Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been reported to be highly expressed in white adipose tissue (WAT) and are associated with the progression of inflammation ...and the development of insulin resistance in obese humans and mice. However, the role of CCL5/CCR5 signaling in obesity-associated dysregulation of energy metabolism remains unclear. Here, we demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold stress-induced energy expenditure and thermogenic function in brown adipose tissue (BAT) than wildtype (WT) mice. DKO mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than WT mice. KEGG pathway analysis indicated that deletion of CCL5/CCR5 further facilitated the cold-induced expression of genes related to oxidative phosphorylation (OxPhos) and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the augmentation of CL-316243-stimulated thermogenic and lipolysis responses was reversed by co-treatment with AMPKα1 and α2 short interfering RNA (siRNA). Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice suppressed cold stress-induced lipolytic processes and thermogenic activities. In contrast, knockdown of BAT CCL5/CCR5 signaling further up-regulated AMPK phosphorylation as well as thermogenic and lipolysis responses to chronic adrenergic stimuli and subsequently decreased level of body weight gain. Chronic knockdown of BAT CCL5/CCR5 signaling improved high-fat diet (HFD)-induced insulin resistance in WT mice. It is suggested that obesity-induced augmentation of adipose tissue (AT) CCL5/CCR5 signaling could, at least in part, suppress energy expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and oxidative metabolism in thermogenic AT to exacerbate the development of obesity and insulin resistance.
Abdominal adiposity is strongly associated with diabetic and cardiovascular comorbidities. The long noncoding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is an important epigenetic regulator ...with fat depot-specific expression. Its functional roles and epigenetic regulation in abdominal adipogenesis remain uncertain.
We collected different fat depots from healthy, severely obese, and uraemic subjects to measure fat-depot specific gene expression and quantify regional adiposity via dual-energy X-ray absorptiometry (DXA). HOTAIR was overexpressed to evaluate its functional roles. Reduced representation bisulfite sequencing (RRBS), RNA-sequencing, real-time qPCR and RNA/chromatin immunoprecipitation were performed to analyse HOTAIR-mediated epigenetic regulation.
A negative correlation between adipose tissue HOTAIR expression (arm or abdominal subcutaneous fat depots) and regional adiposity under the status of severe obesity or uraemia was observed. HOTAIR overexpression using human immortalized abdominal preadipocytes further revealed its anti-adipogenic effects. Integrative analysis of genome-wide DNA methylation by reduced representation bisulfite sequencing (RRBS) and gene expression was performed. Overall, the differentially methylated genes were functionally enriched for nervous system development, suggesting that HOTAIR may be epigenetically associated with cell lineage commitment. We specifically found that HOTAIR-mediated genes showed strong changes in both DNA methylation and gene expression during abdominal adipogenesis. We observed that two HOTAIR-repressed genes, SLITRK4 and PITPNC1, present an obesity-driven fat-depot specific expression pattern that is positively correlated with the central body fat distribution.
Our study indicated that HOTAIR is a key regulator of abdominal adipogenesis via intricate DNA methylation and is likely to be associated with the transcriptional regulation of genes involved in nervous system development and lipid metabolism, such as SLITRK4 and PITPNC1.
•HOTAIR was lowly expressed in abdominal and arm fats compared to the gluteal fat.•Fat-depot-specific HOTAIR expression could be altered in the obese or uraemic status.•HOTAIR overexpression suppressed abdominal adipogenesis and modulated methylome.•HOTAIR-suppressed genes were associated with neural development and lipid metabolism.
Background:
The risk of sudden sensorineural hearing loss associated with metformin use in patients with diabetes mellitus has not been fully examined.
Study design:
It is a retrospective ...matched-cohort study.
Subjects and methods:
We examined the medical records of patients with diabetes mellitus over 18 years old in Taiwan’s National Health Insurance Research Database for the period between 1 January 2000 and 31 December 2013, to establish matched cohorts (14,109 with and 42,327 without metformin use) at a ratio of 1:3 by sex, age and index year.
Results:
We used a Cox regression hazard model to identify risk factors of sudden sensorineural hearing loss during 14 years of follow-up, and the results indicate that a significantly lower percentage of diabetes mellitus patients with metformin use (p = 0.033) developed sudden sensorineural hearing loss compared with those without metformin use (0.21%, 29/14,109 vs 0.32%, 136/42,327). After adjustment for age and other variables adjusted hazard ratio: 0.630 (95% confidence interval: 0.422–0.941, p = 0.024), this study also demonstrated that metformin use appeared to reduce the risk of developing sudden sensorineural hearing loss.
Conclusion:
This study demonstrated an association between metformin use and lower incidence of sudden sensorineural hearing loss among patients with diabetes mellitus.
The urine albumin–creatinine ratio (uACR) is a warning for the deterioration of renal function in type 2 diabetes (T2D). The early detection of ACR has become an important issue. Multiple linear ...regression (MLR) has traditionally been used to explore the relationships between risk factors and endpoints. Recently, machine learning (ML) methods have been widely applied in medicine. In the present study, four ML methods were used to predict the uACR in a T2D cohort. We hypothesized that (1) ML outperforms traditional MLR and (2) different ranks of the importance of the risk factors will be obtained. A total of 1147 patients with T2D were followed up for four years. MLR, classification and regression tree, random forest, stochastic gradient boosting, and eXtreme gradient boosting methods were used. Our findings show that the prediction errors of the ML methods are smaller than those of MLR, which indicates that ML is more accurate. The first six most important factors were baseline creatinine level, systolic and diastolic blood pressure, glycated hemoglobin, and fasting plasma glucose. In conclusion, ML might be more accurate in predicting uACR in a T2D cohort than the traditional MLR, and the baseline creatinine level is the most important predictor, which is followed by systolic and diastolic blood pressure, glycated hemoglobin, and fasting plasma glucose in Chinese patients with T2D.
Chronic inflammation, a hallmark of gout, is implicated in the pathogenesis of atherosclerosis. Thus, in theory, gout can be expected to increase the risk of acute myocardial infarction (AMI). Yet, ...results from several epidemiological studies have been inconclusive. A retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohort comprised 3581 patients with gout (the gout cohort) and 14,324 patients without gout (the non-gout cohort). The primary outcome was the incidence of AMI. To estimate the effect of gout on the risk of AMI, the Lunn-McNeil competing risk model was fitted to estimate cause-specific hazard ratios (HRs) and their 95% confidence intervals (CIs). The cumulative incidence of AMI was significantly higher in the gout cohort than in the non-gout cohort, resulting in an adjusted HR of 1.36 (95% CI 1.04 to 2.76). Further, HRs of gout with incident AMI were higher in patients without hypertension, diabetes mellitus, or hyperlipidemia (ranging from 1.63 to 2.09) than in those with each of these comorbidities (ranging from 0.95 to 1.13). The results of this study suggest that patients with gout have an increased risk of AMI. The AMI risk associated with gout was conditional on patients' cardiovascular risk profile. Future work is needed to confirm these findings.
This study investigated the effect of a combination of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and basal insulin (BI) in poorly controlled type 2 diabetes mellitus previously treated with ...premixed insulin. The possible therapeutic benefit of the subject is mainly hoped to provide a direction for optimizing treatment options to reduce the risk of hypoglycemia and weight gain. A single-arm, open-label study was conducted. The antidiabetic regimen was switched to GLP-1 RA plus BI to replace previous treatment with premixed insulin in type 2 diabetes mellitus subjects. After 3 months of treatment modification, GLP-1 RA plus BI was compared for superior outcomes by continuous glucose monitoring system. There were 34 subjects at the beginning, 4 withdrew due to gastrointestinal discomfort, and finally 30 subjects completed the trial, of which 43% were male; the average age was 58 ± 9 years old, and the average duration of diabetes was 12 ± 6 years, the baseline glycated hemoglobin level was 8.6 ± 0.9 %. The initial insulin dose of premixed insulin was 61 ± 18 units, and the final insulin dose of GLP-1 RA + BI was 32 ± 12 units (P < .001). Time out of range (from 59%-42%), time-in-range (from 39%-56%) as well as glucose variability index including standard deviation also improved, mean magnitude of glycemic excursions, mean daily difference and continuous population in continuous glucose monitoring system, continuous overall net glycemic action (CONGA). Also noted was a decrease in body weight (from 70.9 kg-68.6 kg) and body mass index (all P values < .05). It provided important information for physicians to decide to modify therapeutic strategy as individualized needs.
Papillary thyroid cancer (PTC) is the most common endocrine malignancy with a fast-growing incidence in recent decades. HOTAIR as a long non-coding RNA has been shown to be highly expressed in ...papillary thyroid cancer tissues with only a limited understanding of its functional roles and downstream regulatory mechanisms in papillary thyroid cancer cells.
We applied three thyroid cancer cell lines (MDA-T32, MDA-T41 and K1) to investigate the phenotypic influence after gain or loss of HOTAIR. The Cancer Genome Atlas (TCGA) database were utilised to select candidate genes possibly regulated by HOTAIR with validation in the cellular system and immunohistochemical (IHC) staining of PTC tissues.
We observed HOTAIR was highly expressed in MDA-T32 cells but presents significantly decreased levels in MDA-T41 and K1 cells. HOTAIR knockdown in MDA-T32 cells significantly suppressed proliferation, colony formation, migration with cell cycle retardation at G1 phase. On the contrary, HOTAIR overexpression in MDA-T41 cells dramatically enhanced proliferation, colony formation, migration with cell cycle driven toward S and G2/M phases. Similar phenotypic effects were also observed as overexpressing HOTAIR in K1 cells. To explore novel HOTAIR downstream mechanisms, we analyzed TCGA transcriptome in PTC tissues and found DLX1 negatively correlated to HOTAIR, and its lower expression associated with reduced progression free survival. We further validated DLX1 gene was epigenetically suppressed by HOTAIR via performing chromatin immunoprecipitation. Moreover, IHC staining shows a significantly stepwise decrease of DLX1 protein from normal thyroid tissues to stage III PTC tissues.
Our study pointed out that HOTAIR is a key regulator of cellular malignancy and its epigenetic suppression on DLX1 serves as a novel biomarker to evaluate the PTC disease progression.
Background:
Numerous studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4i) may regulate immunological pathways implicated in asthma. The association between DPP-4i use and risk of asthma ...development is limited, however.
Aim:
We aimed to evaluate if DPP-4i treatment in individuals with type 2 diabetes mellitus (T2DM) is associated with a lower risk and severity of asthma.
Methods:
We performed a population-based retrospective cohort study using the Longitudinal National Health Insurance Research database between 2008 and 2015. After one-to-four propensity score matching from 1,914,201 patients with defined criteria, we enrolled 3001 patients who were on DPP-4i (DPP-4i group) for a diagnosis of T2DM but without a diagnosis of asthma for further analysis. Cox proportional hazards regression analysis was performed to estimate and compare the risk of developing and severity of asthma, including no acute exacerbations event (No-AE), acute exacerbations (AEs), status asthmaticus (Status), and required endotracheal intubation (ET-tube intubated), between the two groups.
Results:
The participants had a mean age of 66.05 ± 17.23 years and the mean follow-up time was 4.96 ± 4.39 years. The risk of asthma development was significantly lower in the DPP-4i group than in the non-DPP-4i group adjusted hazard ratio (HR) = 0.65; 95% confidence interval (CI) = 0.29–0.83; p < 0.001, with a class effect. This trend was observed for severity of asthma as No-AE (HR = 0.55; 95% CI = 0.24–0.70; p < 0.001), AE (HR = 0.57; 95% CI = 0.26–0.73; p < 0.001), and Status (HR = 0.78; 95% CI = 0.35–0.99; p = 0.047), but not in ET-tube intubated cases (HR = 0.96; 95% CI = 0.43–1.22; p = 0.258).
Conclusion:
The use of DPP-4i decreased the risk and severity of asthma with a class effect among No-AE, AE, status of asthma events, but not in ET-tube intubated events. Our report suggests that DPP-4i may play a role in attenuating the impact of asthma on incidence in the future and on more severe forms of disease exacerbation in T2DM patients.
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