Islet-resident macrophage-derived miR-155 promotes ß cell decompensation via targeting PDX1.

Chronic inflammation is critical for the initiation and progression of type 2 diabetes mellitus via causing both insulin resistance and pancreatic ß cell dysfunction. miR-155, highly expressed in macrophages, is a master regulator of chronic inflammation. Here we show that blocking a macrophage-derived exosomal miR-155 (MDE-miR-155) mitigates the insulin resistances and glucose intolerances in high-fat-diet (HFD) feeding and type-2 diabetic db/db mice. Lentivirus-based miR-155 sponge decreases the level of miR-155 in the pancreas and improves glucose-stimulated insulin secretion (GSIS) ability of ß cells, thus leading to improvements of insulin sensitivities in the liver and adipose tissues. Mechanistically, miR-155 increases its expression in HFD and db/db islets and is released as exosomes by islet-resident macrophages under metabolic stressed conditions. MDE-miR-155 enters ß cells and causes defects in GSIS function and insulin biosynthesis via the miR-155-PDX1 axis. Our findings offer a treatment strategy for inflammation-associated diabetes via targeting miR-155.

ß-Cell miRNA-503-5p Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and ß-Cell Decompensation.

Chronic inflammation promotes pancreatic ß-cell decompensation to insulin resistance because of local accumulation of supraphysiologic interleukin 1ß (IL-1ß) levels. However, the underlying molecular mechanisms remain elusive. We show that miR-503-5p is exclusively upregulated in islets from humans with type 2 diabetes and diabetic rodents because of its promoter hypomethylation and increased local IL-1ß levels. ß-Cell-specific miR-503 transgenic mice display mild or severe diabetes in a time- and expression-dependent manner. By contrast, deletion of the miR-503 cluster protects mice from high-fat diet-induced insulin resistance and glucose intolerance. Mechanistically, miR-503-5p represses c-Jun N-terminal kinase-interacting protein 2 (JIP2) translation to activate mitogen-activated protein kinase signaling cascades, thus inhibiting glucose-stimulated insulin secretion (GSIS) and compensatory ß-cell proliferation. In addition, ß-cell miR-503-5p is packaged in nanovesicles to dampen insulin signaling transduction in liver and adipose tissues by targeting insulin receptors. Notably, specifically blocking the miR-503 cluster in ß-cells effectively remits aging-associated diabetes through recovery of GSIS capacity and insulin sensitivity. Our findings demonstrate that ß-cell miR-503-5p is required for the development of insulin resistance and ß-cell decompensation, providing a potential therapeutic target against diabetes. ARTICLE HIGHLIGHTS: Promoter hypomethylation during natural aging permits miR-503-5p overexpression in islets under inflammation conditions, conserving from rodents to humans. Impaired ß-cells release nanovesicular miR-503-5p to accumulate in liver and adipose tissue, leading to their insulin resistance via the miR-503-5p/insulin receptor/phosphorylated AKT axis. Accumulated miR-503-5p in ß-cells impairs glucose-stimulated insulin secretion via the JIP2-coordinated mitogen-activated protein kinase signaling cascades. Specific blockage of ß-cell miR-503-5p improves ß-cell function and glucose tolerance in aging mice.

Expression of miRNA-29 in Pancreatic ß Cells Promotes Inflammation and Diabetes via TRAF3.

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic ß cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key ß cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. ß cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of ß cell miR-29 is largely mediated through macrophages because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and macrophages and, hence, inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of ß cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.

Inhibition of miR-153, an IL-1ß-responsive miRNA, prevents beta cell failure and inflammation-associated diabetes.

OBJECTIVE: Systemic levels of up-regulated IL-1ß and IL-1 receptors promote the pathogenesis of inflammation-associated diabetes. IL-1 receptor antagonist (IL-Ra) has shown slightly elevated beta cell function in patients with type 2 diabetes without significant improvement of hyperglycaemia. We investigated whether miR-153, an IL-1ß responsive miRNA, could mimic IL-1ß effects and whether its interruption would improve blood glucose control then offer an assistant curative approach to inflammation-associated diabetes. MATERIALS/METHODS: Antago-miR-153 and Ago-miR-153 were injected into the abdominal aorta of leptin receptor-mutant db/db mice and C57BL/6 J mice, respectively. Blood glucose levels, glucose tolerance tests, insulin tolerance tests and insulin levels were regularly checked. Proteomic profiling combined with unbiased bioinformatics analysis, as well as experimental techniques, were utilized to identify target genes of miR-153. Anti-miR-153 and plasmid-based recovery assays were also performed using primary mouse islets and beta cell lines. RESULTS: The miR-153 expression level was increased in IL-1ß-treated beta cells and primary islets from the diabetic rodents. Pancreas overexpression of miR-153 caused glucose intolerance in C57BL/6 J mice but no alterations in body weight or insulin sensitivity. The inhibition of miR-153 temporarily reduced hyperglycaemia of db/db mice due to enhanced insulin secretion. Antago-miR-153 treatment ameliorated glucose intolerance in db/db mice during our observation period but did not improve insulin sensitivity. Mechanistically, miR-153 targeted three members of SNAREs to disturb insulin granule docking, thereby decreasing basal insulin secretion. Overexpression of anti-miR-153 or SNARE rescued the IL-1ß-induced basal insulin secretion defect. Furthermore, miR-153 targeted beta cell-specific transcriptional factors and survival molecules to inhibit insulin biosynthesis and cell viability. CONCLUSIONS: The IL-1ß-responsive miR-153 targets SNAREs, beta cell specific TFs and other key factors to eventually causes beta cell failure. Inhibiting miR-153 with Antago-miR-153 prevents hyperglycaemia in db/db mice, indicating that miR-153 may be a promising therapeutic target for the treatment of inflammation-associated diabetes.

[Psychological anxiety evaluation and analysis of graduates at a medical university under employment pressure].

OBJECTIVE: To evaluate the psychological anxiety of graduates at a medical university under the ever-increasing employment pressure, so as to provide ground work for psychological intervention on college students. METHODS: Subjects were randomly drawn from the students who majored in clinical medicine, biomedical engineering, nursing and integrated Chinese and western medicine and graduated in the year of 2008 and 2009, with 25 subjects from each major each year, totaling up to 200. In March of their graduation year, they were evaluated by Hamilton Anxiety Scale (HAMA). A general analysis into their anxiety was first made and then the comparative analysis of anxiety on the basis of gender, year group and major of the subjects. RESULTS: Female students showed a significantly higher anxiety than male students. Graduates in 2009 showed a significantly higher anxiety than those in 2008. In terms of the major difference, the anxiety was in a falling curve from integrated Chinese and western medicine, clinical medicine, biomedical engineering and nursing. There was no major difference in the students majoring integrated Chinese and western medicine, clinical medicine and biomedical engineering, but nursing students showed significantly low anxiety. CONCLUSIONS: The increasing employment pressure has caused the significant increase in the anxiety of college students. The employment rate in different majors may play a positive role in anxiety. Generally, female students showed a higher degree of anxiety than male students.