Current progress in metabolomics of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is one of the most common metabolic disorders of pregnancy and can cause short- and long-term adverse effects in both pregnant women and their offspring. However, the etiology and pathogenesis of GDM are still unclear. As a metabolic disease, GDM is well suited to metabolomics study, which can monitor the changes in small molecular metabolites induced by maternal stimuli or perturbations in real time. The application of metabolomics in GDM can be used to discover diagnostic biomarkers, evaluate the prognosis of the disease, guide the application of diet or drugs, evaluate the curative effect, and explore the mechanism. This review provides comprehensive documentation of metabolomics research methods and techniques as well as the current progress in GDM research. We anticipate that the review will contribute to identifying gaps in the current knowledge or metabolomics technology, provide evidence-based information, and inform future research directions in GDM.

PID1 in adipocytes modulates whole-body glucose homeostasis.

The novel obesity-associated protein Phosphotyrosine Interaction Domain containing 1 (PID1) inhibits insulin-PI3K/Akt signaling pathway and insulin-stimulated glucose uptake in vitro. In this study, we generated fat tissue-specific aP2-PID1 transgenic (aP2-PID1tg) mice and PID1 knockout (PID1-/-) mice to explore how PID1 affects glucose metabolism in vivo. We observed insulin resistance and impaired insulin-PI3K/Akt signaling in aP2-PID1tg mice. Consistent with these data, the PID1-/- mice displayed improved glucose tolerance and insulin sensitivity under chow diet, with increased Akt phosphorylation in white adipose tissue (WAT). We further demonstrated that PID1 could interact with low density lipoprotein receptor-related protein 1 (LRP1) but not the insulin receptor (IR) in adipocytes, and its overexpression could lead to decreased GLUT4 level. Our results thus indentify PID1 as a critical regulator of glucose metabolism in adipocytes.

Long noncoding RNA PVT1 indicates a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically regulating p15 and p16.

BACKGROUND: Mounting evidence indicates that long noncoding RNAs (lncRNAs) could play a pivotal role in cancer biology. However, the overall biological role and clinical significance of PVT1 in gastric carcinogenesis remains largely unknown. METHODS: Expression of PVT1 was analyzed in 80 GC tissues and cell lines by qRT-PCR. The effect of PVT1 on proliferation was evaluated by MTT and colony formation assays, and cell apoptosis was evaluated by Flow-cytometric analysis. GC cells transfected with shPVT1 were injected into nude mice to study the effect of PVT1 on tumorigenesis in vivo. RIP was performed to confirm the interaction between PVT1 and EZH2. ChIP was used to study the promoter region of related genes. RESULTS: The higher expression of PVT1 was significantly correlated with deeper invasion depth and advanced TNM stage. Multivariate analyses revealed that PVT1 expression served as an independent predictor for overall survival (p = 0.031). Further experiments demonstrated that PVT1 knockdown significantly inhibited the proliferation both in vitro and in vivo. Importantly, we also showed that PVT1 played a key role in G1 arrest. Moreover, we further confirmed that PVT1 was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of p15 and p16. To our knowledge, this is the first report showed that the role and the mechanism of PVT1 in the progression of gastric cancer. CONCLUSIONS: Together, these results suggest that lncRNA PVT1 may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer.

Downregulation of lncRNA TUG1 affects apoptosis and insulin secretion in mouse pancreatic ß cells.

BACKGROUND: Increasing evidence indicates that long noncoding RNAs (IncRNAs) perform specific biological functions in diverse processes. Recent studies have reported that IncRNAs may be involved in ß cell function. The aim of this study was to characterize the role of IncRNA TUG1 in mouse pancreatic ß cell functioning both in vitro and in vivo. METHODS: qRT-PCR analyses were performed to detect the expression of lncRNA TUG1 in different tissues. RNAi, MTT, TUNEL and Annexin V-FITC assays and western blot, GSIS, ELISA and immunochemistry analyses were performed to detect the effect of lncRNA TUG1 on cell apoptosis and insulin secretion in vitro and in vivo. RESULTS: lncRNA TUG1 was highly expressed in pancreatic tissue compared with other organ tissues, and expression was dynamically regulated by glucose in Nit-1 cells. Knockdown of lncRNA TUG1 expression resulted in an increased apoptosis ratio and decreased insulin secretion in ß cells both in vitro and in vivo . Immunochemistry analyses suggested decreased relative islet area after treatment with lncRNA TUG1 siRNA. CONCLUSION: Downregulation of lncRNA TUG1 expression affected apoptosis and insulin secretion in pancreatic ß cells in vitro and in vivo. lncRNA TUG1 may represent a factor that regulates the function of pancreatic ß cells.

Transcriptome analysis reveals the potential contribution of long noncoding RNAs to brown adipocyte differentiation.

Brown adipose tissue (BAT) functions to dissipate energy in response to cold exposure or overfeeding. Counteracting obesity has been extensively considered as a promising target. Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. However, the potential biological functions of lncRNAs during mouse brown fat cell differentiation have not been fully understood. Here, we performed lncRNA and mRNA expression profile analysis using microarray technology and identified 1064 lncRNAs with differential expression (fold change| ≥4, p ≤ 0.01) on day 0 and day 8 during differentiation. Furthermore, candidate lncRNAs were characterized by comprehensive examination of their genomic context, gene ontology (GO) enrichment of their associated protein-coding genes and pathway analysis. We identified three lncRNAs (Gm15051, Tmem189 and Cebpd) associated with their flanking coding genes (Hoxa1, C/EBPß and C/EBPδ), which participated in adipose commitment. Collectively, our findings indicated lncRNAs are involved in mouse BAT development and provide potential targets for obesity therapy.

Mesothelin promotes cell proliferation in the remodeling of neonatal rat pancreas.

AIM: To investigate the effect of mesothelin in the remodeling of the endocrine pancreas in neonatal rats. METHODS: Overexpression or downregulation of mesothelin expression in INS-1 cells was carried out to investigate the effect of mesothelin during cell proliferation and cell apoptosis in vitro. Adenovirus-mediated RNA interference was performed to block mesothelin in vivo to directly assess the role of mesothelin in the remodeling of the endocrine pancreas in neonatal rats. RESULTS: Exogenous overexpression of mesothelin promoted cell proliferation, cell colony formation and enhanced cell resistance to apoptosis of INS-1 cells. Down-regulation of mesothelin made no difference in cell proliferation and apoptosis compared with that in the control group. After an injection of adenovirus-mesothelin, a significantly increased number of small islets appeared, and the expression of PCNA was decreased on day 7 and day 14 compared with the Ad-EGFP group. CONCLUSION: Mesothelin was able to promote ß cell proliferation in the remodeling stage of neonatal rats. Mesothelin may have an important role in the remodeling of the endocrine pancreas in neonatal rats.

Long noncoding RNA ANRIL indicates a poor prognosis of gastric cancer and promotes tumor growth by epigenetically silencing of miR-99a/miR-449a.

Long noncoding RNAs are involved in diseases including cancer. Here, we reported that ANRIL (CDKN2B-AS1), a 3.8-kb long noncoding RNA, recruiting and binding to PRC2, was generally upregulated in human gastric cancer (GC) tissues. In a cohort of 120 GC patients, the higher expression of ANRIL was significantly correlated with a higher TNM stage (P=0.041) and tumor size (P=0.001). Multivariate analyses revealed that ANRIL expression served as an independent predictor for overall survival (P=0.036). Further experiments revealed that ANRIL knockdown significantly repressed the proliferation both in vitro and in vivo. We also showed that E2F1 could induce ANRIL and ANRIL-mediated growth promotion is in part due to epigenetic repression of miR-99a/miR-449a in Trans (controlling the targets--mTOR and CDK6/E2F1 pathway) by binding to PRC2, thus forming a positive feedback loop, continuing to promote GC cell proliferation. To our knowledge, this is the first report showed that the role of ANRIL in the progression of GC and ANRIL could crosstalk with microRNAs in epigenetic level. Our results suggest that ANRIL, as a growth regulator, may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer.