To explore the clinical significance of seven diabetes-related serum microRNAs (miR-9, miR-29a, miR-30d, miR34a, miR-124a, miR146a and miR375) during the pathogenesis of type 2 diabetes (T2D), 56 subjects were recruited to this study: 18 cases of newly diagnosed T2D (n-T2D) patients, 19 cases of pre-diabetes individuals (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) and 19 cases of T2D-susceptible individuals with normal glucose tolerance (s-NGT). Serum miRNAs were determined by real-time RT-PCR. Expression levels of single miRNAs and the expression signatures of miRNAs as a panel were analysed among the three groups. In n-T2D, all 7 miRNAs were significantly up-regulated compared with s-NGT and five were significantly up-regulated compared with pre-diabetes, while miRNA expression was not significantly different between s-NGT and pre-diabetes. By Canonical discriminant analysis, 70.6% of n-T2D subjects (12/17) were recognized by canonical discriminant function, while s-NGT and pre-diabetes subjects could not be discriminated from each other. Similar results were found in Hierarchical Clustering analysis based on the expression levels of all seven miRNAs. In different statistical analysis, miR-34a always showed the most significant differences. We conclude that the expression levels of seven diabetes-related miRNAs in serum were significantly elevated in n-T2D compared with pre-diabetes and/or s-NGT, and the latter two groups featured similar expression patterns of these miRNAs, suggesting that during the pathogenesis of T2D, the peripheral diabetes-related miRNAs have not changed significantly from s-NGT at pre-diabetic stage.

Both peroxisome proliferator-activated receptor-alpha (PPARalpha) and pancreatic/duodenal homeobox-1 (PDX-1) have been reported to be associated with glucose-stimulated insulin secretion (GSIS), but the relationship between PPARalpha and PDX-1 is not yet fully understood. In the present study, we tested the hypothesis that PPARalpha regulates the expression of PDX-1 in beta-cells. Isolated pancreatic islets from Wistar rats and rat pancreatic insulinoma (INS-1) beta-cells were cultured in media supplemented with and without 0.2 or 0.4 mm palmitate, and treated with and without a PPARalpha agonist (fenofibrate) or PPARalpha antagonist (MK886). Results indicated that treatment with fenofibrate significantly enhanced PPARalpha mRNA and protein expression in cells cultured with elevated palmitate concentrations compared with cells that did not receive fenofibrate treatment. In turn, this enhanced expression led to an increase in PDX-1 mRNA and nuclear protein, as well as DNA binding activity of PDX-1 with the insulin promoter. Accordingly, the expression of the PDX-1 downstream targets, insulin and glucose transporter-2, increased, resulting in increased intracellular insulin content and GSIS. Treatment with MK886 inhibited expression of PPARalpha, blocking PPARalpha-regulated PDX-1 expression, and the downstream transcription events of PDX-1. EMSA revealed that nuclear protein might bind with the peroxisome proliferator response element sequence located in the PDX-1 promoter. Collectively, these results demonstrate a regulatory relationship between PPARalpha and PDX-1 in INS-1 cells. Furthermore, PPARalpha activation potentiates GSIS under elevated palmitate conditions possibly via up-regulation of PDX-1. Our findings have potential clinical implications for the use of PPARalpha agonists in the treatment of type 2 diabetes.

Our findings strongly suggested that the two novel mutations in the SLC12A3 gene are the causative agents of GS, which may provide further insights into the function of this gene and help clinicians better understand this disorder.

Short DNA motifs are involved in a multitude of functions such as for example chromosome segregation, DNA replication or mismatch repair. Distribution of such motifs is often not random and the specific chromosomal pattern relates to the respective motif function. Computational approaches which quantitatively assess such chromosomal motif patterns are necessary. Here we present a new computer tool DistAMo (Distribution Analysis of DNA Motifs). The algorithm uses codon redundancy to calculate the relative abundance of short DNA motifs from single genes to entire chromosomes. Comparative genomics analyses of the GATC-motif distribution in γ-proteobacterial genomes using DistAMo revealed that (i) genes beside the replication origin are enriched in GATCs, (ii) genome-wide GATC distribution follows a distinct pattern, and (iii) genes involved in DNA replication and repair are enriched in GATCs. These features are specific for bacterial chromosomes encoding a Dam methyltransferase. The new software is available as a stand-alone or as an easy-to-use web-based server version at http://www.computational.bio.uni-giessen.de/distamo.

Hyperthyroidism is a clinical state that results from increased thyroid hormone levels which has a significant impact on cardiac function and structure. Graves' disease is the most common cause of hyperthyroidism in iodine-replete areas. Hyperthyroid heart disease may be associated with pulmonary hypertension in patients who have overt hyperthyroidism. To investigate the association of pulmonary hypertension induced by hyperthyroid heart disease and autoantibody, one hundred and one cases with hyperthyroid heart disease who were consecutively admitted to the inpatient department of endocrinology and metabolism of the Shandong Provincial Hospital between November 2014 and April 2018 were collected and analyzed statistically. According to the Independent samples T-test, variance analysis, chi-square test, Pearson linear correlation analysis, and logistic regression, there was a good correlation between pulmonary artery systolic pressure and thyroid stimulating hormone (TSH) and receptor antibodies (TRAb) (r = 0.264, P=0.025) (OR = 1.037, P=0.029), but there was no significant correlation between the pulmonary artery systolic pressure and other thyroid-related parameters (FT3, FT4, TSH, anti-TPO, and anti-TG). Based on variance analysis, PASP rose as the level of TRAb gets higher. What is more, patients with HHD combined with PH showed a significantly higher serum level of TRAb; moreover, serum TRAb concentration was remarkably correlated with the PASP level. Therefore, TRAb participates in the process of pulmonary hypertension caused by hyperthyroid heart disease.

Previous studies have demonstrated that sustained high leucine exposure decreases glucose-stimulated insulin secretion (GSIS). However, whether this effect is recoverable following the removal of leucine is unclear. Pancreatic/duodenal homeobox-1 (PDX-1) and its downstream target, glucose transporter 2 (GLUT2), are reported to be positively associated with insulin secretion. However, it also remains unclear whether the effect of leucine on GSIS is accompanied by alterations in PDX-1 and GLUT2. In the present study, insulin secretion, insulin content, PDX-1 and GLUT2 protein expression in INS-1 (rat insulinoma cell line) cells were assessed following a 24-h incubation in 40 mmol/l leucine. Half of the cells were incubated in leucine-free media for a further 24 h to observe the abovementioned effects. In contrast to the control, 40 mmol/l leucine for 24 or 48 h diminished GSIS at high glucose concentrations by 11% (P=0.026) or 22% (P=0.003), insulin content by 14% (P=0.008) or 20% (P=0.002), as well as decreasing PDX-1 and GLUT2 expression. When leucine was removed from the media for a further 24-h incubation, in comparison with those cells that were maintained in leucine treatment for 24 and 48 h, the high GSIS increased by 13% (P=0.032) and 27% (P=0.002), insulin content was augmented by 10% (P=0.014) and 20% (P=0.003), and the protein expression of PDX-1 and GLUT2 also increased. The present study demonstrates that sustained high concentrations of leucine induce a reversible impairment of GSIS and alter insulin content, which is mediated by PDX-1 and GLUT2, in INS-1 cells.

AimBranched-chain amino acids (BCAAs) have been reported owning curative effects in early diabetic nephropathy. However, the mechanisms of its action have not been elucidated. The aim of this study is to investigate the effect of possible mechanism(s) of BCAAs on cultured rat mesangial cells (RMCs).MethodsRMCs were treated with high glucose (30 mmol/L) and BCAAs (10 mmol/L) respectively. Cell proliferation was detected using an MTT assay. Expression of transforming growth factor (TGF)-β1 and gremlin mRNA was detected by semiquantitative reverse-transcription (RT) PCR. TGF-β1 and fibronectin (FN) protein levels were measured using enzyme-linked immunosorbent assays (ELISAs). Gremlin, bone morphogenic protein (BMP)-7, and Smad2/3 proteins were detected by immunofluorescence. Smad1/5/8 and phosphorylated (p)-Smad1/5/8 were detected by Western blotting.ResultsThe proliferation rate of the RMCs in the high glucose group alone was 1.45-times of cells in the CON group, and it was reduced by 32% upon co-treatment with BCAAs. The expression of TGF-β1, gremlin, p-Smd2/3 and FN mRNA or protein in the HG group was higher than that in the CON group. In the BCAAs group, the corresponding levels were lower than that in HG group. The expression of BMP-7 and p-Smad1/5/8 were significantly lower in the HG group than in the CON group. Moreover, the expression of BMP-7 and p-Smad1/5/8 were higher in the BCAAs group than in the HG group.ConclusionBCAAs showed an antidiabetic effect via reducing TGF-β1-Smad2/3 pathway and Gremlin expression and upregulating BMP-7-Smad1/5/8 pathway in rat mesangial cells, consequently lessening ECM deposition in renal tissue.

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy is an international, peer-reviewed open-access journal committed to the rapid publication of the latest laboratory and clinical findings in the fields of diabetes, metabolic syndrome and obesity research. Original research, review, case reports, hypothesis formation, expert opinion and commentaries are all considered for publication. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.