Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are antidiabetic medications with remarkable cardiovascular(CV)benefits proven by multiple randomised controlled trials and real-world data.These drugs are also useful...Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are antidiabetic medications with remarkable cardiovascular(CV)benefits proven by multiple randomised controlled trials and real-world data.These drugs are also useful in the prevention of CV disease(CVD)in patients with diabetes mellitus(DM).Although DM as such is a huge risk factor for CVD,the CV benefits of SGLT-2i are not just because of antidiabetic effects.These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well.There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated.Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases.This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.展开更多
Objective: To observe the cerebral protective effect of dagliflozin, a sodium-glucose co-transport protein 2 (SGLT2) inhibitor, in aging mice and to explore its molecular mechanism. Methods: 1. 66 male C57BL/6 mice we...Objective: To observe the cerebral protective effect of dagliflozin, a sodium-glucose co-transport protein 2 (SGLT2) inhibitor, in aging mice and to explore its molecular mechanism. Methods: 1. 66 male C57BL/6 mice were divided into control group (13) and model group (53), and the model group was moulded by subcutaneous injection of D-galactose into the back of the neck, while the control group was treated with equal amount of saline for 8 weeks. The weight of each group of mice was observed and recorded every 7 days, and two groups of mice were randomly selected for frozen sections of brain tissue at the end of the modelling period to verify the aging model. 2. After the aging model was successfully established, the aging groups were divided into 5 groups: model group, dagliflozin-treated group (high and low dose), and dagliflozin + ex527-inhibited group (high and low dose). Fasting blood glucose was measured in each group every 2 weeks for 8 weeks. At the end of treatment, Morris water maze was performed at the end of the treatment. After execution of the mice, the organ indices of heart, brain, liver, kidney and spleen were measured;the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in serum were determined. Results: After the successful establishment of the aging model, it was found that during the treatment phase of dagliflozin. 1) The organ indices of mice in the aging group were significantly lower than those of other groups, and no significant hypoglycemia was observed throughout the treatment process. 2) In the water maze test, mice in the aging group had a significantly longer latency in the plateau phase compared to the control and treatment groups, while the number of times the mice crossed the original plateau and the percentage of time spent exploring the original plateau quadrant were reduced after the plateau was removed. 3) The nerve cells in the aging mice were disorganized and the nuclei of the mice were deeply stained;the dagliflozin group improved the morphological changes in the brain of aging mice. 4) In addition, compared with the control mice, the serum MDA level was significantly increased and the antioxidant enzyme SOD activity was significantly decreased in the aging group, while compared with the aging group, dagliflozin significantly decreased the MDA level and increased the SOD activity. 5) The expression of SIRT1 and PGC-1α was significantly upregulated in the low and high doses of dagliflozin compared to the aging group. Conclusion: The present study suggests that dagliflozin can delay organ aging, improve the learning and memory ability of aging mice, and exert antioxidant effects, probably through upregulating the SIRT1/PGC-1α signaling pathway.展开更多
The sodium-dependent glucose transporters 2(SGLT2)plays important role in renal reabsorption of urinal glucose back to plasma for maintaining glucose homeostasis.The approval of SGLT2 inhibitors for treatment of type ...The sodium-dependent glucose transporters 2(SGLT2)plays important role in renal reabsorption of urinal glucose back to plasma for maintaining glucose homeostasis.The approval of SGLT2 inhibitors for treatment of type 2 diabetes highlights the SGLT2 as a feasible and promising drug target in recent years.Current methods for screening SGLT2 inhibitors are complex,expensive and labor intensive.Particularly,these methods cannot directly measure nonradioactive glucose uptake in endogenous SGLT2-expressing kidney cells.In present work,human kidney cells,HK-2,was incubated with a fluorescent D-glucose derivant 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose(2-NBDG)and the fluorescent intensity of 2-NBDG was employed to measure the amount of glucose uptake into the cells.By optimizing the passages of HK-2 cells,2-NBDG concentration and incubation time,and by measuring glucose uptake treated by Dapagliflozin,a clinical drug of SGLT2 inhibitors,we successfully developed a new assay for measuring glucose uptake through SGLT2.The nonradioactive microplate and microscope-based high-throughput screening assay for measuring glucose can be a new method for screening of SGLT2 inhibitors and implied for other cell assays for glucose measurement extensively.展开更多
The sodium and glucose co-transporter inhibitors type 2 (SGLT2) comprises a new class of hypoglycemic drugs to control type 2 diabetes mellitus, in an attempt to add new non-existing benefits to the so far arising cla...The sodium and glucose co-transporter inhibitors type 2 (SGLT2) comprises a new class of hypoglycemic drugs to control type 2 diabetes mellitus, in an attempt to add new non-existing benefits to the so far arising classes. Regarding this new class of drugs, represented by dapaglifozin, canaglifozin and empaglifozin, it is important to highlight the benefits brought by these medications to combat hyperglycemia with insulin-independent mechanisms that are beyond glucose reduction, such as cardiovascular events prevention, reduction in HbA1c, weight loss and blood pressure lowering. Recently, a relevant study (Empa-Reg) brought hope and set the spotlight on the prevention of cardiac events among diabetic patients, which is the main cause of mortality within this group. However, despite coming out as a good treatment option, SGLT2 inhibitors are under constant clinical research and, as a new drug, it should be carefully carried out regarding the long-term effects of glycosuria and other possible side effects, such as the observed increase in the incidence of bladder, breast cancer and bone fractures, which require further studies. Therefore, these compounds might represent a landmark approach for the treatment of diabetes.展开更多
Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug,the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors(SGLT2i)showed efficacy in decreasing overall mort...Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug,the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors(SGLT2i)showed efficacy in decreasing overall mortality,hospitalization,and sudden death in patients of this very population,in whom chronic or acute ischemia count among the first cause.Remarkably,this benefit was observed independently from diabetic status,and benefited both preserved and altered ventricular ejection fraction.This feature,observed in several large randomized controlled trials,suggests additional effects from SGLT2i beyond isolated glycemia control.Indeed,both in-vitro and animal models suggest that inhibiting the Na+/H+exchanger(NHE)may be key to preventing ischemia/reperfusion injuries,and by extension may hold a similar role in ischemic damage control and ischemic preconditioning.Yet,several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules.Because of a large therapeutic margin with few adverse events,ease of prescription and potential pharmacological efficacity,SGLT2i could be candidate for wider indications.In this review,we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation,by first listing known mechanisms,including metabolic switch,prevention of lethal arrythmias and others,which portend the latter,and second,hypothesize how the former may interact with these mechanisms.展开更多
目的 探讨ADAMTSL3(Adisintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3)在大鼠糖尿病肾病心肌纤维化中的作用机制和SGLT-2抑制剂(Sodium-glucose co-transporter 2)的应用效果。方法 SPF级雄性Wi...目的 探讨ADAMTSL3(Adisintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3)在大鼠糖尿病肾病心肌纤维化中的作用机制和SGLT-2抑制剂(Sodium-glucose co-transporter 2)的应用效果。方法 SPF级雄性Wistar大鼠28只经高脂高糖饲料喂养联合腹腔注射链脲佐菌素(SMZ)50 mg/kg进行糖尿病肾病造模,造模成功后分为模型组和治疗组,另设正常对照组大鼠,治疗组给予SGLT-2抑制剂(卡格列净10 mg/kg)灌胃。3组大鼠进行心脏B超动态分析心脏结构改变。对大鼠心肌组织进行病理染色、qRT-PCR、Western Blot检测ADAMTSL3基因表达水平,同时观察使用SGLT-2抑制剂后大鼠心肌的病理改变。结果 与正常对照组相比,模型组在左心室重量(LVM)、左心室收缩末壁厚度(LVPWs)、左心室短轴缩短率(LVFS%)、左射血分数(LVEF%)上的差异均有统计学意义(P<0.05)。与模型组相比,治疗组大鼠糖尿病肾病诱导心肌组织纤维化相对面积降低,以及在大鼠心肌纤维化中的Ⅰ型胶原蛋白(CollagenⅠ)、纤维连接蛋白(Fibronectin)表达降低(P<0.05)。与正常对照组相比,模型组大鼠心肌组织的ADAMTSL3蛋白表达显著增加;与模型组相比,治疗组大鼠心肌组织的ADAMTSL3蛋白表达显著降低(P<0.05)。与正常对照组相比,模型组中衰老标志物p-p53、p21、p16表达水平升高;与模型组相比,治疗组p-p53、p16表达水平均降低,差异有统计学意义(P<0.05)。结论 ADAMTSL3表达与纤维化相关,因此ADAMTSL3参与促进糖尿病肾病大鼠心肌纤维化,SGLT-2抑制剂治疗可逆转其心肌纤维化病变。展开更多
文摘Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are antidiabetic medications with remarkable cardiovascular(CV)benefits proven by multiple randomised controlled trials and real-world data.These drugs are also useful in the prevention of CV disease(CVD)in patients with diabetes mellitus(DM).Although DM as such is a huge risk factor for CVD,the CV benefits of SGLT-2i are not just because of antidiabetic effects.These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well.There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated.Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases.This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.
文摘Objective: To observe the cerebral protective effect of dagliflozin, a sodium-glucose co-transport protein 2 (SGLT2) inhibitor, in aging mice and to explore its molecular mechanism. Methods: 1. 66 male C57BL/6 mice were divided into control group (13) and model group (53), and the model group was moulded by subcutaneous injection of D-galactose into the back of the neck, while the control group was treated with equal amount of saline for 8 weeks. The weight of each group of mice was observed and recorded every 7 days, and two groups of mice were randomly selected for frozen sections of brain tissue at the end of the modelling period to verify the aging model. 2. After the aging model was successfully established, the aging groups were divided into 5 groups: model group, dagliflozin-treated group (high and low dose), and dagliflozin + ex527-inhibited group (high and low dose). Fasting blood glucose was measured in each group every 2 weeks for 8 weeks. At the end of treatment, Morris water maze was performed at the end of the treatment. After execution of the mice, the organ indices of heart, brain, liver, kidney and spleen were measured;the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in serum were determined. Results: After the successful establishment of the aging model, it was found that during the treatment phase of dagliflozin. 1) The organ indices of mice in the aging group were significantly lower than those of other groups, and no significant hypoglycemia was observed throughout the treatment process. 2) In the water maze test, mice in the aging group had a significantly longer latency in the plateau phase compared to the control and treatment groups, while the number of times the mice crossed the original plateau and the percentage of time spent exploring the original plateau quadrant were reduced after the plateau was removed. 3) The nerve cells in the aging mice were disorganized and the nuclei of the mice were deeply stained;the dagliflozin group improved the morphological changes in the brain of aging mice. 4) In addition, compared with the control mice, the serum MDA level was significantly increased and the antioxidant enzyme SOD activity was significantly decreased in the aging group, while compared with the aging group, dagliflozin significantly decreased the MDA level and increased the SOD activity. 5) The expression of SIRT1 and PGC-1α was significantly upregulated in the low and high doses of dagliflozin compared to the aging group. Conclusion: The present study suggests that dagliflozin can delay organ aging, improve the learning and memory ability of aging mice, and exert antioxidant effects, probably through upregulating the SIRT1/PGC-1α signaling pathway.
基金supported by Yunnan Provincial Science and Technology Department of China to WX(2017FA044 and 2013HA023)Ministry of Science and Technology of the People’s Republic of China-The National Key Research and Development Program(2017YFC1700906).
文摘The sodium-dependent glucose transporters 2(SGLT2)plays important role in renal reabsorption of urinal glucose back to plasma for maintaining glucose homeostasis.The approval of SGLT2 inhibitors for treatment of type 2 diabetes highlights the SGLT2 as a feasible and promising drug target in recent years.Current methods for screening SGLT2 inhibitors are complex,expensive and labor intensive.Particularly,these methods cannot directly measure nonradioactive glucose uptake in endogenous SGLT2-expressing kidney cells.In present work,human kidney cells,HK-2,was incubated with a fluorescent D-glucose derivant 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose(2-NBDG)and the fluorescent intensity of 2-NBDG was employed to measure the amount of glucose uptake into the cells.By optimizing the passages of HK-2 cells,2-NBDG concentration and incubation time,and by measuring glucose uptake treated by Dapagliflozin,a clinical drug of SGLT2 inhibitors,we successfully developed a new assay for measuring glucose uptake through SGLT2.The nonradioactive microplate and microscope-based high-throughput screening assay for measuring glucose can be a new method for screening of SGLT2 inhibitors and implied for other cell assays for glucose measurement extensively.
文摘The sodium and glucose co-transporter inhibitors type 2 (SGLT2) comprises a new class of hypoglycemic drugs to control type 2 diabetes mellitus, in an attempt to add new non-existing benefits to the so far arising classes. Regarding this new class of drugs, represented by dapaglifozin, canaglifozin and empaglifozin, it is important to highlight the benefits brought by these medications to combat hyperglycemia with insulin-independent mechanisms that are beyond glucose reduction, such as cardiovascular events prevention, reduction in HbA1c, weight loss and blood pressure lowering. Recently, a relevant study (Empa-Reg) brought hope and set the spotlight on the prevention of cardiac events among diabetic patients, which is the main cause of mortality within this group. However, despite coming out as a good treatment option, SGLT2 inhibitors are under constant clinical research and, as a new drug, it should be carefully carried out regarding the long-term effects of glycosuria and other possible side effects, such as the observed increase in the incidence of bladder, breast cancer and bone fractures, which require further studies. Therefore, these compounds might represent a landmark approach for the treatment of diabetes.
文摘Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug,the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors(SGLT2i)showed efficacy in decreasing overall mortality,hospitalization,and sudden death in patients of this very population,in whom chronic or acute ischemia count among the first cause.Remarkably,this benefit was observed independently from diabetic status,and benefited both preserved and altered ventricular ejection fraction.This feature,observed in several large randomized controlled trials,suggests additional effects from SGLT2i beyond isolated glycemia control.Indeed,both in-vitro and animal models suggest that inhibiting the Na+/H+exchanger(NHE)may be key to preventing ischemia/reperfusion injuries,and by extension may hold a similar role in ischemic damage control and ischemic preconditioning.Yet,several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules.Because of a large therapeutic margin with few adverse events,ease of prescription and potential pharmacological efficacity,SGLT2i could be candidate for wider indications.In this review,we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation,by first listing known mechanisms,including metabolic switch,prevention of lethal arrythmias and others,which portend the latter,and second,hypothesize how the former may interact with these mechanisms.
文摘目的 探讨ADAMTSL3(Adisintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3)在大鼠糖尿病肾病心肌纤维化中的作用机制和SGLT-2抑制剂(Sodium-glucose co-transporter 2)的应用效果。方法 SPF级雄性Wistar大鼠28只经高脂高糖饲料喂养联合腹腔注射链脲佐菌素(SMZ)50 mg/kg进行糖尿病肾病造模,造模成功后分为模型组和治疗组,另设正常对照组大鼠,治疗组给予SGLT-2抑制剂(卡格列净10 mg/kg)灌胃。3组大鼠进行心脏B超动态分析心脏结构改变。对大鼠心肌组织进行病理染色、qRT-PCR、Western Blot检测ADAMTSL3基因表达水平,同时观察使用SGLT-2抑制剂后大鼠心肌的病理改变。结果 与正常对照组相比,模型组在左心室重量(LVM)、左心室收缩末壁厚度(LVPWs)、左心室短轴缩短率(LVFS%)、左射血分数(LVEF%)上的差异均有统计学意义(P<0.05)。与模型组相比,治疗组大鼠糖尿病肾病诱导心肌组织纤维化相对面积降低,以及在大鼠心肌纤维化中的Ⅰ型胶原蛋白(CollagenⅠ)、纤维连接蛋白(Fibronectin)表达降低(P<0.05)。与正常对照组相比,模型组大鼠心肌组织的ADAMTSL3蛋白表达显著增加;与模型组相比,治疗组大鼠心肌组织的ADAMTSL3蛋白表达显著降低(P<0.05)。与正常对照组相比,模型组中衰老标志物p-p53、p21、p16表达水平升高;与模型组相比,治疗组p-p53、p16表达水平均降低,差异有统计学意义(P<0.05)。结论 ADAMTSL3表达与纤维化相关,因此ADAMTSL3参与促进糖尿病肾病大鼠心肌纤维化,SGLT-2抑制剂治疗可逆转其心肌纤维化病变。
