Objective To investigate the effects of ketogenic amino acid ( KAA) replacement diet on insulin resistance in mice fed with high fat diet(HFD) and to analyze the possible mechanism. Methods C57BL mice were fed with a control diet, HFD, and KAA-fortified HFD(HFDKAAR)from the age of 8 weeks, and 8 weeks after HFD initiation, the HFD-fed mice were divided into two groups:one group of mice were fed the same HFD, the other group were fed HFDKAAR ( HFD→HFDKAAR ) . The metabolic evaluations were performed at the end of 16 weeks. Blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 min after the injection of glucose ( 1 g/kg BW intraperitoneal glucose tolerance test, ipGTT) . The insulin,β-hydroxybutyrate, and acetoacetate levels in the plasma were measured via ELISA. The insulin resistance index ( IRI) and area under curve ( AUC) were calculated. The expression of hepatic LKB1 ( liver kinase B1 ) , AMP-activated protein kinase ( AMPK ) , and mTOR ( Mammalian target of rapamycin ) protein, and mcp-1 mRNA were measured by western blot and real-time PCR respectively. Results HFD-fed group of mice displayed significantly heavier body weight,heavier intra-abdominal fat weight, and significant deterioration of glucose tolerance at the end of 16 weeks in addition to higher insulin levels( all P<0. 05), HFDKAAR-fed mice exhibited significantly ameliorated high fat diet-induced obesity and glucose intolerance compared to the HFD-fed mice, which was associated with decreased insulin levels, IRI, AUC, and mcp-1 mRNA expression (all P<0. 05). HFD suppressed hepatic LKB1 and AMPK phosphorylation expression, and increased mTOR phosphorylation levels compared to the control diet-fed mice(all P<0. 05). In contrast, treatment with the HFDKAAR diet increased LKB1and p-AMPK expression, which was associated with suppressed p-mTOR levels compared to the HFD-fed mice(all P<0. 05). Conclusion KAA may ameliorate high fat diet-induced obesity, glucose intolerance, via normalizing the hepatic LKB1-AMPK-mTOR nutritional signal passageway. KAA replacement diet seems to be a potential nutritional intervention for the treatment for patients with metabolic defects, such as obesity, glucose intolerance, as well as metabolic syndrome.

To investigate the effects of short-chain fatty acids(SCFAs)on oxidative stress and inflammation in cultured glomerular mesangial cells(GMCs)under high glucose.SV-40 MES 13 mouse GMCs were exposed to 30 mmol/L glucose, exogenous SCFAs or their specific G-protein coupled receptor 43(GPR43)agonist were used individually as an intervention.GPR43 expression was suppressed by transfection with GPR43-specifc siRNA.The oxidative stress-related factors reactive oxygen species and malondialdehyde were detected and the expression of GPR43,monocyte chemotactic protein 1(MCP-1),and interleukin-1β(IL-1β)were observed.GPR43 expression were significantly down-regulated,but reactive oxygen species and malondialdehyde production and MCP-1 and IL-1β releases were induced by high glucose(all P<0.05),treatment with SCFAs or GPR43 agonist reversed high glucose-induced oxidative stress and inflammation in a dose-dependent manner(all P<0.05).However, these SCFAs-mediated effects were blunted by siRNA-mediated knockdown GPR43(all P<0.05).SCFAs mitigates high glucose-induced oxidative stress and inflammatory injury in part via GPR43 signaling pathway,suggesting a likely mechanism for SCFAs-induced therapeutic effect in diabetic kidney disease.

Objective: To investigate the role of sweet taste receptors(STRs)in the activation of reactive oxygen species (ROS)-NLRP3 inflammasome signaling in diabetic kidney disease(DKD). Methods: DKD mouse were established by high-fat diet and streptozotocin. After mouse glomerular mesangial cells(GMCs)were exposed to high glucose, STRs(T1R2/T1R3)and associated signaling components and NLRP3 inflammasome signaling components expressions were detected. After GMCs were treated with STRs inhibitor lactisole, the production of ROS was detected and the role of STRs in the activation of NLRP3 signaling was investigated. Results: Under high glucose condition, the expressions of T1R2, T1R3, Gα-gustducin, phospholipase C-β2, and TRPM5 were significantly decreased in vivo and in vitro(all P<0.05)and ROS-NLRP3 signaling was activated(all P<0.05). Lactisole significantly mitigated the production of ROS and the activation of NLRP3 inflammasome signaling stimulated by high glucose in GMCs(all P<0.05). Conclusion The STRs(T1R2/T1R3)-mediated signaling pathway may be involved in the regulation of ROS-NLRP3 inflammatory signaling, suggesting that STRs may act as new therapeutic targets of DKD. (Chin J Endocrinol Metab, 2018, 34: 587-593)

Objective:To observe the clinical characteristics and prognosis of patients with acute respiratory distress syndrome (ARDS) in sepsis combined with acute gastrointestinal injury (AGI) of different grades, and to further explore the risk factors associated with the poor prognosis of patients.Methods:The clinical data of patients with septic ARDS admitted to the intensive care unit (ICU) of Tianjin First Central Hospital from March to October 2023 were collected. According to the 2012 European Association of Critical Care Medicine AGI definition and grading criteria, the patients were categorized into AGI grade 0-Ⅳ groups. The clinical characteristics and 28-day clinical outcomes of the patients were observed; the risk factors related to the prognosis of patients with septic ARDS combined with AGI were analyzed by using univariate and multivariate Logistic regression; and the receiver operator characteristic curve (ROC curve) and calibration curves were plotted to evaluate the predictive value of each risk factor on the prognosis of patients with septic ARDS combined with AGI.Results:A total of 92 patients with septic ARDS were enrolled, including 7 patients in the AGI 0 group, 20 patients in the AGIⅠgroup, 38 patients in the AGIⅡ group, 23 patients in the AGIⅢ group, and 4 patients in the AGI Ⅳ group. The incidence of AGI was 92.39%. With the increase of AGI grade, the ARDS grade increased, and acute physiology and chronic health evaluationⅡ(APACHEⅡ), sequential organ failure assessment (SOFA), intra-abdominal pressure (IAP), white blood cell count (WBC), neutrophil count (NEU), lymphocyte count (LYM), lymphocyte percentage (LYM%), and 28-day mortality all showed a significant increasing trend, while the oxygenation index (PaO 2/FiO 2) showed a significant decreasing trend (all P < 0.05). Pearson correlation analysis showed that APACHEⅡscore, SOFA score, and ARDS classification were positively correlated with patients' AGI grade (Pearson correlation index was 0.386, 0.473, and 0.372, respectively, all P < 0.001), and PaO 2/FiO 2 was negatively correlated with patients' AGI grade (Pearson correlation index was -0.425, P < 0.001). Among the patients with septic ARDS combined with AGI, there were 68 survivors and 17 deaths at 28 days. The differences in APACHEⅡscore, SOFA score, ARDS grade, AGI grade, PaO 2/FiO 2, IAP, AGI 7-day worst value, length of ICU stay, and total length of hospital stay between the survival and death groups were statistically significant. Univariate Logistic regression analysis showed that SOFA score [odds ratio ( OR) = 1.350, 95% confidence interval (95% CI) was 1.071-1.702, P = 0.011], PaO 2/FiO 2 ( OR = 0.964, 95% CI was 0.933-0.996, P = 0.027) and AGI 7-day worst value ( OR = 2.103, 95% CI was 1.194-3.702, P = 0.010) were the risk factors for 28-day mortality in patients with septic ARDS combined with AGI. Multivariate Logistic regression analysis showed that SOFA score ( OR = 1.384, 95% CI was 1.153-1.661, P < 0.001), PaO 2/FiO 2 ( OR = 0.983, 95% CI was 0.968-0.999, P = 0.035) and AGI 7-day worst value ( OR = 1.992, 95% CI was 1.141-3.478, P = 0.015) were the independent risk factors for 28-day mortality in patients with septic ARDS combined with AGI. ROC curve analysis showed that SOFA score, PaO 2/FiO 2 and AGI 7-day worst value had predictive value for the 28-day prognosis of patients with septic ARDS combined with AGI. The area under the ROC curve (AUC) was 0.824 (95% CI was 0.697-0.950), 0.760 (95% CI was 0.642-0.877) and 0.721 (95% CI was 0.586-0.857), respectively, all P < 0.01; when the best cut-off values of the above metrics were 5.50 points, 163.45 mmHg (1 mmHg≈0.133 kPa), and 2.50 grade, the sensitivities were 94.1%, 94.1%, 31.9%, respectively, and the specificities were 80.9%, 67.6%, 88.2%, respectively. Conclusions:The incidence of AGI in patients with septic ARDS is about 90%, and the higher the AGI grade, the worse the prognosis of the patients. SOFA score, PaO 2/FiO 2 and AGI 7-day worst value have a certain predictive value for the prognosis of patients with septic ARDS combined with AGI, among which, the larger the SOFA score and AGI 7-day worst value, and the smaller the PaO 2/FiO 2, the higher the patients' mortality.

Objective:To explore whether the food additive sodium benzoate(NAB) induces pancreatic inflammation and β cell apoptosis through the benzoylation(Kbz) modification pathway.Methods:In vivo experiments: C57BL/6J male mice(8 weeks old, 18-20 g) were randomly divided into normal control group(double distilled water feeding) and NAB feeding group(1 g/kg NAB feeding). Blood glucose were measured. After 20 weeks, fasting serum insulin, interleukin(IL)-18, IL-1β, and benzoyl-CoA levels were detected by ELISA method. Bax, IL-18, Pan-Kbz and Pan-Kac were detected by immunohistochemistry staining. In vitro experiments: β-TC-6 cells were cultured with NAB(6 mmol/L) or benzoyl-CoA(100 μmol/L) as stimulator and acyltransferase P300 inhibitor A485(10 μmol/L) as intervention factor. 24 hours later, inflammation, apoptosis, insulin secretion and Pan-Kbz level were detected by qRT-PCR, ELISA and Western blotting.Results:In the in vivo experiments, compared to the NC group, mice in the NAB group exhibited impaired glucose tolerance, decreased fasting insulin levels, significantly increased serum benzoyl coenzyme A concentrations, relatively elevated pancreatic IL-1β, IL-18, and Bax protein expressions, increased levels of Pan-Kbz, while Pan-Kac levels were downregulated(all P<0.05); In vitro experiments, NAB dose-dependently inhibited insulin secretion, promoted the release of Pan-Kbz and inflammatory factors IL-18 and TNF- α, inhibited Bcl-2 expression and up-regulated Bax expression, A485 reversed NAB-induced Pan-Kbz modification, improved NAB-induced inflammation and apoptosis, and promoted insulin secretion(all P<0.05). Conclusion:NAB may induce pancreatic inflammation, β-cell apoptosis, and impair insulin secretion through Kbz modification pathway.