BACKGROUND The sodium/glucose cotransporter-2 inhibitors(SGLT-2i)and glucagon-like-1 receptor agonists(GLP-1RA)are antidiabetic agents effective both in hemoglobin A1c(HbA1c)reduction(with a low risk of hypoglycemia)a...BACKGROUND The sodium/glucose cotransporter-2 inhibitors(SGLT-2i)and glucagon-like-1 receptor agonists(GLP-1RA)are antidiabetic agents effective both in hemoglobin A1c(HbA1c)reduction(with a low risk of hypoglycemia)and cardiovascular event prevention.In patients with type 2 diabetes,the add-on value of combination therapy of GLP-1RA and an SGLT-2i seems promising.AIM To investigate whether the efficacy of GLP-1RA and SGLT-2i combination observed in randomized controlled trials translates into therapeutic benefits in the Croatian population during routine clinical practice and follow-up.METHODS We included 200 type 2 diabetes patients with poor glycemic control and analyzed the effects of treatment intensification with(1)GLP-1RA on top of SGLT-2i,(2)SGLT-2i on top of GLP-1RA compared to(3)simultaneous addition of both agents.The primary study endpoint was the proportion of participants with HbA1c<7.0%and/or 5%bodyweight reduction.Secondary outcomes included changes in fasting plasma glucose(FPG),prandial plasma glucose,lowdensity lipoprotein cholesterol,estimated glomerular filtration rate(eGFR),and cardiovascular(CV)incidents assessment over a follow-up period of 12 mo.RESULTS The majority of patients were over 65-years-old,had diabetes duration for more than 10 years.The initial body mass index was 39.41±5.49 kg/m2 and HbA1c 8.32±1.26%.Around half of the patients in all three groups achieved target HbA1c below 7%.A more pronounced decrease in the HbA1c seen with simultaneous SGLT-2i and GLP-1RA therapy was a result of higher baseline HbA1c and not the effect of initiating combination therapy.The number of patients achieving FPG below 7.0 mmol/L was significantly higher in the SGLT-2i group(P=0.021),and 5%weight loss was dominantly achieved in the simultaneous therapy group(P=0.044).A composite outcome(reduction of HbA1c below 7%(53 mmol/mol)with 5%weight loss)was achieved in 32.3%of total patients included in the study.Only 18.2%of patients attained composite outcome defined as HbA1c below 7%(53 mmol/mol)with 5%weight loss and low-density lipoprotein cholesterol<2.5 mmol/L.There were no significant differences between treatment groups.No differences were observed regarding CV incidents or eGFR according to treatment group over a follow-up period.CONCLUSION Combination therapy with GLP-1RA and SGLT-2i is effective in terms of metabolic control,although it remains to be determined whether simultaneous or sequential intensification is better.展开更多
Objective To reveal the effects and related mechanisms of chlorogenic acid(CGA)on intestinal glucose homeostasis.Methods Forty male Sprague-Dawley rats were randomly and equally divided into four groups:normal chow(NC...Objective To reveal the effects and related mechanisms of chlorogenic acid(CGA)on intestinal glucose homeostasis.Methods Forty male Sprague-Dawley rats were randomly and equally divided into four groups:normal chow(NC),high-fat diet(HFD),HFD with low-dose CGA(20 mg/kg,HFD-LC),and HFD with high-dose CGA(90 mg/kg,HFD-HC).The oral glucose tolerance test was performed,and fast serum insulin(FSI)was detected using an enzyme-linked immunosorbent assay.The m RNA expression levels of glucose transporters(Sglt-1 and Glut-2)and proglucagon(Plg)in different intestinal segments(the duodenum,jejunum,ileum,and colon)were analyzed using quantitative real-time polymerase chain reaction.SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.Results At both doses,CGA ameliorated the HFD-induced body weight gain,maintained FSI,and increased postprandial 30-min glucagon-like peptide 1 secretion.High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression.Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.Conclusion An HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis.CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg,thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.展开更多
[ Objective] To express and purify the intracellular hydrophilic domains of bovine membrane carrier proteins：anion exchanger, member 1 （AE1） and electregenic sodium bicarbonate cotransporter 1 （NBCel）, which were...[ Objective] To express and purify the intracellular hydrophilic domains of bovine membrane carrier proteins：anion exchanger, member 1 （AE1） and electregenic sodium bicarbonate cotransporter 1 （NBCel）, which were associated with bicarbonate ion transport. [ Method] The hydrophilic domains of bovine AE1 and NBCel were amplified by PCR and inserted into the prokaryotic expression vector pET-28a, respectively. The recombinant plasmids were transformed into the expression strain E. coli BL21 （DE3） and then induced by IPTG. The expressed proteins were purified by nickel ion affinity chromatography and analyzed by 15% SDS-PAGE. [Result] The hydrophilic domains of bovine AE1 and NBCel were amplified respectively by PCR and expressed by prokaryotic expression system with the induction of IPTG. They were mainly expressed in the cyto- plasm of E. coli and high-purity was achieved by nickel ion affinity chromatography. [Condusion] The expression of the hydrophilic domains of bovine AE1 and NBCel provides a major exit route for preparation of antibodies and the regulatory mechanisms of carrier proteins.展开更多
AIM： To study the effect of glucose on sodium butyrate- induced proliferation inhibition and apoptosis in HT-29 cell line, and explored its possible mechanisms. METHODS： HT-29 cells were grown in RPMI-1640 medium su...AIM： To study the effect of glucose on sodium butyrate- induced proliferation inhibition and apoptosis in HT-29 cell line, and explored its possible mechanisms. METHODS： HT-29 cells were grown in RPMI-1640 medium supplemented with 10% fetal calf serum, and were allowed to adhere for 24 h, and then replaced with experimental medium. Cell survival rates were detected by MTr assay. Apoptosis was detected by TUNEL assay. Glucose transport protein 1 （GLUT1） and monocarboxylate transporter 1 （MCT1） mRNA expression was detected by RT-PCR. RESULTS： Low concentration of glucose induced apoptosis and regulated proliferation in HT-29 cell line, and glucose can obviously inhibit the effect of proliferation inhibition and apoptosis induced by sodium butyrate. Glucose also down-regulated the expression of MCT1mRNA （0.28 ± 0.07 vs 0.19± 0.10, P 〈 0.05）, and decreased the expression of GLUTlmRNA slightly （0.18 ± 0.04 vs 0.13 ± 0.03, P 〈 0.05）. CONCLUSION： Glucose can regulate the effect of proliferation inhibition and apoptosis induced by sodium butyrate and this influence may be associated with the intracellular concentration of glucose and sodium butyrate.展开更多
Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2(SGLT2) inhibitor—SGLT2 inhibitors,in combination with insulin for type 1 diabetes mellitus(T1DM). Methods We searched Medline,E...Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2(SGLT2) inhibitor—SGLT2 inhibitors,in combination with insulin for type 1 diabetes mellitus(T1DM). Methods We searched Medline,Embase,and the Cochrane Collaboration Library to identify the eligible studies published between January 2010 and July 2016 without restriction of language. The Food and Drug Administration(FDA) data and Clinical Trials(http://www.clinicaltrials.gov) were also searched. The included studies met the following criteria:randomized controlled trials; T1DM patients aged between 18 and 65 years old; patients were treated with insulin plus SGLT2 inhibitors for more than 2 weeks; patients' glycosylated hemoglobin(HbA1c) levels were between 7% and 12%. The SGLT2 inhibitors group was treated with SGLT2 inhibitors plus insulin,and the placebo group received placebo plus insulin treatment. The outcomes should include one of the following items:fasting blood glucose,HbA1c,glycosuria,or adverse effects. Data were analyzed by two physicians independently. The risk of bias was evaluated by using the Cochrane Collaboration's Risk of Bias tool and heterogeneity among studies was assessed using Chi-square test. Random effect model was used to analyze the treatment effects with Revman 5.3. Results Three trials including 178 patients were enrolled. As compared to the placebo group,SGLT2 inhibitor absolutely decreased fasting blood glucose [mean differences(MD)-2.47 mmol/L,95% confidence interval(CI)-3.65 to-1.28,P<0.001] and insulin dosage(standardized MD-0.75 U,95%CI-1.17 to-0.33,P<0.001). SGLT2 inhibitors could also increase the excretion of urine glucose(MD 131.09 g/24 h,95%CI 91.79 to 170.39,P<0.001). There were no significant differences in the incidences of hyperglycemia [odds ratio(OR) 1.82,95%CI 0.63 to 5.29,P=0.27],urinary tract infection(OR 0.95,95%CI 0.19 to 4.85,P=0.95),genital tract infection(OR 0.27,95%CI 0.01 to 7.19,P=0.43),and diabetic ketoacidosis(OR 6.03,95%CI 0.27 to 135.99,P=0.26) between the two groups. Conclusion SGLT2 inhibitors combined with insulin might be an efficient and safe treatment modality for T1DM patients.展开更多
文摘BACKGROUND The sodium/glucose cotransporter-2 inhibitors(SGLT-2i)and glucagon-like-1 receptor agonists(GLP-1RA)are antidiabetic agents effective both in hemoglobin A1c(HbA1c)reduction(with a low risk of hypoglycemia)and cardiovascular event prevention.In patients with type 2 diabetes,the add-on value of combination therapy of GLP-1RA and an SGLT-2i seems promising.AIM To investigate whether the efficacy of GLP-1RA and SGLT-2i combination observed in randomized controlled trials translates into therapeutic benefits in the Croatian population during routine clinical practice and follow-up.METHODS We included 200 type 2 diabetes patients with poor glycemic control and analyzed the effects of treatment intensification with(1)GLP-1RA on top of SGLT-2i,(2)SGLT-2i on top of GLP-1RA compared to(3)simultaneous addition of both agents.The primary study endpoint was the proportion of participants with HbA1c<7.0%and/or 5%bodyweight reduction.Secondary outcomes included changes in fasting plasma glucose(FPG),prandial plasma glucose,lowdensity lipoprotein cholesterol,estimated glomerular filtration rate(eGFR),and cardiovascular(CV)incidents assessment over a follow-up period of 12 mo.RESULTS The majority of patients were over 65-years-old,had diabetes duration for more than 10 years.The initial body mass index was 39.41±5.49 kg/m2 and HbA1c 8.32±1.26%.Around half of the patients in all three groups achieved target HbA1c below 7%.A more pronounced decrease in the HbA1c seen with simultaneous SGLT-2i and GLP-1RA therapy was a result of higher baseline HbA1c and not the effect of initiating combination therapy.The number of patients achieving FPG below 7.0 mmol/L was significantly higher in the SGLT-2i group(P=0.021),and 5%weight loss was dominantly achieved in the simultaneous therapy group(P=0.044).A composite outcome(reduction of HbA1c below 7%(53 mmol/mol)with 5%weight loss)was achieved in 32.3%of total patients included in the study.Only 18.2%of patients attained composite outcome defined as HbA1c below 7%(53 mmol/mol)with 5%weight loss and low-density lipoprotein cholesterol<2.5 mmol/L.There were no significant differences between treatment groups.No differences were observed regarding CV incidents or eGFR according to treatment group over a follow-up period.CONCLUSION Combination therapy with GLP-1RA and SGLT-2i is effective in terms of metabolic control,although it remains to be determined whether simultaneous or sequential intensification is better.
基金supported by the National Natural Science foundation of China(No.31071531)the Scientific Research Fund of the Hunan Provincial Education Department(No.14A071)the China National Tobacco Corp Hunan Branch(15-17Aa04)
文摘Objective To reveal the effects and related mechanisms of chlorogenic acid(CGA)on intestinal glucose homeostasis.Methods Forty male Sprague-Dawley rats were randomly and equally divided into four groups:normal chow(NC),high-fat diet(HFD),HFD with low-dose CGA(20 mg/kg,HFD-LC),and HFD with high-dose CGA(90 mg/kg,HFD-HC).The oral glucose tolerance test was performed,and fast serum insulin(FSI)was detected using an enzyme-linked immunosorbent assay.The m RNA expression levels of glucose transporters(Sglt-1 and Glut-2)and proglucagon(Plg)in different intestinal segments(the duodenum,jejunum,ileum,and colon)were analyzed using quantitative real-time polymerase chain reaction.SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.Results At both doses,CGA ameliorated the HFD-induced body weight gain,maintained FSI,and increased postprandial 30-min glucagon-like peptide 1 secretion.High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression.Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.Conclusion An HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis.CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg,thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.
基金financially supported by Key Project of Jiangsu Science and Technology Department (BC2004365)
文摘[ Objective] To express and purify the intracellular hydrophilic domains of bovine membrane carrier proteins：anion exchanger, member 1 （AE1） and electregenic sodium bicarbonate cotransporter 1 （NBCel）, which were associated with bicarbonate ion transport. [ Method] The hydrophilic domains of bovine AE1 and NBCel were amplified by PCR and inserted into the prokaryotic expression vector pET-28a, respectively. The recombinant plasmids were transformed into the expression strain E. coli BL21 （DE3） and then induced by IPTG. The expressed proteins were purified by nickel ion affinity chromatography and analyzed by 15% SDS-PAGE. [Result] The hydrophilic domains of bovine AE1 and NBCel were amplified respectively by PCR and expressed by prokaryotic expression system with the induction of IPTG. They were mainly expressed in the cyto- plasm of E. coli and high-purity was achieved by nickel ion affinity chromatography. [Condusion] The expression of the hydrophilic domains of bovine AE1 and NBCel provides a major exit route for preparation of antibodies and the regulatory mechanisms of carrier proteins.
文摘目的:观察联合使用胰高血糖素样肽-1受体激动剂(glucagons-like peptide-1 receptor agonist,GLP-1RA)与钠-葡萄糖协同转运蛋白2抑制剂(sodium glucose cotransporter 2 inhibitor,SGLT2i)治疗超重/肥胖2型糖尿病(type 2 diabetes,T2DM)的效果及安全性。方法:将T2DM合并超重/肥胖患者随机分为GLP-1RA组(A组,n=39)、SGLT2i组(B组,n=37)、GLP-1RA+SGLT2i组(C组,n=38),对照组(D组,n=36),观察12周。收集患者治疗前后的体质量、腰围、血压、血糖谱、空腹胰岛素、血脂。计算体质量指数(body mass index,BMI)、稳态模型的胰岛素抵抗指数(homeostasis model assessment of insulin resistance,HOMA-IR)、胰岛β细胞功能指数(homeostasis model assessment of beta cell function index,HOMA-β)。比较各组组内及组间临床疗效及安全性。结果:4组糖化血红蛋白、空腹血糖和餐后2 h血糖较治疗前均显著下降(均P<0.001),C组降幅最大。A、B和C组的体质量、腰围和BMI均显著下降(均P<0.001),下降幅度从高到低依次为C组、A组、B组(P<0.01)。治疗后A、B和C组的HOMA-IR均显著改善(P<0.01)。治疗后,B和C组患者收缩压降低(均P<0.05),A、C组的高密度脂蛋白胆固醇升高(均P<0.05),C组低密度脂蛋白胆固醇下降(P<0.05)。不良反应:A、C组以胃肠道的症状为主,B组以泌尿道感染多见。结论:GLP-1RA与SGLT2i联合治疗在降糖、减重、减少胰岛素抵抗、改善心血管风险因素方面有优势。GLP-1RA主要不良反应为胃肠道反应,SGLT2i主要为尿路感染。
基金Supported by the Key Technologies R&D Program of Hubei Province, No. 2004AA304B08
文摘AIM： To study the effect of glucose on sodium butyrate- induced proliferation inhibition and apoptosis in HT-29 cell line, and explored its possible mechanisms. METHODS： HT-29 cells were grown in RPMI-1640 medium supplemented with 10% fetal calf serum, and were allowed to adhere for 24 h, and then replaced with experimental medium. Cell survival rates were detected by MTr assay. Apoptosis was detected by TUNEL assay. Glucose transport protein 1 （GLUT1） and monocarboxylate transporter 1 （MCT1） mRNA expression was detected by RT-PCR. RESULTS： Low concentration of glucose induced apoptosis and regulated proliferation in HT-29 cell line, and glucose can obviously inhibit the effect of proliferation inhibition and apoptosis induced by sodium butyrate. Glucose also down-regulated the expression of MCT1mRNA （0.28 ± 0.07 vs 0.19± 0.10, P 〈 0.05）, and decreased the expression of GLUTlmRNA slightly （0.18 ± 0.04 vs 0.13 ± 0.03, P 〈 0.05）. CONCLUSION： Glucose can regulate the effect of proliferation inhibition and apoptosis induced by sodium butyrate and this influence may be associated with the intracellular concentration of glucose and sodium butyrate.
文摘Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2(SGLT2) inhibitor—SGLT2 inhibitors,in combination with insulin for type 1 diabetes mellitus(T1DM). Methods We searched Medline,Embase,and the Cochrane Collaboration Library to identify the eligible studies published between January 2010 and July 2016 without restriction of language. The Food and Drug Administration(FDA) data and Clinical Trials(http://www.clinicaltrials.gov) were also searched. The included studies met the following criteria:randomized controlled trials; T1DM patients aged between 18 and 65 years old; patients were treated with insulin plus SGLT2 inhibitors for more than 2 weeks; patients' glycosylated hemoglobin(HbA1c) levels were between 7% and 12%. The SGLT2 inhibitors group was treated with SGLT2 inhibitors plus insulin,and the placebo group received placebo plus insulin treatment. The outcomes should include one of the following items:fasting blood glucose,HbA1c,glycosuria,or adverse effects. Data were analyzed by two physicians independently. The risk of bias was evaluated by using the Cochrane Collaboration's Risk of Bias tool and heterogeneity among studies was assessed using Chi-square test. Random effect model was used to analyze the treatment effects with Revman 5.3. Results Three trials including 178 patients were enrolled. As compared to the placebo group,SGLT2 inhibitor absolutely decreased fasting blood glucose [mean differences(MD)-2.47 mmol/L,95% confidence interval(CI)-3.65 to-1.28,P<0.001] and insulin dosage(standardized MD-0.75 U,95%CI-1.17 to-0.33,P<0.001). SGLT2 inhibitors could also increase the excretion of urine glucose(MD 131.09 g/24 h,95%CI 91.79 to 170.39,P<0.001). There were no significant differences in the incidences of hyperglycemia [odds ratio(OR) 1.82,95%CI 0.63 to 5.29,P=0.27],urinary tract infection(OR 0.95,95%CI 0.19 to 4.85,P=0.95),genital tract infection(OR 0.27,95%CI 0.01 to 7.19,P=0.43),and diabetic ketoacidosis(OR 6.03,95%CI 0.27 to 135.99,P=0.26) between the two groups. Conclusion SGLT2 inhibitors combined with insulin might be an efficient and safe treatment modality for T1DM patients.
