Loss of pancreatic β cells is involved in pathogenesis of gestational diabetes mellitus (GDM). Recently, several studies have elucidated the connection between microRNAs (miRNAs) and diabetes mellitus (DM), but the role of miRNAs in GDM remains unclear. The aim of this study was to evaluate the potential functions of miRNAs in GDM and to investigate the underlying mechanisms of action. First, we explored the expression profile of miRNAs in placenta tissue from GDM patients using microarray. Validation analysis was performed in peripheral blood specimens using quantitative reverse transcription PCR (qRT-PCR). Then the role and regulating mechanism of miR-503 in weaken the function of pancreatic β cell was investigated. We found that miR-503 was markedly upregulated in placenta tissue from GDM patients, as elevated in peripheral blood specimens, and the high level was positively correlated to blood glucose concentration. Knockdown of miR-503 enhanced insulin secretion of pancreatic β-cells, promoted cell proliferation and protected cells from apoptosis, whereas overexpression of miR-503 showed the opposite effects. Furthermore, mammalian target of rapamycin (mTOR) was identified as a direct target of miR-503 and mTOR silencing could reverse the improving effects of miR-503 knockdown on insulin secretion and pancreatic β-cells proliferation. High expression of miR-503 in peripheral blood may be acted as a diagnosis biomarker of GDM. MiR-503 regulated functions of pancreatic β-cells by targeting the mTOR pathway, suggesting that targeting miR-503/mTOR axis could serve as a novel therapeutic target for GDM.
Abstract Farnesoid X receptor (FXR) has been considered as a promising target for nonalcoholic steatohepatitis (NASH), while existing FXR agonists suffer from serious side effects. Thus, it is very necessary to identify novel FXR agonists with good safety. Auraptene (AUR) is a new FXR agonist with excellent safety and extensive pharmacological activities, while the lactone of AUR is vulnerable to esterolysis. In this study, the lactone of AUR was converted to metabolically stable amide moiety, and the obtained analog SU5 revealed comparable activity and better metabolic stability than that of AUR. In NASH model, SU5 showed stronger efficacy than AUR on fatty liver by upregulating gene expressions related to FXR in vivo. Moreover, SU5 improved lipid metabolism by downregulating the gene expressions of lipid synthesis, while upregulating the gene expressions of fatty acid β‐oxidation and triglyceride metabolism. Besides, the inflammation‐related genes were significantly decreased in SU5‐treated group. These positive results highlighted the pharmacological potential of SU5 for the treatment of NASH.
Abstract Frataxin (FXN) is required for iron-sulfur cluster biogenesis, and its loss causes the early-onset neurodegenerative disease Friedreich ataxia (FRDA). Loss of FXN is a susceptibility factor in the development of diabetes, a common metabolic complication after myocardial hypertrophy in patients with FRDA. The underlying mechanism of FXN deficient-induced hyperglycemia in FRDA is, however, poorly understood. In this study, we confirmed that the FXN deficiency mouse model YG8R develops insulin resistance in elder individuals by disturbing lipid metabolic homeostasis in adipose tissues. Evaluation of lipolysis, lipogenesis, and fatty acid β-oxidation showed that lipolysis is most severely affected in white adipose tissues. Consistently, FXN deficiency significantly decreased expression of lipolytic genes encoding adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) resulting in adipocyte enlargement and inflammation. Lipolysis induction by fasting or cold exposure remarkably upregulated FXN expression, though FXN deficiency lessened the competency of lipolysis compared with the control or wild type mice. Moreover, we found that the impairment of lipolysis was present at a young age, a few months earlier than hyperglycemia and insulin resistance. Forskolin, an activator of lipolysis, or pioglitazone, an agonist of PPARγ, improved insulin sensitivity in FXN-deficient adipocytes or mice. We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.
Objective
To study the single nucleotide polymorphism of rs13266634 (the genotype and the frequency) in SLC30A8 gene and its association with Gestational Diabetes Mellitus and relevant metabolic parameters.
Methods
A total of 451 24-28 weeks of pregnant women who visited Affiliated Hospital of Jining Medical College from October 2010 to March 2012 were enrolled in this case-control study. All the participants underwent 75 g oral glucose tolerance test (OGTT), 203 of them were diagnosed GDM (GDM group), and the others (248) were normal glucose tolerance (NGT group). The rs13266634 polymorphism in SLC30A8 gene was genotyped in 203 patients with Gestational Diabetes Mellitus and 248 pregnant women with normal glucose tolerance by PCR-RFLP analysis (polymerase chain reaction-restriction fragment length polymorphism). Meanwhile clinical characteristics such as body mass index(BMI), blood pressure(Bp), triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterin (LDL-C), high density lipoprotein cholesterin (HDL-C), etc were measured and calculated. HOMA-β and HOMA-IR were used to estimate β-cell function and insulin resistance. We used t-testing of independent samples to compare the difference between two groups and used analysis of variance to test the difference among the several groups. χ2analysis was used to compare the difference in genotype and allele frequencies. Logistic regression analysis was used to test for association between rs13266634 polymorphism in SLC30A8 gene and GDM.
Results
(1)In GDM group, the frequency of CC genotype (42.9%, 87/203) and C allele (65.5%, 266/406)were significantly higher than those (31.4%, 78/248 and 56.0%, 278/496)in the NGT group (χ2 were 6.259 and 8.362, both P<0.05); The TT genotype(11.8%, 24/203) and T allele(34.5%, 140/406) were significantly lower than those(19.4%, 48/248 and 44.0%, 218/496) in the NCT group (χ2 were 4.721 and 8.362, both P<0.05). (2)The C-allele significantly increased GDM risk with an allelic odd ratio (OR) of 1.49(OR=1.490, 95%CI: 1.136-1.953, P=0.004); Compared with non-carriers, homozygous carriers of C-allele were liable to have GDM with OR of 2.60(OR=2.600, 95%CI: 1.321-5.119, P=0.006). (3)From CC→CT→TT gene, HOMA-β level showed a growing trend (5.1±0.5→5.4±0.6→5.6±0.6, P<0.01).
Conclusions
The rs13266634 polymorphism in SLC30A8 gene is association with GDM in Shandong Jining, the C-allele might be a risk factor for GDM. SLC30A8 gene might be one of susceptible genes of GDM in this area.
Key words:
Single nucleotide polymorphism; SLC30A8 gene; Gestational diabetes mellitus; Association study
In inflammatory bowel disease microenvironment, transdifferentiation of myeloid-derived suppressor cells (MDSCs) and M2 macrophage accumulation are crucial for the transition of colitis-to-cancer. New insights into the cross-talk and the underling mechanism between MDSCs and M2 macrophage during colitis-to-cancer transition are opening new avenues for colitis-associated cancer (CAC) prevention and treatment.The role and underlying mechanism that granulocytic MDSCs (G-MDSCs) or exosomes (Exo) regulates the differentiation of monocytic MDSCs (M-MDSCs) into M2 macrophages were investigated using immunofluorescence, FACS, IB analysis, etc, and employing siRNA and antibodies. In vivo efficacy and mechanistic studies were conducted with dextran sulfate sodium-induced CAC mice, employed IL-6 Abs and STAT3 inhibitor.G-MDSCs promote the differentiation of M-MDSC into M2 macrophages through exosomal miR-93-5 p which downregulating STAT3 activity in M-MDSC. IL-6 is responsible for miR-93-5 p enrichment in G-MDSC exosomes (GM-Exo). Mechanistically, chronic inflammation-driven IL-6 promote the synthesis of miR-93-5 p in G-MDSC via IL-6R/JAK/STAT3 pathway. Early use of IL-6 Abs enhances the effect of STAT3 inhibitor against CAC.IL-6-driven secretion of G-MDSC exosomal miR-93-5 p promotes the differentiation of M-MDSC into M2 macrophages and involves a STAT3 signaling mechanism that promote colitis-to-cancer transition. Combining STAT3 inhibitors with strategies that inhibit IL-6-mediated G-MDSC exosomal miR-93-5 p production is beneficial for the prevention and treatment of CAC.
Objective: To investigate the clinical efficacy of glargine injected subcutaneously in bad-controlled diabetes mellitus. Methods: 80 patients with type 2 diabetes mellitus were divided into insulin glargine group (A) and NPH insulin group (B). Comparation was made between them in terms of fasting blood glucose (FBG), total daily insulin dose, duration of glycemic control, glycemic excursion and hypoglycemic episodes. Results: There was a significant difference between the two groups (P0.05). FBG, duration of glycemic controlling, glycemic excursion and hypoglycemic episode were lower in insulin glargine group than those in NPH group. Conclusion: Insulin glargine had greater efficacy in lowering blood glucose, it is also much safer than NPH insulin.
Diabetic peripheral neuropathy (DPN) is considered one of the most common chronic complications of diabetes. Impairment of mitochondrial function is regarded as one of the causes. Iron-sulfur clusters are essential cofactors for numerous iron-sulfur (Fe-S)-containing proteins/enzymes, including mitochondrial electron transport chain complex I, II, and III and aconitase.
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