Vitronectin promotes insulin resistance in trophoblast cells by activating JNK in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a common disorder in the clinic, which may lead to severe detrimental outcomes both for mothers and infants. However, the underlying mechanisms for GDM are still not clear. In the present study, we performed label-free proteomics using placentas from GDM patients and normal controls. Vitronectin caused our attention among differentially expressed proteins due to its potential role in the pathological progression of GDM. Vitronectin was increased in the placentas of GDM patients, which was confirmed by Western blot analysis. Vitronectin represses insulin signal transduction in trophoblast cells, whereas the knockdown of vitronectin further potentiates insulin-evoked events. Neutralization of CD51/61 abolishes the repressed insulin signal transduction in vitronectin-treated trophoblast cells. Moreover, vitronectin activates JNK in a CD51/61-depedent manner. Inhibition of JNK rescues impaired insulin signal transduction induced by vitronectin. Overall, our data indicate that vitronectin binds CD51/61 in trophoblast cells to activate JNK, and thus induces insulin resistance. In this regard, increased expression of vitronectin is likely a risk factor for the pathological progression of GDM. Moreover, blockade of vitronectin production or its receptors (CD51/61) may have therapeutic potential for dealing with GDM.

Recent advances of long non-coding RNAs in control of hepatic gluconeogenesis.

Gluconeogenesis is the main process for endogenous glucose production during prolonged fasting, or certain pathological conditions, which occurs primarily in the liver. Hepatic gluconeogenesis is a biochemical process that is finely controlled by hormones such as insulin and glucagon, and it is of great importance for maintaining normal physiological blood glucose levels. Dysregulated gluconeogenesis induced by obesity is often associated with hyperglycemia, hyperinsulinemia, and type 2 diabetes (T2D). Long noncoding RNAs (lncRNAs) are involved in various cellular events, from gene transcription to protein translation, stability, and function. In recent years, a growing number of evidences has shown that lncRNAs play a key role in hepatic gluconeogenesis and thereby, affect the pathogenesis of T2D. Here we summarized the recent progress in lncRNAs and hepatic gluconeogenesis.

Identification of methylation-driven genes, circulating miRNAs and their potential regulatory mechanisms in gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a major pregnancy complication. The purpose of this study is to investigate the molecular regulatory mechanisms of GDM. METHODS: RNA-seq and methylation data of GDM were retrieved from the Gene Expression Omnibus database. Following principal component analysis (PCA), differentially expressed mRNAs and microRNAs (miRNAs) in the blood were highlighted between GDM and the control. Then, an abnormally expressed miRNA-mRNA network was constructed, based on which a protein-protein interaction (PPI) network was established to identify hub genes. Differentially expressed and methylated genes were identified for GDM, followed by functional enrichment analysis. RESULTS: According to PCA results, no outlier samples were found. A total of 35 differentially expressed circulating miRNAs were identified for GDM. The miRNA-mRNA regulatory network consisted of 94 miRNA-mRNA pairs. The PPI network contained 10 hub genes, including HIF1A, TLR2, FOS, IL6R, MYLIP, ABCA1, SELL, BCL3, AP1G1 and NECAP1. Furthermore, 22 down-regulated and hypermethylated genes and 8 up-regulated and hypomethylated genes were identified for GDM, which are related to helper T cell (Th) differentiation. CONCLUSION: We identified methylation-driven genes and circulating miRNAs for GDM, which have the potential to serve as novel diagnostic biomarkers.

Decreased expression of programmed death-1 on CD8+ effector memory T lymphocytes correlates with the pathogenesis of type 1 diabetes.

AIMS: Chronic inflammation of autoimmune diseases, including type 1 diabetes (T1D), is mainly mediated by memory T(Tm) cells, predominantly effector memory T (Tem) cells. The roles of the programmed death-1 (PD-1) receptor on lymphocytes have been well studied in tumor and other infection models. However, little is known about the relationship between the expression of PD-1 on CD8+ Tem cells and the pathogenesis of T1D. METHODS: A total of 52 patients diagnosed with T1D and 39 gender-, age-, and ethnically matched health control individuals were enrolled in this study. Peripheral blood mononuclear cells from these individuals were isolated and analyzed by flow cytometry. We evaluated the frequencies of PD-1+ CD8+ memory T cell subsets from patients' peripheral blood with T1D and the spleen cells of nonobese diabetic (NOD) mice in the present study. We also investigated the effects of blocking PD-1/PD-L1 pathway on islet's inflammation in NOD mice. RESULTS: Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73 ± 12.72 vs 47.43 ± 15.56, *p < 0.05). The frequencies of PD-1+ CD8+ Tem cells were decreased in patients with T1D who were positive for two or more autoantibodies compared with the patients with one autoantibody (13.46% vs 46.95 ± 12.72%, *p < 0.05). Meanwhile, the frequencies of PD-1+ CD8+ central memory T (Tcm) cells were also significantly decreased in patients with two or more autoantibodies compared with other groups (≥ 2AAb vs HC 33.1 ± 8.92% vs 43.71 ± 11.78%, *p < 0.05; ≥ 2AAb vs AAb-33.1 ± 8.92% vs 41.65 ± 11.2%, *p < 0.05; ≥ 2AAb vs 1AAb 33.1 ± 8.92% vs 48.09 ± 10.58%, ***p < 0.001). The frequencies of PD-1+CD8+ Tem cells were positively correlated with fasting serum C-peptide levels (r = 0.4308, *p < 0.05) and C-peptide levels 2 h after meal in T1D patients (r = 0.5723, **p < 0.01). The frequencies of PD-1+CD8+ Tcm cells were only negatively correlated with the levels of HbA1c (r = - 0.2992, *p < 0.05). Similarly, the frequencies of PD-1+CD8+ Tem were significantly decreased in intervention group (anti-mouse PD-1 mAb) compared with the control group (14.22 ± 6.455% vs 27.69 ± 9.837%, *p < 0.05). Pathologically, CD8, PD-1 and PD-L1 were strongly expressed in the islets of diabetic mice after PD-1 blockade. CONCLUSIONS: It is the first report of the expression of PD-1 on CD8+ Tem cells in T1D in the present study. Our observations suggest that the PD-1/PD-L1 signal pathway on CD8+ Tem cells of T1D subjects might identify a new pathway for delaying the occurrence and development by inhibiting autoimmunity.

The expression of Tim-1 and Tim-4 molecules in regulatory T cells in type 1 diabetes.

PURPOSE: The TIM family comprises of eight genes in the mouse, three of which are conserved in humans (TIM-1, TIM-3, and TIM-4). Previous studies have revealed the relationships between Tim3+ Tregs and autoimmune disease. There was little study about the expression of Tim1 and Tim4 surface molecules on Tregs. We evaluated the frequency of the Tim1+Tregs and Tim4+Tregs in type 1 diabetes (T1D) in the present study. METHODS: A total of 28 patients with T1D and 14 gender-, age-, and ethnically matched healthy volunteers were recruited. PBMCs from these individuals were isolated and analyzed by flow cytometry. Splenocytes from mice were also analyzed by flow cytometry. RESULTS: There is no difference in the frequency of Treg cells in peripheral blood isolated from T1D patients. Tim1 on CD4+CD25+ T cells decreased significantly in PBMC of patients with T1D(1.19 ± 0.17% vs 2.78 ± 0.38%, 95% CI:0.87-2.31, P < 0.0001), while expression of Tim4 on CD4+CD25+ T cells in PBMC was less frequent in patients with T1D than healthy people(3.0 ± 0.39% vs 6.25 ± 1.08%, 95% CI:1.08-5.43, P = 0.0044). The frequencies of CD4+CD25+Tim1+ T cells and CD4+CD25+Tim4+ T cells also decreased in spleen of hyperglycemic NOD mice. There were no significant correlations between CD4+CD25+Tim1+T-cells, CD4+CD25+Tim4+T-cells and any clinical features such as age, HbA1c, Fasting C-peptide, diabetic autoantibodies, disease duration, total cholesterol, LDL, HDL, and TG. CONCLUSIONS: It is the first report of the expression of Tim1 and Tim4 molecules on Treg cells in T1D in the present study. We also presented evidence that the frequencies of Tim1+Tregs and Tim4+Tregs decreased significantly in both type 1 diabetic patients and hyperglycemic NOD mice. However, the specific functions of Tim1+Tregs and Tim4+Tregs are still unclear.