepatic fibrosis and highlights the potential of endothelin receptor antagonist as a therapeutic intervention for fibrotic diseases.

Intrauterine inflammation induced white matter injury protection by fibrinogen-like protein 2 deficiency in perinatal mice.

BACKGROUND: White matter injury (WMI) induced by intrauterine inflammation can cause adverse neurological outcomes. Fibrinogen-like protein 2 (FGL2)/fibroleukin is an important trigger of inflammatory responses and is involved in some cerebral diseases. However, the role of FGL2 in intrauterine inflammation-induced WMI remains unclear. METHODS: Lipopolysaccharide (LPS) was intraperitoneally injected into wild-type and FGL2 knockout mice to induce intrauterine inflammation. Body weight and brain weight of offspring were monitored. Major basic protein (MBP) expression was evaluated to demonstrate the myelination of offspring. To investigate the regulatory mechanism of FGL2, cytokine expression, microglial polarization, and the activation of mitogen-activated protein kinase (MAPK) signaling pathway in the offspring were analyzed. RESULTS: Upon LPS exposure, FGL2 knockout offspring showed a significant increase in body weight loss. MBP reduction induced by LPS was prevented in FGL2 knockout offspring. Expression levels of proinflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α, and M1 marker CD86 were suppressed, while the expression levels of anti-inflammatory cytokines IL-10 and M2 marker CD206 were increased. FGL2 deficiency significantly inhibited the phosphorylation of p38MAPK and c-Jun N-terminal kinase (JNK) protein. CONCLUSIONS: FGL2 deficiency can ameliorate WMI induced by intrauterine inflammation, reducing inflammatory cascade and improving hypomyelination, through the regulation of microglial polarization and MAPK signaling pathways. IMPACT: Intrauterine inflammation induces WMI leading to severe neurological sequelae. FGL2 plays an important role in the progression of WMI induced by intrauterine inflammation. FGL2 deficiency can protect against WMI by inhibiting p38 MAPK and JNK phosphorylation, regulating microglia polarization, and reducing inflammation response. FGL2 could be a novel molecular target for protecting against WMI induced by intrauterine inflammation.

MicroRNA-29a-3p prevents Schistosoma japonicum-induced liver fibrosis by targeting Roundabout homolog 1 in hepatic stellate cells.

BACKGROUND: Schistosomiasis is a serious but neglected parasitic disease in humans that may lead to liver fibrosis and death. Activated hepatic stellate cells (HSCs) are the principal effectors that promote the accumulation of extracellular matrix (ECM) proteins during hepatic fibrosis. Aberrant microRNA-29 expression is involved in the development of fibrotic diseases. However, less is known about the role of miR-29 in Schistosoma japonicum (S. japonicum)-induced hepatic fibrosis. METHODS: The levels of microRNA-29a-3p (miR-29a-3p) and Roundabout homolog 1 (Robo1) were examined in liver tissues during S. japonicum infection. The possible involvement of the miR-29a-3p-Robo1 signaling pathway was determined. We used MIR29A conditional knock-in mice and mice injected with an miR-29a-3p agomir to investigate the role of miR-29a-3p in schistosomiasis-induced hepatic fibrosis. The functional contributions of miR-29a-3p-Robo1 signaling in liver fibrosis and HSC activation were investigated using primary mouse HSCs and the human HSC cell line LX-2. RESULTS: MiR-29a-3p was downregulated in humans and mice with schistosome-induced fibrosis, and Robo1 was upregulated in liver tissues. The miR-29a-3p targeted Robo1 and negatively regulated its expression. Additionally, the expression level of miR-29a-3p in schistosomiasis patients was highly correlated with the portal vein and spleen thickness diameter, which represent the severity of fibrosis. Furthermore, we demonstrated that efficient and sustained elevation of miR-29a-3p reversed schistosome-induced hepatic fibrosis. Notably, we showed that miR-29a-3p targeted Robo1 in HSCs to prevent the activation of HSCs during infection. CONCLUSIONS: Our results provide experimental and clinical evidence that the miR-29a-3p-Robo1 signaling pathway in HSCs plays an important role in the development of hepatic fibrosis. Therefore, our study highlights the potential of miR-29a-3p as a therapeutic intervention for schistosomiasis and other fibrotic diseases.

Case Report: Glycogen Storage Disease Type Ia in a Chinese Child Treated With Growth Hormone.

Background: Glycogen storage disease type Ia is a rare metabolic disorder that leads to excessive glycogen and fat accumulation in organs, characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, puberty delay, and growth retardation. Here, we report on a patient with glycogen storage disease type Ia treated with growth hormone. Case Presentation: A 10-year-old boy had growth retardation for 6 years, and was admitted to clarify the cause of his short stature. We found that his bone age was 5.5 years, significantly lower than his physical age, while his serum IGF-1 and IGFBP-3 were 23.30 and 1620.0 ng/mL, respectively, both lower than normal. His medical history revealed that he had suffered from steatohepatitis, hyperlipidemia, and hypoglycemia since he was 11 months of age. Whole exome sequencing (WES) showed compound heterozygous mutations in exons 2 and 5 of the glucose-6-phosphatase (G6PC) gene on chromosome 17: c.G248A (p.R83H) and c.G648T (p.L216L). The patient was finally diagnosed with GSD Ia. After growth hormone (GH) treatment and corn starch therapy for 14 months, his height significantly increased (by 13 cm). The serum IGF-1 level increased to the normal range but his lipid levels and liver function did not significantly increase. Conclusion: We describe a young patient with a compound heterozygous G6PC variant in a Chinese family; his height increased significantly after growth hormone and corn starch interventions. This case emphasizes that WES is essential for early diagnosis, and that growth hormone treatment may increase the height of patients with GSD Ia safely.

Clinical and Functional Characterization of a Novel Mutation in AVPR2 Causing Nephrogenic Diabetes Insipidus in a Four-Generation Chinese Family.

Background: Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease that is caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 (AQP2). Functional analysis of the mutated receptor is necessary to verify the impact of the mutation on receptor function and suggest some possible therapeutic strategies for specific functional defects. Methods: Family history and clinical information were collected. Whole-exome sequencing and sanger sequencing were performed to determine the potential genetic cause of diabetes insipidus. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. Bioinformatic analysis was performed to predict the function of the identified variation. Moreover, wild-type and mutated AVPR2 vectors were constructed and transfection to HEK-293T cells. Immunofluorescence experiments were performed to investigate the expression and localization of the mutated protein and cAMP parameter assays were used to measure its activity in response to AVP. Results: The heights of the adult members affected with polyuria and polydipsia were normal, but all affected children had growth retardation. Next-generation sequencing identified a novel mutation in AVPR2 gene (c.530T > A) in this family. Bioinformatic analysis indicated that the mutation in AVPR2 changed the hydropathic characteristic of the protein and was probably deleterious. Although immunofluorescence showed that the mutated AVPR2 was normally expressed in the cell surface, the intracellular cAMP concentration stimulated by AVP was significantly lower in cells transfected with mutated AVPR2 than cells transfected with wild-type AVPR2. Based on the ACMG criteria, the novel c.530T > A variant of the AVPR2 gene was likely pathogenic and the affected family members were diagnosed as CNDI. After the confirmation of the diagnosis, the proband was treated with compound amiloride hydrochloride and rhGH, the symptoms of polyuria, polydipsia and growth retardation were all improved. Conclusion: These findings suggested that the novel mutation in AVPR2 (c.530T > A) was a true disease-causing variant with mild effects, which could be classified as a type III mutant receptor. Moreover, investigations of the function of growth hormone axis could be important for the pediatric CNDI patients with extreme short stature, and rhGH treatment might improve the final adult heights in these patients.