Diagnosis and genetic analysis of a case of Waardenburg syndrome type 2 with hypogonadotropic hypogonadism caused by SOX10 gene deletion.

Hypogonadotropic hypogonadism (HH) is a disease defined by dysfunction of the hypothalamic- pituitary-gonadal hormone axis, leading to low sex hormone levels and impaired fertility. HH with anosmia or hyposmia is known as Kallmann syndrome (KS). Waardenburg syndrome (WS) is a rare autosomal dominant genetic disorder characterized by sensorineural hearing loss and abnormal pigmentation. In this report, we collected the clinical data of a patient with hypogonadotropic hypogonadism and congenital hearing loss of unknown cause. The patient had no obvious secondary sexual characteristics development after puberty, and had a heterozygous deletion (at least 419 kb) in 22q13.1 region (Chr.22:38106433-38525560), which covered the SOX10 gene. The abnormalities were not found in gene sequencing analysis of both the parents and sister of the proband. By summarizing and analyzing the characteristics of this case, we further discussed the molecular biological etiological association between HH and WS type 2. This case also enriches the clinical data of subsequent genetic studies, and provides a reference for the diagnosis and treatment of such diseases.

Association of Interleukin-6 -174G/C Polymorphism with the Risk of Diabetic Nephropathy in Type 2 Diabetes: A Meta-analysis.

Previous studies reported the association between interleukin-6 (IL-6) -174G/C gene polymorphism and the risk of diabetic nephropathy in type 2 diabetes mellitus (T2DN). However, the results remain controversial. In the present study, we conducted a meta-analysis to further examine this relationship between IL-6-174G/C gene polymorphism and T2DN. Three databases (PubMed, SinoMed and ISI Web of Science) were used to search clinical case-control studies about IL-6-174G/C polymorphism and T2DN published until Apr. 14, 2018. Fixed- or random-effects models were used to calculate the effect sizes of odds ratio (OR) and 95% confidence intervals (95% CI). Moreover, subgroup analysis was performed in terms of the excretion rate of albuminuria. All the statistical analyses were conducted using Stata 12.0. A total of 11 case-control studies were included in this study, involving 1203 cases of T2DN and 1571 cases of T2DM without DN. Meta-analysis showed that there was an association between IL-6-174G/C polymorphism and increased risk of T2DN under the allelic and recessive genetic models (G vs. C: OR=1.10, 95%CI 1.03-1.18, P=0.006; GG vs. CC+GC: OR=1.11, 95%CI 1.02-1.21 P=0.016). In the subgroup analysis by albuminuria, a significant association of IL-6-174G/C polymorphism with risk of T2DN was noted in the microalbuminuria group under the recessive model (OR=1.54, 95% CI 1.02-2.32, _P=0.038). In conclusion, this meta-analysis suggests that IL-6-174G/C gene polymorphism is associated with the risk of T2DN.

Liraglutide protects ß-cell function by reversing histone modification of Pdx-1 proximal promoter in catch-up growth male rats.

AIMS: Catch-up growth after a period of nutritional deprivation in adulthood is related to the onset of metabolic disorders. This process involves chromatin remodelling of the Pdx-1 gene in pancreas. The objective of this study was to determine the chromatin remodelling mechanism of GLP-1 analogue Liraglutide upon Pdx-1 in catch-up growth rats in vivo and in vitro. METHODS: Five-week-old male specific pathogen free (SPF) Wistar rats were randomly divided into normal group, catch-up growth group and Liraglutide group. Hyperglycemic clamp test and glucose-stimulated insulin secretion test were carried out to evaluate ß-cell function in vivo and in vitro. The histone H3 modification changes at the Pdx-1 proximal promoter were assessed by chromatin immunoprecipitation. RESULTS: The catch-up growth state was characterized by less recruitment of histone H3 lysine4 trimethylation and histone H3 acetylation and more recruitment of histone H3 lysine9 dimethylation at the Pdx-1 proximal promoter. Liraglutide treatment reversed these epigenetic changes and increased Pdx-1 expression, which could be abrogated by GLP-1 receptor antagonist Exendin 9-39. The ß-cell function of catch-up growth rats was improved after Liraglutide treatment. CONCLUSIONS: The protective effects of Liraglutide on pancreatic islet ß-cell function may be related to histone H3 modification at the Pdx-1 proximal promoter during catch-up growth and could be used to treat catch-up growth-related metabolic disorders.

Insulin sensitizers improve the GLP-1 secretion and the amount of intestinal L cells on high-fat-diet-induced catch-up growth.

OBJECTIVE: The aim of this study was to investigate whether insulin resistance can result in impaired glucagon-like peptide (GLP)-1 secretion and to determine whether insulin-sensitizing drugs could improve the secretion of GLP-1 in catch-up growth rats. METHODS: Male Sprague Dawley rats were used to establish a catch-up growth model. At the end of weeks 6 and 14, these rats were euthanized to measure energy intake, body weight, plasma triacylglycerol, and nonesterified fatty acid. Fat mass percentage was analyzed by dual-energy x-ray absorptiometry scan. The GLP-1 concentrations were measured by enzyme-linked immunosorbent assay, the glucose infusion rates were measured by hyperinsulinemic-glucose clamp experiment. Quantification of the GLP-1 positive cells in distal ileum was done by immunohistochemical staining method. The L cell line NCI-H716 cells were treated in vitro with palmitate acid, the cells' viability, the carnitine palmitoyl transferase-1, and the insulin signaling pathway were detected. RESULTS: Rats fed a high-fat diet rats had rapidly developed insulin resistance, impaired incretin effect, and a reduction in the number of intestinal L cells. The insulin sensitizers, metformin and pioglitazone, improved insulin resistance and the concentration of circulating GLP-1, increased the relative number of intestinal L cells to a certain degree. In vitro, the NCI-H716 cell viability was decreased and impaired insulin signaling pathway with palmitate acid treatment, metformin treatment could reverse these effects, whereas pioglitazone could not. CONCLUSIONS: Insulin resistance caused by a high-fat diet could result in reduced GLP-1 secretion; the insulin sensitizing drugs were able to improve the incretin effect in catch-up growth rats.

Pharmacokinetic and immunosuppressive effects of tacrolimus-loaded biodegradable microspheres.

The objective of this study was to characterize the pharmacokinetics and immunosuppression of a tacrolimus-loaded biodegradable microsphere (TLBM) in rats. We prepared TLBM. DA/Slc rats were given TLBM at a dose of 1.6 mg/kg (n = 9), 2.4 mg/kg (n = 5), or 7.2 mg/kg (n = 7) tacrolimus contents by a single subcutaneous administration to achieve sustained release over a long period. DA/Slc rats were given TLBM by a single subcutaneous administration at a dose of 4.8 mg/kg (n = 6) tacrolimus contents to clarify the main site of TLBM uptake in the organs. In the rat liver transplantation model, the recipients were given TLBM at a dose of 0.16 mg/kg (n = 5), 2.4 mg/kg (n = 4), or 4.8 mg/kg (n = 5) tacrolimus contents by a single subcutaneous administration on the first day after operation. Overall survival days were compared. Continuous flat parallel concentration profiles were significant for 10 days from the first day after a single subcutaneous administration of TLBM (P <.01). The relationship between the dosages of TLBM administration and area under the concentration-time curve (AUC) up to 18 days demonstrated a linear regression line (P <.01). In addition, the relationship between the dose of TLBM and the survival days of the recipients in the liver transplantation model showed a positive correlation. The current pharmacokinetic study of TLBM revealed significantly increased tacrolimus levels in the regional lymph nodes compared with other organs except bone marrow (P <.01). In conclusion, TLBM allowed tacrolimus to release gradually in a very stable manner for 10 days, with dose-dependent immunosuppression after a single subcutaneous administration. The main site of TLBM uptake after subcutaneous administration was the regional lymph node of administration site.