miR-344-5p Modulates Cholesterol-Induced ß-Cell Apoptosis and Dysfunction Through Regulating Caveolin-1 Expression.

Diabetes is a metabolic disorder induced by the modulation of insulin on glucose metabolism, and the dysfunction and decreased number of islets ß-cells are the main causes of T2DM (type 2 diabetes mellitus). Among multiple factors that might participate in T2DM pathogenesis, the critical roles of miRNAs in T2DM and ß-cell dysfunction have been reported. Through bioinformatics analyses and literature review, we found that miR-344 might play a role in the occurrence and progression of diabetes in rats. The expression levels of miR-344-5p were dramatically decreased within cholesterol-stimulated and palmitic acid (PA)-induced rats' islet ß-cells. In cholesterol-stimulated and PA-induced diabetic ß-cell model, cholesterol-caused and PA-caused suppression on cell viability, increase in intracellular cholesterol level, decrease in GSIS, and increase in lip droplet deposition were dramatically attenuated via the overexpression of miR-344-5p, whereas aggravated via the inhibition of miR-344-5p. miR-344-5p also inhibited cholesterol-induced ß-cell death via affecting the apoptotic caspase 3/Bax signaling. Insulin receptor downstream MPAK/ERK signaling was involved in the protection of miR-344-5p against cholesterol-induced pancreatic ß-cell dysfunction. Moreover, miR-344-5p directly targeted Cav1; Cav1 silencing could partially reverse the functions of miR-344-5p inhibition upon cholesterol-induced ß-cell dysfunction, ß-cell apoptosis, the apoptotic caspase 3/Bax signaling, and insulin receptor downstream MPAK/ERK signaling. In conclusion, the miR-344-5p/Cav1 axis modulates cholesterol-induced ß-cell apoptosis and dysfunction. The apoptotic caspase 3/Bax signaling and MAPK/ERK signaling might be involved.

Predictors of Type 2 Diabetes Mellitus Remission After Metabolic Surgery in Asian Patients with a BMI < 32.5 kg/m2.

BACKGROUND: Metabolic surgery is an effective treatment for type 2 diabetes mellitus (T2DM) in patients with obesity. However, the efficacy in patients with body mass index (BMI) < 32.5 kg/m2, especially in Asian populations, has not been widely reported, and there are few studies on the prediction of diabetes remission. METHODS: We evaluated 112 patients with T2DM who underwent metabolic surgery between October 2008 and November 2019. The basic data of the patients were collected, and clinical variables were measured at 6 months, 1 year, and 2 years after metabolic surgery. Four independent predictors of surgical outcomes were identified to construct the prediction score. RESULTS: Diabetes remission occurred for 38 of the 112 patients. Ninety patients underwent Roux-en-Y gastric bypass, while the remaining 22 patients underwent sleeve gastrectomy. Weight, glucose, and lipid metabolism parameters were improved significantly after metabolic surgery. Age, BMI, insulin use, and duration were independent predictors of T2DM remission. The above four factors were defined with scores and developed ABID (age, BMI, insulin use, duration) scoring system. Patients with greater ABID scores had a greater probability of diabetes remission (from 0% at score 0 to 100% at score 4). CONCLUSIONS: The ABID score is a simple and easy-to-implement prediction score system of diabetes remission after metabolic surgery for T2DM patients with a BMI < 32.5 kg/m2.

GLP1R Single-Nucleotide Polymorphisms rs3765467 and rs10305492 Affect ß Cell Insulin Secretory Capacity and Apoptosis Through GLP-1.

The increased secretion of glucagon-like peptide-1 (GLP-1) after Roux-en-Y gastric bypass (RYGB) is regarded as the main reason for the improvement of blood glucose. However, the single-nucleotide polymorphisms (SNPs) of GLP-1 Receptor (GLP1R) impair receptor function, subsequently affecting ß cell insulin secretion function, ultimately affecting the efficacy of RYGB. In this study, we revealed that two SNPs in GLP1R gene, rs3765467 and rs10305492, could significantly reduce the insulin secreted by ß cells and the cyclic AMP concentration, whereas promote ß cell apoptosis. Under high glucose exposure, rs3765467 and rs10305492 impaired ß cell secretion of insulin and ß cell viability in the same way; in other words, GLP1R rs3765467 and rs10305492 exert an effect on pancreatic ß cell glucose-stimulated insulin secretion. Moreover, GLP-1 antagonist Exendin (9-39) further enhanced, whereas GLP-1 agonist Exendin-4 partially attenuated the effects of SNPs on the functions and apoptosis of ß cells. In conclusion, the rs3765467 and rs10305492 SNPs in GLP1R show to exert a critical effect on regulating insulin secretory capacity of ß cells and ß cell mass. Through leading to the dysfunction and apoptosis of ß cells, GLP1R rs3765467 and rs10305492 might also impair GLP-1 interaction with GLP1R, therefore attenuating the therapeutic effect of RYGB.

Effect of Roux-en-Y Gastric Bypass for Patients with Type 2 Diabetes Mellitus and a BMI < 32.5 kg/m2: a 6-Year Study in Chinese Patients.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is an effective treatment for morbidly obese patients to improve type 2 diabetes mellitus (T2DM). Recently, T2DM patients with a lower body mass index (BMI) have been receiving more attention, and these patients could benefit from RYGB. METHODS: Fifty-two patients with T2DM underwent RYGB between October 2008 and December 2012 in our hospital. Weight, BMI, oral glucose tolerance test (OGTT), insulin release test (IRT), C-peptide release test (CRT), glycosylated hemoglobin (HbA1c), and lipid metabolic parameters were measured at baseline and at 3 and 6 months and 1, 2, 3, 4, 5, and 6 years after surgery. RESULTS: The mean age of the 52 patients was 46.8 ± 9.5 years, and 57.7% were male. The mean duration of T2DM was 6.5 ± 4.6 years. Compared with the baseline values, weight and BMI were significantly decreased at several time points after surgery. HbA1c decreased from 8.2 ± 1.7% at baseline to 6.5 ± 1.4% at 3 months, 6.5 ± 1.4% at 6 months, 7.2 ± 1.3% at 4 years, and 7.5 ± 1.2% at 6 years. OGTT, OGTT-IRT, and OGTT-CRT improved after surgery. There was a decrease in triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein (LDL) and an increase in high-density lipoprotein (HDL). At 6 years after surgery, 16.7% of patients achieved complete remission of T2DM, and 66.7% achieved improvement in T2DM. CONCLUSION: RYGB may be a safe and effective treatment for T2DM patients with a BMI < 32.5 kg/m2 in China. However, a long-term study without loss to follow-up is necessary for better evaluation.

The Relationship Between BMI, Body Composition, and Fat Mass Distribution in Rou-en-Y Gastric Bypass Patients.

BACKGROUND: Type 2 diabetes mellitus (T2DM) with central obesity is a common clinical presentation in Chinese patients. Body mass index (BMI) is a criterion determining central obesity that, when combined with dual-energy X-ray absorptiometry (DXA), accurately reflects body composition and fat mass distribution. The utility of DXA-derived measures in the evaluation of metabolic surgery still needs to be investigated. METHODS: In this cohort study, 78 Chinese patients with central obesity (WC ≥ 90 cm for males, WC ≥ 85 cm for females) or BMI above 27.5 kg/m2 underwent gastric bypass between October 2010 and October 2012. The patients were followed for 12 months. Preoperative, perioperative, and postoperative metabolic parameters and DXA results were prospectively collected and analyzed. RESULTS: A total of 57 of 78 cases (73.1%) were diagnosed with central obesity. There was a significant decrease in BMI, WC, and WHR at each point in time (P < 0.05), with fasting plasma glucose (FPG), fasting insulin secretion (FINS), and the homeostasis model assessment of insulin resistance index (HOMA-IR) also significantly improved. Body fat mass percentage (%BF) results showed significant decreases in different regions. %BF regions, except for trunk region %BF, were significantly correlated with BMI and WC (P < 0.01). Pearson correlation coefficients of 0.562 and 0.577 were evident between BMI and total %BF, and android %BF and WC, respectively. Linear regression analysis was conducted to assess the linear relationship between BMI and %BF, and android %BF, WC, and WHR; linear formulas were derived. CONCLUSIONS: %BF is a more significant predictor of obesity, with BMI significantly underestimating visceral adipose tissue (VAT). In addition to BMI, total %BF and android %BF have clinical utility as indicators for metabolic surgery evaluation as well as patient selection.

The Effect of Bariatric Surgery on Asian Patients with Type 2 Diabetes Mellitus and Body Mass Index < 30 kg/m2: a Systematic Review and Meta-analysis.

BACKGROUND: The effect of bariatric surgery on the glycemic control of patients with obesity and type 2 diabetes mellitus is obvious. However, the effect in patients with body mass index (BMI) < 30 kg/m2 especially Asian population has not been widely reported and acknowledged. METHODS: We performed a literature search in Medline, Embase, and the Cochrane Library from January 2000 to March 2018. All the studies involving the effect of bariatric surgery on patients with type 2 diabetes and BMI < 30 kg/m2 from Asian countries or regions were included in this meta-analysis. RESULTS: Twelve studies including 697 patients were examined in this meta-analysis. Clinical indexes in 6, 12, and 24 months follow-up were analyzed, respectively. BMI and waist circumference reduced by 2.88 kg/m2 and 12.92 cm, respectively, at 12 months postoperatively. There were reductions in fasting plasma glucose, 2-h postprandial plasma glucose, and glycated hemoglobin A1c at all the three time points after surgery, 3.13 mmol/L, 5.46 mmol/L, and 2.13% at 6 months; 3.22 mmol/L, 6.46 mmol/L, and 2.38% at 12 months; 1.99 mmol/L, 5.84 mmol/L, and 1.58% at 2 years. Insulin only reduced by 1.70 µU/ml at 12 months. C-peptide reduced by 0.70 ng/ml and 0.40 ng/ml at 6 months and 2 years. Bariatric surgery led to reduction in total cholesterol, triglyceride, and low-density lipoprotein cholesterol, while augment in high-density lipoprotein cholesterol at 6 and 12 months. Glucagon-like peptide 1 increased by 2.48 pmol/L and 4.00 pmol/L at half a year 1 year. CONCLUSIONS: Asian patients with type 2 diabetes and BMI < 30 kg/m2 could achieve significant improvement in weight, glycemic control, lipid profiles, and ß-cell function in short and medium terms after bariatric surgery, but long-term follow-up is necessary to evaluate the effectiveness.

Bromodomain protein 4 is a novel predictor of survival for gastric carcinoma.

Expression of bromodomain protein 4 (BRD4) has been reported to predict a worse prognosis in solid tumors. However, its expression profile and prognostic value in gastric carcinoma (GC) remains unknown. Here we investigated BRD4 expression in GC and explored its association with patient survival. Tissue samples were obtained from 95 GC patients who underwent surgical resection to remove the primary tumor from January 2009 to December 2010. Immunohistochemistry was used to detect the expression of BRD4 in GC tissues and adjacent normal tissues. Kaplan-Meier survival curves and Cox proportional hazards regression were used to analyze the data of BRD4 expression profile and clinicopathological characteristics. Immunohistochemical analysis revealed BRD4 was overexpressed in GC tissue compared with adjacent normal tissue. BRD4 expression was significantly associated with TNM stage (p < 0.001), lymphatic permeation (p = 0.011), and vital status at the end of follow-up (p < 0.001). Kaplan-Meier survival curves and the log-rank test demonstrated that higher BRD4 expression was an adverse predictive factor for survival in GC. Multivariate analysis by Cox proportional hazards regression revealed that BRD4 expression was an independent worse prognostic factor in GC. In conclusion, BRD4 could act as a potential biomarker for prognostic assessment of GC.

Potential analgesic effects of a novel N-acylethanolamine acid amidase inhibitor F96 through PPAR-α.

Pharmacological blockade of N-acylethanolamine acid amidase (NAAA) activity is an available approach for inflammation and pain control through restoring the ability of endogenous PEA. But the recently reported NAAA inhibitors suffer from the chemical and biological unstable properties, which restrict functions of NAAA inhibition in vivo. It is still unrevealed whether systematic inhibition of NAAA could modulate PEA-mediated pain signalings. Here we reported an oxazolidinone imide compound 3-(6-phenylhexanoyl) oxazolidin-2-one (F96), which potently and selectively inhibited NAAA activity (IC50 = 270 nM). Intraperitoneal (i.p.) injection of F96 (3-30 mg/kg) dose-dependently reduced ear edema and restored PEA levels of ear tissues in 12-O-Tetradecanoylphorbol-13-acetate (TPA) induced ear edema models. Furthermore, F96 inhibited acetic acid-induced writhing and increased spared nerve injury induced tactile allodynia thresholds in a dose-dependent manner. Pharmacological effects of F96 (10 mg/kg, i.p.) on various animal models were abolished in PPAR-α(-/-) mice, and were prevented by PPAR-α antagonist MK886 but not by canabinoid receptor type 1 (CB1) antagonist Rimonabant nor canabinoid receptor type 2 (CB2) antagonist SR144528. Zebrafish embryos experiments showed better security and lower toxicity for F96 than ibuprofen. These results revealed that F96 might be useful in treating inflammatory and neuropathic pain by NAAA inhibition depending on PPAR-α receptors.