Insulin resistance levels predicted metabolic improvement and weight loss after metabolic surgery in Chinese patients with type 2 diabetes.

BACKGROUND: The causes for failure of metabolic improvement and inadequate weight loss after metabolic surgery (MS) in Chinese patients with type 2 diabetes (T2D) have not been fully elucidated. The effect of insulin resistance (IR) on the outcome of T2D, hypertension, hyperlipidemia, and obesity after MS in Chinese patients with T2D and a body mass index (BMI) of 25-32.5 kg/m2 warrants further study. OBJECTIVES: Patients with T2D and a BMI of 25-32.5 kg/m2 who underwent MS between July 2019 and June 2021 were included. SETTING: University hospital, China. METHODS: IR levels were evaluated with the glucose disposal rate (GDR). Improvement of T2D, hypertension, and hyperlipidemia was assessed with the composite triple endpoint (CTEP), and weight loss was assessed with the percent of total weight loss (%TWL). Partial correlation analysis, binary logistic regression analysis, multiple linear regression analysis, receiver operating characteristic curve (ROC) analysis, and subgroup analysis were used to analyze the relationship between the CTEP, %TWL at 1 year postoperative, and GDR preoperative. RESULTS: This study analyzed the data of 51 patients with T2D and a BMI of 25-32.5 kg/m2 (30 men and 21 women) with a mean preoperative GDR of 3.72 ± 1.48 mg/kg/min. Partial correlation coefficients between CTEP, %TWL, and GDR were .303 (P = .041) and .449 (P = .001), respectively. The preoperative GDR was significantly positively correlated with CTEP (OR = 1.610, P = .024) and %TWL (ß = 1.38, P = .003). The preoperative GDR predicted cutoff values of 4.36 and 5.35 mg/kg/min for CTEP attainment and %TWL ≥ 20%, respectively. CONCLUSION: IR levels predicted metabolic improvement and weight loss 1 year after MS in Chinese patients with T2D and a BMI of 25-32.5 kg/m2.

Clinical factors associated with remission of obese acanthosis nigricans after laparoscopic sleeve gastrectomy: a prospective cohort study.

BACKGROUND: Acanthosis nigricans (AN) involves skin hyperpigmentation in body folds and creases. Obesity-associated AN (OB_AN) is the most common type of AN. The skin condition of obese patients with AN can be improved through bariatric surgery, such as laparoscopic sleeve gastrectomy (LSG), after weight loss. However, the contributing factors to the remission of AN after surgery are still not fully determined. The authors aimed to assess the metabolic and pathological factors associated with remission of AN following LSG in obese individuals. METHODS: The study included 319 obese patients who underwent LSG at our hospital. The subjects were divided into obesity (OB) only (OB, n =178) or OB with AN (OB_AN, n =141) groups. The basic clinical and metabolic indices and the dermatological features via reflectance confocal microscopy and histology were collected from patients prior to and after LSG. RESULTS: OB_AN patients had higher fasting plasma glucose, homeostatic model assessment for insulin resistance, and testosterone levels than OB patients. LSG could significantly improve the biochemical and histopathological features of OB_AN patients. The remissive rate of OB_AN patients was about 86.5% (122 out of 141) after surgery. The remission of OB_AN skin lesions was positively correlated with testosterone levels ( P <0.01). In addition, there was a significant positive correlation between changes in AN scores and epidermal thickness and skin pigmentation scores after surgery ( P <0.01). CONCLUSION: The remissive rate of OB_AN after LSG is associated with improved testosterone levels and reduced epidermal thickness and skin pigmentation levels.

Targeting survivin with Tanshinone IIA inhibits tumor growth and overcomes chemoresistance in colorectal cancer.

The inhibitor of apoptosis protein survivin has a critical regulatory role in carcinogenesis and treatment tolerance in colorectal cancer (CRC). However, the targeted drugs for survivin protein are extremely limited. In the present research, we discovered that Tanshinone IIA (Tan IIA) played a dual regulatory role in inhibiting tumorigenesis and reversing 5-Fu tolerance via modulating the expression and phosphorylation of survivin in CRC cells. Mechanistically, Tan IIA suppressed the Akt/WEE1/CDK1 signaling pathway, which led to the downregulation of survivin Thr34 phosphorylation and destruction of the interaction between USP1 and survivin to promote survivin ubiquitination and degradation. Furthermore, Tan IIA significantly facilitated chemoresistant CRC cells to 5-Fu sensitivity. These results revealed that Tan IIA possessed a strong antitumor activity against CRC cells and could act as an up-and-coming agent for treating CRC and overcoming chemotherapy resistance.

Sex-Specific Changes in Body Composition Following Metabolic and Bariatric Surgery Are Associated with the Remission of Metabolic Syndrome.

PURPOSE: Metabolic and bariatric surgery (MBS) is the most effective treatment for metabolic syndrome (MetS). However, the mechanism of MetS remission after MBS remains unclear. We aimed to explore the relationship between sex differences, body composition, and the remission of MetS after MBS. MATERIALS AND METHODS: Cross-sectional study of 80 patients with obesity and MetS who underwent MBS with case-control design. The International Diabetes Federation criteria were used to define MetS. Body composition was measured using dual-energy X-ray absorptiometry before and 1 year after the operation. In addition to calculating changes in MetS and its prevalence, we performed a multiple logistic regression to determine predictors of MetS remission. RESULTS: There were significant differences in body composition between males and females after MBS. Both males and females had significant improvements in the overall prevalence of MetS, decreasing from 100 to 21.74% (P <0.001) and from 100 to 35.29% (P <0.001), respectively. A higher percentage of visceral adipose tissue (VAT) reduction tends to be associated with a higher chance of MetS remission in men. In females, the MetS nonremission subgroup had a higher %Trunk lean body mass (LBM), and %Android LBM reduction than the remission subgroup, but the multiple logistic regression analysis result was not statistically significant. CONCLUSION: After MBS, reduced VAT might be related to MetS reversibility in males, while reduced LBM may result in MetS nonremission in females.

Effect of laparoscopic sleeve gastrectomy on mobilization of site-specific body adipose depots: a prospective cohort study.

BACKGROUND: Effect of bariatric surgery on mobilization of site-specific body adipose depots is not well investigated. Herein, the authors conducted a prospective cohort study to assess whether bariatric surgery can differentially affect specific fat storage pools and to further investigate correlations between site-specific fat mobilization and clinical outcomes. MATERIALS AND METHODS: In this single-centre prospective cohort study, 49 participants underwent laparoscopic sleeve gastrectomy (LSG) from 24 May 2022 to 20 October 2022 and underwent MRI to estimate subcutaneous fat area, visceral fat area (VFA), hepatic and pancreatic proton density fat fraction (PDFF) at baseline and 3 months after surgery. The protocol for this study was registered on clinicaltrials.gov. RESULTS: Among 49 patients who met all inclusion criteria, the median [interquartile range (IQR)] age was 31.0 (23.0-37.0) years, the median (IQR) BMI was 38.1 (33.7-42.2) kg/m 2 and 36.7% were male. Median (IQR) percentage hepatic PDFF loss was the greatest after bariatric surgery at 68.8% (47.3-79.7%), followed by percentage pancreatic PDFF loss at 51.2% (37.0-62.1%), percentage VFA loss at 36.0% (30.0-42.4%), and percentage subcutaneous fat area loss at 22.7% (17.2-32.4%) ( P <0.001). By calculating Pearson correlation coefficient and partial correlation coefficient, the positive correlations were confirmed between change in VFA and change in glycated haemoglobin ( r =0.394, P =0.028; partial r =0.428, P =0.042) and between change in hepatic PDFF and change in homoeostatic model assessment of insulin resistance ( r =0.385, P =0.025; partial r =0.403, P =0.046). CONCLUSIONS: LSG preferentially mobilized hepatic fat, followed by pancreatic fat and visceral adipose tissue, while subcutaneous adipose tissue was mobilized to the least extent. Reduction in visceral adipose tissue and hepatic fat is independently associated with the improvement of glucose metabolism after LSG.

Effects of Sleeve Gastrectomy on Patients with Obesity and Polycystic Ovary Syndrome: a Meta-analysis.

PURPOSE: This study aimed to evaluate the efficacy of sleeve gastrectomy (SG) on patients with obesity and polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science to identify relevant studies published prior to December 2, 2022. Meta-analysis was performed on menstrual irregularity, total testosterone, sex hormone-binding globulin (SHBG), anti-Mullerian hormone (AMH), glucolipid metabolism indicators, and body mass index (BMI) following SG. RESULTS: Six studies and 218 patients were included in the meta-analysis. Following SG, menstrual irregularity significantly decreased (odds ratio [OR] 0.03; 95% confidence intervals [CIs], 0.00-0.24; P=0.001). Additionally, SG can lower total testosterone levels (MD -0.73; 95% CIs -0.86-0.60; P< 0.0001), as well as BMI (MD -11.59; 95% CIs -13.10-10.08; P<0.0001). A significant increase was observed in the levels of SHBG and high-density lipoprotein (HDL) after SG. In addition to reducing fasting blood glucose, insulin, triglycerides (TG), and low-density lipoprotein levels, SG significantly reduced low-density lipoprotein levels as well. CONCLUSIONS: Following SG, we firstly demonstrated significant improvements in menstrual irregularity, testosterone and SHGB levels, glycolipid metabolism indicators, and BMI. Therefore, SG may be considered as a new option for the clinical treatment of patients with obesity and PCOS.

Disease-specific mortality and major adverse cardiovascular events after bariatric surgery: a meta-analysis of age, sex, and BMI-matched cohort studies.

BACKGROUND: Obesity is associated with a significant predisposition towards cardiovascular events and acts as an important risk factor for mortality. Herein, we conducted a comprehensive meta-analysis to estimate the protective effect of bariatric surgery on disease-specific mortality and major adverse cardiovascular events (MACEs) in patients with severe obesity. METHODS: PubMed and Embase were searched from inception to 4 June 2022. Eligible studies were age, sex, and BMI-matched cohort studies. The protocol for this meta-analysis was registered on PROSPERO (ID: CRD42022337319). RESULTS: Forty matched cohort studies were identified. Bariatric surgery was associated with a lower risk of disease-specific mortality including cancer mortality [hazard ratio with 95% confidence interval: 0.46 (0.37-0.58)], cardiovascular mortality [0.38 (0.29-0.50)], and diabetes mortality [0.25 (0.11-0.57)]. Bariatric surgery was associated with a lower incidence of MACEs [0.58 (0.51-0.66)] and its components including all-cause mortality [0.52 (0.47-0.58)], atrial fibrillation [0.79 (0.68-0.92)], heart failure [0.52 (0.42-0.65)], myocardial infarction [0.55 (0.41-0.74)], and stroke [0.75 (0.63-0.89)]. According to subgroup analysis on all-cause mortality, patients with severe obesity and type 2 diabetes benefited more from bariatric surgery than those with severe obesity only (heterogeneity between groups: P =0.001), while different surgical approaches brought similar benefits (heterogeneity between groups: P =0.87). CONCLUSIONS: This meta-analysis of 40 matched cohort studies supports that bariatric surgery reduces disease-specific mortality and incidence of both MACEs and its components in patients with severe obesity compared with nonsurgical subjects. Bariatric surgery deserves a more aggressive consideration in the management of severe obesity.

Extracellular Vesicles Secreted by TGF-ß1-Treated Mesenchymal Stem Cells Promote Fracture Healing by SCD1-Regulated Transference of LRP5.

Bone fracture repair is a multiphased regenerative process requiring paracrine intervention throughout the healing process. Mesenchymal stem cells (MSCs) play a crucial role in cell-to-cell communication and the regeneration of tissue, but their transplantation is difficult to regulate. The paracrine processes that occur in MSC-derived extracellular vesicles (MSC-EVs) have been exploited for this study. The primary goal was to determine whether EVs secreted by TGF-ß1-stimulated MSCs (MSCTGF-ß1-EVs) exhibit greater effects on bone fracture healing than EVs secreted by PBS-treated MSCs (MSCPBS-EVs). Our research was conducted using an in vivo bone fracture model and in vitro experiments, which included assays to measure cell proliferation, migration, and angiogenesis, as well as in vivo and in vitro gain/loss of function studies. In this study, we were able to confirm that SCD1 expression and MSC-EVs can be induced by TGF-ß1. After MSCTGF-ß1-EVs are transplanted in mice, bone fracture repair is accelerated. MSCTGF-ß1-EV administration stimulates human umbilical vein endothelial cell (HUVEC) angiogenesis, proliferation, and migration in vitro. Furthermore, we were able to demonstrate that SCD1 plays a functional role in the process of MSCTGF-ß1-EV-mediated bone fracture healing and HUVEC angiogenesis, proliferation, and migration. Additionally, using a luciferase reporter assay and chromatin immunoprecipitation studies, we discovered that SREBP-1 targets the promoter of the SCD1 gene specifically. We also discovered that the EV-SCD1 protein could stimulate proliferation, angiogenesis, and migration in HUVECs through interactions with LRP5. Our findings provide evidence of a mechanism whereby MSCTGF-ß1-EVs enhance bone fracture repair by regulating the expression of SCD1. The use of TGF-ß1 preconditioning has the potential to maximize the therapeutic effects of MSC-EVs in the treatment of bone fractures.

A bibliometric and visual analysis of obesity and polycystic ovary syndrome from 2012 to 2022.

Background: Obesity is associated with polycystic ovary syndrome (PCOS). We aimed to elucidate the research status and explore research trends and future directions of research on obesity and PCOS. Methods: A bibliometric analysis of the published papers in the field of obesity and PCOS between 2012 and 2022 was conducted on the basis of the Web of Science Core Collection database. The collaboration networks, research trends, literature sources, citation analysis, co-citation analysis, and keywords analysis were statistically analyzed and visualized using the VOSviewer software. Results: We retrieved 2843 records from 681 journals by 12307 authors from 2942 institutes in 99 countries. The number of published papers and citations had a roughly increasing trend annually. The United States and China contributed the majority of the records. Monash University, Shanghai Jiaotong University, Aristotle University of Thessaloniki, Karolinska Institute, University of São Paulo, and Tehran University of Medical Sciences were the biggest nodes in their cluster of the collaboration network map, and Moran LJ, Teede HJ, Joham AE, Escobar-Morreale HF, and Macut D were prolific authors. Research trends and hotspots were identified and visualized in the field of obesity and PCOS. Research hotspots in this field focused on insulin resistance (IR), metabolic syndrome, metformin, and inflammation. Bariatric surgery, mitochondrial dysfunction, binding globulins, and comorbidities may be the frontiers of future research. Conclusions: We concluded the research status and trends in the field of obesity and PCOS. A better understanding of collaboration patterns, research hotspots, and frontiers may be useful for researchers.

Bariatric Surgery Improves Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis.

PURPOSE: Bariatric surgery has been uncovered to relieve nonalcoholic fatty liver disease (NAFLD) in patients with obesity, while current studies have neutral or opposite results. This systematic review and meta-analysis aimed to evaluate the effects of bariatric surgery on NAFLD in patients with obesity. MATERIALS AND METHODS: PubMed, Embase, Cochrane Central, and Web of Science databases were performed to obtain publications containing comparison results of liver biopsy before and after bariatric surgery in obesity. Primary outcomes were biopsy-confirmed remission of NAFLD and NAFLD activity scores. Secondary outcomes were liver function. This study was registered with PROSPERO, CRD42021240346. RESULTS: Thirty-seven studies were included. After bariatric surgery, a biopsy-confirmed resolution of steatosis was improved in 56% of patients, ballooning degeneration in 49%, inflammation in 45%, and fibrosis in 25%. Bariatric surgery significantly decreased mean NAFLD activity scores. RYGB achieved the most obviously improvements in steatosis, and SG attained the most notably ameliorations in fibrosis. The percentage of patients with improved steatosis and hepatic fibrosis in Asian countries was higher than non-Asian countries. The reduction of ALT and AST was 11.95U/L and 6.44 U/L after surgery. CONCLUSION: Our study has revealed that bariatric surgery brought out significantly resolution of NAFLD in individuals with obesity. RYGB and SG have been proved to be of benefit to many hepatic parameters, and the improvement of liver steatosis and fibrosis, particularly in Asian countries. It is strongly suggested that bariatric surgery should be considered as a novel treatment for NAFLD.

Liquid biopsy at the frontier of detection, prognosis and progression monitoring in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide and a leading cause of carcinogenic death. To date, surgical resection is regarded as the gold standard by the operator for clinical decisions. Because conventional tissue biopsy is invasive and only a small sample can sometimes be obtained, it is unable to represent the heterogeneity of tumor or dynamically monitor tumor progression. Therefore, there is an urgent need to find a new minimally invasive or noninvasive diagnostic strategy to detect CRC at an early stage and monitor CRC recurrence. Over the past years, a new diagnostic concept called "liquid biopsy" has gained much attention. Liquid biopsy is noninvasive, allowing repeated analysis and real-time monitoring of tumor recurrence, metastasis or therapeutic responses. With the advanced development of new molecular techniques in CRC, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and tumor-educated platelet (TEP) detection have achieved interesting and inspiring results as the most prominent liquid biopsy markers. In this review, we focused on some clinical applications of CTCs, ctDNA, exosomes and TEPs and discuss promising future applications to solve unmet clinical needs in CRC patients.

Insulin Resistance Remission Following Laparoscopic Roux-en-Y Gastric Bypass and Laparoscopic Sleeve Gastrectomy in Chinese Type 2 Diabetes Mellitus Patients With a Body Mass Index of 27.5-32.5 kg/m2.

Background: Insulin resistance (IR) is closely associated with the pathogenesis of type 2 diabetes mellitus (T2DM). However, remission of insulin sensitivity after bariatric surgery in patients with T2DM and a body mass index (BMI) of 27.5-32.5 kg/m2 has not been fully elucidated. Methods: Thirty-six T2DM patients with a BMI of 27.5-32.5 kg/m2 were prospectively consecutively recruited for laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG). Hyperinsulinemic euglycemic clamp, oral glucose tolerance test (OGTT), and other indicators were tested at baseline and 6 months postoperative. Glucose disposal rate (GDR), time to reach euglycemia, homeostatic model assessment of IR, quantitative insulin sensitivity check index (QUICKI), triglyceride glucose (TyG) index, 30-min insulinogenic index (IGI30), and disposition index (DI) were calculated at baseline and 6 months after surgery. The criterion for remission in T2DM patients was the achievement of the triple composite endpoint. Results: Anthropometric and glucolipid metabolism parameters significantly improved following surgery. The GDR increased significantly from baseline to 6 months after LRYGB (from 4.28 ± 1.70 mg/kg/min to 8.47 ± 1.89 mg/kg/min, p < 0.0001) and LSG (from 3.18 ± 1.36 mg/kg/min to 7.09 ± 1.69 mg/kg/min, p < 0.001). The TyG index decreased after surgery (RYGB group, from 9.93 ± 1.03 to 8.60 ± 0.43, p < 0.0001; LSG group, from 10.04 ± 0.79 to 8.72 ± 0.65, p = 0.0002). There was a significant reduction in the IGI30 (RYGB group, from 2.04 ± 2.12 to 0.83 ± 0.47, p = 0.005; LSG group, from 2.12 ± 1.73 to 0.92 ± 0.66, p = 0.001). The mean DI significantly increased from 1.14 ± 1.35 to 7.11 ± 4.93 in the RYGB group (p = 0.0001) and from 1.25 ± 1.78 to 5.60 ± 4.58 in the LSG group (p = 0.003). Compared with baseline, HOMR-IR, QUICKI, area under the curve-C-peptide release test (AUC-CRT), and AUC-OGTT were significantly changed at 6 months postoperative. Overall, 52.63% of patients in the LRYGB group versus 29.41% of patients in the LSG group achieved the triple composite endpoint. Conclusion: Both LRYGB and LSG effectively induced remission of IR in patients with T2DM and a BMI of 27.5-32.5 kg/m2.

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.

GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic ß-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux.

T2DM (Type 2 diabetes) is a complex, chronic disease characterized as insulin resistance and islet ß-cell dysfunction. Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) surgery and laparoscopic sleeve gastrectomy (LSG) have become part of a critical treatment regimen in the treatment of obesity and T2DM. Moreover, GLP-1 increase following bariatric surgery has been regarded as a significant event in bariatric surgery-induced remission of T2DM. In this study, a high concentration cholesterol-induced lipotoxicity was observed in INS-1 cells, including inhibited cell viability and insulin secretion. Enhanced cell apoptosis and inhibited cholesterol efflux from INS-1 cells; meanwhile, ABCA1 protein level was decreased by cholesterol stimulation. Cholesterol-induced toxicity and ABCA1 downregulation were attenuated by GLP-1 agonist EX-4. GLP-1 induced AMPK phosphorylation during the protection against cholesterol-induced toxicity. Under cholesterol stimulation, GLP-1-induced AMPK activation inhibited PARP-1 activity, therefore attenuating cholesterol-induced toxicity in INS-1 cells. In INS-1 cells, PARP-1 directly interacted with LXR, leading to the poly(ADP-ribosyl)ation of LXRα and downregulation of LXR-mediated ABCA1 expression. In the STZ-induced T2DM model in rats, RYGB surgery or EX-4 treatment improved the glucose metabolism and lipid metabolism in rats through GLP-1 inhibition of PARP-1 activity. In conclusion, GLP-1 inhibits PARP-1 to protect islet ß cell function against cholesterol-induced toxicity in vitro and in vivo through enhancing cholesterol efflux. GLP-1-induced AMPK and LXR-mediated ABCA1 expression are involved in GLP-1 protective effects.

Five-year Changes in Body Composition in Type 2 Diabetes Mellitus Patients with a BMI < 32.5 kg/m2 Undergoing Laparoscopic Roux-en-Y Gastric Bypass Surgery.

PURPOSE: Information is scarce on the five-year effect of laparoscopic Roux-en-Y Gastric Bypass (LRYGB) on body composition for Type 2 diabetes mellitus (T2DM) patients with a low BMI. This study aimed to evaluate the five-year changes in body composition in a Chinese T2DM cohort with a BMI < 32.5 kg/m2 after LRYGB. METHODS: Twenty-seven T2DM patients were assessed preoperatively (baseline) and 3 months, 6 months, 1 year, 3 years, and 5 years after LRYGB with dual-energy X-ray absorptiometry (DXA). RESULTS: DXA assessments were completed in 100%, 85%, 85%, 85%, 48%, and 37% at baseline and 3 months, 6 months, 1 year, 3 years, and 5 years, respectively. For the whole body, fat-free mass and muscle mass decreased from 6 months to 5 years after LRYGB (P < 0.05), while bone mineral content decreased at 5 years after LRYGB (P < 0.05). Fat mass of different regions decreased from 3 months to 1 year (P < 0.05), and a similar magnitude of variation was observed in body fat mass percentage. A fat redistribution characterized by the regional fat proportion of trunk and android decreasing and the regional fat proportion of limbs gaining (P < 0.05) occurred at 5 years after LRYGB. CONCLUSION: For low BMI patients with T2DM, LRYGB led to a short-term reduction in FM and a lasting reduction in FFM. A metabolically healthy fat redistribution occurring 5 years after LRYGB might be a promising mechanism to explain the lasting benefits of LRYGB for T2DM patients with a low BMI.

Gender-specific associations between apolipoprotein A1 and arterial stiffness in patients with nonalcoholic fatty liver disease.

BACKGROUND: Lipid metabolism factors may play an important role in the progression of nonalcoholic fatty liver disease (NAFLD) and its related cardiovascular dysfunctions. The study aims to assess whether Apolipoprotein A-1 (ApoA1) was associated with vascular stiffness in NAFLD patients. METHODS: From 2012 to 2013, we included 2,295 non-alcohol users with fatty liver disease (1,306 male patients) and completely excluded subjects who drank any alcohol ever to eliminate the effect of alcohol intake. The serum ApoA1 levels and the brachial-ankle pulse wave velocity (baPWV) were measured. RESULTS: The baPWV in men was much higher than in female patients (1,412.79 cm/s vs. 1,358.69 cm/s, P < 0.001). ApoA1 level was positively associated with baPWV odd ratio (OR), 4.18; 95% confidence interval (CI) [1.16-15.1], P < 0.05) in patients with AST/ALT < 1 and (OR, 4.70; 95% CI [1.36-16.23], P < 0.05) in patients with AST/ALT ≥ 1 respectively. Only arterial stiffness in men was associated with ApoA1 (OR, 3.96; 95% CI [1.29-12.30], P < 0.05) in logistics regression models adjusted for age, gender, body mass index, education attainment, physical activity, smoking, history of hypertension and high-density lipoprotein. The relationship between ApoA1 and baPWV in male NAFLD patients remained significant (confidence, 156.42; 95% CI [49.34-263.50], P < 0.05) in the fully adjusted linear regression model. CONCLUSION: The serum ApoA1 was associated with arterial stiffness in male NAFLD patients. Increased ApoA1 level should be considered as an independent risk factor for arterial stiffness in male NAFLD patients, suggesting that NAFLD may alter arterial stiffness by "ApoA1-related" mechanism in men.

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.

A novel epigenetic mechanism of FXR inhibiting GLP-1 secretion via miR-33 and its downstream targets.

Type II diabetes is a complex, chronic, and progressive disease. Previously, we demonstrate that FXR inhibits GLP-1 secretion via interacting with CREB to inhibit the transcriptional activity of CREB, thus promoting the development of type II diabetes. Epigenetic modifications, such as DNA methylation, histone acetylation, and post-transcriptional RNA regulation, are essential mediators contributing to diabetes-associated morbidity and mortality. Thus, we attempted to investigate the epigenetic mechanisms of FXR modulating GLP-1 secretion. Firstly, the involvement of histone acetylation, DNA methylation, and post-transcriptional regulation in FXR inhibiting GLP-1 secretion was verified. As FXR overexpression significantly inhibited the activity of GCG 3'-UTR, we hypothesize that miRNA might participate in the mechanism. Two online tools and real-time PCR revealed that FXR promoted miR-33 expression. Moreover, miR-33 inhibited the expression of GCG and CREB1 through direct targeting in STC-1 cells. FXR overexpression in STC-1 cells significantly reduced the mRNA expression and protein levels of both GCG and CREB1, as well as the secretion of GLP-1; miR-33 inhibition exerted opposing effects. More importantly, the effects of FXR overexpression were significantly reversed by miR-33 inhibition, indicating that FXR inhibited GLP-1 secretion through promoting miR-33 expression, therefore inhibiting the expression of miR-33 targets, GCG and CREB1. In conclusion, we provide a novel epigenetic mechanism by which FXR inhibits the secretion of GLP-1 through miR-33 and its two downstream targets, GCG and CREB1. These findings might provide innovative strategies for improving type II diabetes, which needs further in vivo and clinical investigation.