International Journal of Endocrinology最新文献

Background: Patatin-like phospholipase domain-containing 3 (PNPLA3) is a major susceptibility gene for nonalcoholic fatty liver disease (NAFLD), and its rs738409 (I148M) polymorphism is associated with the occurrence and progression of NAFLD. Endoplasmic reticulum (ER) stress-related hepatocyte lipoapoptosis contributes to the progress of NAFLD. PNPLA3 is also known as a member of the calcium-independent phospholipase A2ε family, which can hydrolyze fatty acids to generate lysophosphatidylcholine (LPC) that induces ER stress-related hepatocyte lipoapoptosis. Whether the PNPLA3 risk genotype 148M/M is involved in more severe ER stress-associated lipoapoptosis is unclear.

Methods: A PNPLA3148I knock-in HepG2 cell model was constructed based on HepG2 expressing PNPLA3 148M/M using the Cas9/sgRNA system. PNPLA3 148M/M, I/M, and I/I cells were treated with 0.3 mM palmitic acid (PA) for 24 h to induce lipid deposition. Cellular lipid deposition was detected by oil red staining. Apoptosis was observed by TUNEL. LPC was determined by ELISA, and the expression of PNPLA3, the ER stress marker Bip, molecules involved in the ER stress PERK/elF-2a pathway, and its downstream C/EBP homologous protein (CHOP)-mediated apoptotic pathway were detected by western blot.

Results: The results showed no difference in PNPLA3 basal expression and basal hepatocyte lipid content between the three genotypes of cells. Lipid deposition and apoptosis were more severe in PNPLA3 148M/M and 148I/M cells than in I/I cells after PA treatment. PA-induced upregulation of protein expression of Bip, ER stress-responsive PERK pathway molecules p-PERK, p-eIF2α, CHOP, and CHOP-associated apoptotic molecules PUMA and Bax were more pronounced in PNPLA3 148M/M cells than in PNPLA3 148I/I cells. The basal LPC levels and the PA-treated increase of LPC levels in the cell culture supernatants did not differ between the three genotypic cells.

Conclusion: PNPLA3 148M/M cells were more susceptible to PA-induced lipid deposition and ER stress-related apoptosis than 148I/I cells, and the proapoptotic susceptibility of PNPLA3 148M/M is independent of LPC.

Introduction: Insulin-like growth factor receptor 2 (IGF2R) regulates placental nutrient transport, and its soluble form is related to obesity in adults. If the placental expression of IGF2R is altered in women with obesity is unknown. Whether maternal supplementation with docosahexaenoic acid (DHA), a polyunsaturated fatty acid with anti-inflammatory properties, has a modulatory role in IGF2R's function has not been elucidated. We hypothesized that maternal obesity (Ob) would be associated with alterations in placental IGF2R expression, which may be prevented with DHA supplementation during pregnancy.

Methods: At delivery, we obtained placentas from women with Ob (BMI ≥ 30 kg/m², n = 17), Ob supplemented with 800 mg/day of DHA during pregnancy (Ob + DHA, n = 13), and normal-weight women (Nw, BMI ≥ 18.5 ≤ 24.9 kg/m², n = 14). The IGF2R mRNA and protein were determined by RT-PCR and western blotting, respectively. Moreover, we quantified the gene expression of molecules that modulate the IGF2R function in the extracellular domain, such as TACE/ADAM17, PLAU, and IGF2. Mann-Whitney and Kruskal-Wallis nonparametric tests were used to compare results between two or three groups accordingly.

Results: The IGF2R levels in the Ob placentas of the male offspring were higher than in the Nw group. The DHA supplementation prevented this effect, suggesting an unknown relationship between IGF2R-Ob-DHA in placental tissues.

Conclusion: We report, for the first time, that DHA supplementation during pregnancy in women with obesity normalizes the increased IGF2R levels in male placentas, reducing the risk of adverse outcomes related to the IGF2/IGF2R system in male newborns.

Diabetes mellitus (DM) is a chronic disease that threatens human health. Although many drugs are available to treat DM, various complications caused by DM are unavoidable. As an emerging treatment for DM, mesenchymal stem cells (MSCs) have shown many advantages and are gradually gaining public attention. This review summarizes the clinical studies on the use of MSCs to treat DM and the potential mechanisms of complications such as pancreatic dysfunction, cardiovascular lesions, renal lesions, neurological lesions, and trauma repair. This review focuses on the research progress on MSC-mediated secretion of cytokines, improvements in the microenvironment, repair of tissue morphology, and related signaling pathways. At present, the sample sizes in clinical studies of MSCs in treating DM are small, and there is a lack of standardized quality control systems in the preparation, transportation, and infusion methods, so we need to conduct more in-depth studies. In conclusion, MSCs have shown superior potential for use in the treatment of DM and its complications and will hopefully become a novel therapeutic approach in the future.

Introduction: Giant prolactinoma (GP) is a rare pituitary lactotropic cell tumor larger than 4 cm in its widest dimension, and is less likely than a smaller prolactinoma to achieve prolactin normalization on dopamine agonist (DA) monotherapy. There is a paucity of data on the circumstances and outcomes of second-line management of GP with surgery. Herein, our institution's experience with the surgical management of GPs is described.

Methods: A single-center retrospective analysis was conducted of patients who underwent surgery for giant prolactinoma from 2003 to 2018. A chart review was conducted for demographic data, clinical features, laboratory and radiographic findings, operative and pathology reports, perioperative management, and clinical outcomes in follow-up. Descriptive statistics were used.

Results: Of 79 prolactinoma cases, 8 patients had GP with a median age of 38 years (range 20-53), 75% (6/8) were male, with a median largest tumor dimension of 6 cm (range 4.6-7.7), and a median prolactin level of 2,500 μg/L (range 100->13,000). Six patients had transsphenoidal surgery for dopamine agonist (DA) resistance or intolerance. Two patients had a craniotomy for a missed diagnosis; one was due to the hook effect. No tumor resections were complete by either surgical approach; all had persistent hyperprolactinemia requiring postoperative DA therapy, and two patients had an additional craniotomy procedure for further tumor debulking. There was no recovery of pituitary axes and postoperative deficits were common. Remission as defined by prolactin normalization occurred in 63% (5/8) at a median time of 36 months (range 14-63 months) on DA therapy after surgery with a follow-up of 3-13 years.

Conclusions: GPs infrequently require surgical resection, which is generally incomplete and requires adjuvant therapy. Given the rarity of surgery for GPs, multi-institutional or registry studies would yield clearer guidance on optimal management.

Background: Type 2 diabetes mellitus increases the risk of sarcopenia, which is characterized by decreased muscle mass, strength, and function. However, there are no effective drugs to treat diabetic sarcopenia, and its underlying mechanism remains unknown. Here, we aimed to determine whether the GLP-1 receptor agonist (GLP-1RA) dulaglutide (Dul) affects the progression of diabetic sarcopenia.

Methods: db/db mice were injected intraperitoneally with 0.6 mg/kg dulaglutide for 10 weeks. Mouse muscle tissues were then pathologically evaluated and stained with F4/80 or MPO to detect macrophages and neutrophils, respectively. In addition, inflammatory factors and FNDC5 in the muscle tissues were detected using qRT-PCR. Moreover, C2C12 cells were induced to enable their differentiation into skeletal muscle cells, and muscle factor levels were then detected. Furthermore, changes in muscle factor levels were detected at various glucose concentrations (11 mM, 22 mM, and 44 mM).

Results: In vivo, dulaglutide alleviated muscle tissue injury; reduced levels of the inflammatory factors, IL-1β, IL-6, CCL2, and CXCL1; and reversed the level of FNDC5 in the muscle tissues of db/db mice. In vitro, a C2C12 cell differentiation model was established through the observation of cell morphology and determination of myokine levels. Upon stimulation with high glucose, the differentiation of C2C12 cells was inhibited. Dulaglutide improved this inhibitory state by upregulating the levels of both FNDC5 mRNA and protein.

Conclusions: Treatment with the GLP-1RA dulaglutide protects db/db mice against skeletal muscle injury by inhibiting inflammation and regulating the differentiation of myoblasts. High glucose inhibited the differentiation of C2C12 cells and decreased the mRNA and protein levels of myokines. Dulaglutide could reverse the differentiation state induced in C2C12 cells by high glucose.

Inhibiting podocyte autophagy promotes the development of diabetic nephropathy (DN). This study aims to explore the upstream regulatory mechanism of the autophagy-related gene BECN1 in high glucose (HG)-induced podocytes. C57BL/6 mice were treated with 50 mg/kg streptozotocin to construct a DN model. Biochemical indexes, pathological morphology of renal tissue, the morphology of renal podocytes, and the expressions of autophagy-related proteins in DN mice and normal mice were detected. The upstream miRNAs of BECN1 and the upstream long noncoding RNAs (lncRNAs) of miR-30d-5p were predicted by bioinformatics analysis and verified by dual-luciferase reporter assay. Mouse podocyte clone 5 (MPC5) cells were exposed to HG to construct a DN cell model. The levels of miR-30d-5p, X inactive specific transcript (XIST), and BECN1 in mouse kidney and MPC5 cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The regulation of XIST/miR-30d-5p on the viability, apoptosis as well as proteins related to apoptosis, epithelial-mesenchymal transition (EMT), and autophagy in MPC5 cells were determined by rescue experiments. The levels of glucose, urinary protein, serum creatinine, and blood urea nitrogen were upregulated, but the kidney tissues and podocytes were damaged in DN mice. XIST targeted miR-30d-5p to promote viability while suppressing the apoptosis of HG-induced MPC5 cells. In kidney tissues or HG-induced MPC5 cells, the expressions of Beclin-1, light chain 3 (LC3) II/I, XIST, B-celllymphoma-2 (Bcl-2), and E-cadherin were downregulated, while the expressions of P62, miR-30d-5p, Bcl-2-associated X protein (Bax), cleaved-caspase-3, vimentin, and alpha-smooth muscle actin (α-SMA) were upregulated, which were reversed by XIST overexpression. The reversal effect of XIST overexpression was offset by miR-30d-5p mimic. Collectively, XIST promotes the autophagy of podocytes by regulating the miR-30d-5p/BECN1 axis to protect podocytes from HG-induced injury.

Purpose: Glycogen storage disease type III (GSDIII) is a uncommon autosomal recessive inherited metabolic disorder, which is caused by variants in the AGL gene. The purpose of this study was to elucidate the clinical and functional features of two novel variants in two families with GSDIIIa.

Methods: We collected the clinical and laboratory data of the two patients. Genetic testing was performed using GSDs gene panel sequencing, and the identified variants were classified according to the American College of Medical Genetics (ACMG) criteria. The pathogenicity of the novel variants was furthermore assessed through bioinformatics analysis and cellular functional validation experiments.

Results: The two patients were hospitalized with abnormal liver function or hepatomegaly, which was characterized by remarkably elevated liver enzyme and muscle enzyme levels, as well as hepatomegaly, and were eventually diagnosed with GSDIIIa. Genetic analysis detected two novel variants of AGL gene in the two patients: c.1484A > G (p.Y495C), c.1981G > T (p.D661Y). Bioinformatics analysis indicated that the two novel missense mutations most likely altered the protein's conformation and therefore made the enzyme it encodes less active. Based on the ACMG criteria, both variants were considered likely pathogenic, in accordance with the functional analysis results, which demonstrated that the mutated protein was still localized in the cytoplasm and that the glycogen content of cells transfected with the mutated AGL was increased compared to cells transfected with the wild-type one.

Conclusion: These findings indicated that the two newly identified variants in the AGL gene (c.1484A > G; c.1981G > T) were undoubtedly pathogenic mutations, inducing a slight reduction in glycogen debranching enzyme activity and a mild increase in intracellular glycogen content. Two patients who visited us with abnormal liver function, or hepatomegaly, improved dramatically after treatment with oral uncooked cornstarch, but the effects on skeletal muscle and myocardium required further observation.

Background: Gemstone spectral contrast-enhanced CT with virtual noncontrast (VNC) images and iodine maps can potentially reduce the number of required CT scans for thyroid lesions. However, data regarding the clinical utility of VNC images and iodine maps in characterizing thyroid lesions and distinguishing thyroid papillary carcinoma from nodular goiter are still limited.

Purpose: To determine whether VNC images and iodine density could reliably aid in characterizing thyroid lesions and distinguishing thyroid papillary carcinoma from nodular goiter compared with true noncontrast (TNC) images.

Methods: This retrospective study included patients with thyroid papillary carcinoma or nodular goiter who underwent TNC and contrast-enhanced gemstone spectral CT scans. The consistency of qualitative parameters, including intralesional calcification, necrosis, lesion boundary, thyroid edge interruption, and lymph node metastasis, between TNC and VNC images, was analyzed using the kappa statistic. TNC attenuation, VNC attenuation, absolute attenuation between TNC and VNC, and iodine density were compared between thyroid papillary carcinoma and nodular goiter by using Student's t-test. The diagnostic performance for distinguishing papillary carcinoma from nodular goiter was evaluated by using the area under the receiver operating characteristic curve (AUC) value, sensitivity, and specificity.

Results: VNC and TNC imaging showed comparable performance in delineating calcification, necrosis, lesion boundary, thyroid edge interruption, and lymph node metastasis (all k > 0.75). Papillary carcinoma showed significantly lower absolute attenuation between VNC and TNC than nodular goiter (7.86 ± 6.74 vs. 13.43 ± 10.53, P=0.026), which was similarly observed for iodine density (31.45 ± 8.51 vs. 37.27 ± 10.34, P=0.016). The iodine density showed higher diagnostic performance (AUC = 0.727), accuracy (0.773 vs. 0.667), sensitivity (0.750 vs. 0.708), and specificity (0.786 vs. 0.643) than the absolute attenuation between TNC and VNC images (AUC = 0.683).

Conclusions: VNC imaging, a promising substitute for TNC imaging, has comparable diagnostic efficacy for reliably characterizing thyroid lesions. Iodine density could be valuable for distinguishing thyroid papillary carcinoma from nodular goiter.

Objective: Preservation of fertility in Turner syndrome (TS) patients may be feasible through cryopreservation of ovarian tissue before follicles begin to disappear. Anti-Müllerian hormone (AMH) is said to be a predictive factor of spontaneous pubertal development in TS. We aimed to determine the cut-off values of AMH for the diagnosis of TS girls with spontaneous puberty. Design and methods: A total of 95 TS patients between 4 and 17 years were evaluated at the Department of Pediatric Genetic Metabolism and Endocrinology from July 2017 to March 2022. Serum AMH, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were analyzed according to age, karyotype, pubertal development, and ultrasound ovarian visualization. Receiver-operating characteristic (ROC) curve analyzes were used to test the utility of AMH for the diagnosis of TS girls with spontaneous puberty.

Results: One-fourth of TS girls aged 8-17 years had spontaneous breast development, with the ratios as follows: 45, X (6/28, 21.4%), mosaicism (7/12, 58.3%), and mosaicism with structural X chromosome abnormalities (SCA) (2/13, 15.4%), SCA (1/13, 7.7%), and Y chromosome (1/3, 33.3%). The AMH cut-off value for the prediction of spontaneous puberty in TS patients was 0.07 ng/ml, with sensitivity and specificity both at 88%. FSH, LH levels, and Karyotypes could not be considered as markers of spontaneous puberty in TS (P > 0.05). A strong relationship was observed between serum AMH levels and spontaneous puberty or ultrasound bilateral ovarian visualization.

Conclusions: The AMH cut-off value for the prediction of spontaneous puberty in TS girls aged 8-17 years was 0.07 ng/ml, with sensitivity and specificity both at 88%. However, spontaneous puberty in these patients is not predictable based on karyotype or FSH or LH levels.

Objective: Many patients with type 2 diabetes have an abnormal body mass index (BMI) and hypertension together, but few studies on the interaction of the two on the risk of T2DM are reported. We aim to explore the effect of the interaction between abnormal BMI and hypertension on the risk of type 2 diabetes mellitus (T2DM) in Uyghur residents.

Methods and results: Based on the physical examination data of 27,4819 Uygur residents in Moyu County, a logistic regression model was used to analyze the correlation between BMI abnormality, hypertension, and T2DM disease, and then, the effect of their interaction on the risk of T2DM was evaluated by an additive model and a multiplicative model. The results showed that the detectable rate of T2DM was 5.58%, the proportion of abnormal BMI was 59.49%, and the proportion of hypertension was 25.14%. The risk of T2DM in people with an abnormal BMI and hypertension was higher than that in people with a normal weight and without hypertension, and the difference was statistically significant (P < 0.05). The additive model showed that after adjusting for confounding factors such as gender, age, family history of diabetes, abdominal obesity, and alcohol consumption, abnormal BMI and hypertension had a synergistic effect on the risk of T2DM and the evaluation indicators RERI, AP, and S were 0.90 (0.32∼1.49), 0.20 (0.11∼0.30), and 1.36 (1.17∼1.57), respectively. But there was no multiplicative interaction between the two (OR = 0.97, (95% CI: 0.89∼1.06). 3).

Conclusion: The interaction between abnormal BMI and hypertension can increase the risk of T2DM, and improving BMI and controlling blood pressure within the normal range can effectively reduce the risk of T2DM.