钠-葡萄糖协同转运蛋白与糖尿病

钠-葡萄糖协同转运蛋白(SGLTs)在葡萄糖的跨细胞转运中发挥重要作用,其中SGLT1负责膳食葡萄糖的吸收,SGLT2负责肾脏中葡萄糖的重吸收.在糖尿病状态下,肠道SGLT1表达的增加将促进葡萄糖的吸收,从而加重了高血糖,而涎腺导管SGLT1表达的增加则使唾液分泌减少,促进了口腔并发症的发生;肾脏SGLT2和SGLT1...     

钠-葡萄糖协同转运蛋白2抑制剂治疗糖尿病研究新进展

钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂通过抑制SGLT2促进肾脏排出葡萄糖以改善血糖水平。与其他口服降糖药或胰岛素联用可增加降糖效果。还可通过尿液排出过多卡路里以减轻体重,为糖尿病患者提供更好的治疗效果。随着病情进展,糖尿病患者肾小球滤过功能降低,SGLT2抑制剂可能有肾脏保护作用。     

SGLT2抑制剂的心血管获益及治疗心力衰竭的研究综述

心力衰竭（心衰）是多种心血管疾病的严重终末阶段,尽管其药物治疗已取得很大进步,但其预后仍不乐观,接受标准治疗的心衰患者仍存在高死亡和再住院风险。目前已有多项大型随机对照研究证实降糖药物钠-葡萄糖共转运蛋白2（SGLT2）抑制剂有明显的心血管获益,可以明显降低心衰患者心血管死亡率,降低心衰恶化风险,且无论是否伴有糖尿病均可获益。本文就SGLT2抑制剂的心血管获益和治疗心衰的研究和机制进行综述,期待SGLT2抑制剂可以打破传统心衰治疗的金三角（血管紧张素转化酶抑制剂/血管紧张素II受体拮抗剂/血管紧张素受体脑啡肽酶抑制剂、盐皮质激素受体拮抗剂和β受体阻滞剂）,实现与金三角使用的四联治疗。     

钠-葡萄糖协同转运蛋白抑制剂对肠肾之间Cross-Talk的影响

肠上皮细胞和肾小管上皮细胞均表达钠-葡萄糖协同转运蛋白(SGLT)，在一些营养物质转运和调节中发挥着核心作用，与腹型肥胖、高血压、2型糖尿病和肾脏疾病密切相关。SGLT表达水平受到营养素、激素、炎症、氧化应激等调控。SGLT抑制剂是治疗糖尿病的新型药物，肠道和肾脏是其靶向作用器官，除减轻体重和降低血糖等，研究发现肾素-血管紧张素系统、肾交感神经活性、肠道炎症、肠道微生物和氧化应激是SGLT抑制剂发挥心肾保护作用的潜在机制。本文旨在以肠道和肾脏SGLT表达为靶点，为代谢性疾病治疗提供新思路。     

葡萄糖协同转运蛋白2抑制剂防治心力衰竭的研究进展

心力衰竭是合并动脉粥样硬化性心血管疾病(ASCVD)和ASCVD高危因素2型糖尿病(T2DM)患者最常见的并发症之一。临床试验显示葡萄糖协同转运蛋白2抑制剂(SGLT2i)可有效预防心力衰竭住院的发生。新的证据表明SGLT2i治疗确诊的合并和不合并T2DM的心力衰竭患者明显获益,更多的循证医学依据正在积累中。虽然SGLT2i耐受性良好,但应对严重不良作用进行监测。本文主要介绍SGLT2i防治心力衰竭的获益、不良作用和可能机制。     

SGLT2抑制剂治疗2型糖尿病合并心力衰竭的疗效和安全性的Meta分析

目的 系统评价钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)治疗2型糖尿病(T2DM)合并心力衰竭(心衰,HF)的有效性和安全性.方法 系统检索了CocHRane图书馆、Web of science、PubMed、Embase数据库,检索时限均为建库起至2020年11月20日,搜索了SGLT2i对比安慰剂治疗T2DM合并...     

SGLT2抑制剂对2型糖尿病患者血尿酸水平的影响

钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂是一种新型降糖药,可控制血糖、降低心血管事件、改善肾功能等。越来越多的数据表明,SGLT2抑制剂也可降低血尿酸水平。可能的机制是近端肾小管腔内葡萄糖的排泄增强,通过顶端膜上葡萄糖转运蛋白(GLUT)9亚型2促进细胞内尿酸盐的交换,导致尿酸分泌增加,且SGLT2抑制剂抑制肾小管重吸收葡萄糖,导致尿中葡萄糖增加,这可能会抑制集合管中GLUT9亚型2介导的尿酸重吸收。另一种可能的机制是SGLT2抑制剂通过降低血清胰岛素浓度,减少尿酸盐重吸收转运蛋白1(URAT1)对尿酸的重吸收。     

钠-葡萄糖协同转运蛋白-2抑制剂在射血分数保留的心力衰竭中的作用及机制研究进展

钠-葡萄糖协同转运蛋白-2抑制剂(SGLT2i)是一种新型降糖药物, 可通过抑制近端小管对葡萄糖的重吸收而降低血糖, 广泛用于2型糖尿病的临床治疗。SGLT2i不仅可降低血糖, 还具有多种心血管益处。随着多个大型临床随机对照试验结果的发布, SGLT2i在射血分数保留的心力衰竭(HFpEF)中的安全性和有效性已被证实。现就SGLT2i降低射血分数保留的心力衰竭患者心血管事件的风险其潜在机制的研究进行综述。     

SGLT2抑制剂治疗2型糖尿病的相关研究

钠-葡萄糖协同转运蛋白2( SGLT2)存在于近端肾小管上皮细胞,在肾脏血糖的重吸收中发挥重要作用,因此选择性抑制SGLT2活性,从而特异性抑制肾脏对葡萄糖的重吸收,增加尿糖排泄可以达到降糖目的.目前研发的SGLT2抑制剂包括T-1095、BI-10773、dapagliflozin等.SGLT2抑制剂与体重、低血糖、糖尿病肾病、泌尿系统感染及口渴、多饮、多尿症状的关系未明确,目前已有大量研究证明了其有效性及安全性,这将为糖尿病患者提供一种新的降糖途径.     

钠-葡萄糖协同转运蛋白2抑制剂治疗射血分数保留性心力衰竭的循证医学证据及机制

钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂是一种新型降糖药物,其通过阻断位于肾脏近端小管的低亲和力、高容量的SGLT2,减少近端小管对葡萄糖的重吸收和增加尿中葡萄糖的排泄率来降低血糖.研究显示,SGLT2还可以降低心力衰竭住院风险和减少心血管事件.目前,SGLT2抑制剂在射血分数降低的心力衰竭(HFrEF)治疗中的价...     

钠-葡萄糖共转运蛋白2抑制剂心血管获益机制研究进展

近年来,新型口服降糖药物钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）在2型糖尿病患者心血管获益方面涌现出大量证据,多项临床试验显示SGLT2i可以显著降低2型糖尿病患者心血管死亡风险,并减少心力衰竭住院率,其中达格列净被证实对非糖尿病的心力衰竭患者同样具有心血管保护作用。目前针对SGLT2i心血管获益具体机制方面的研究已取得部分进展,本文将从容量调节学说、改善血管内皮功能、改善心脏能量代谢、改善心室重构和调节全身代谢 5个方面阐述SGLT2i心血管获益的机制。     

Metabolic and hemodynamic effects of sodium‐dependent glucose cotransporter 2 inhibitors on cardio‐renal protection in the treatment of patients with type 2 diabetes mellitus

The specific sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) inhibit glucose reabsorption in proximal renal tubular cells, and both fasting and postprandial glucose significantly decrease because of urinary glucose loss. As a result, pancreatic β‐cell function and peripheral insulin action significantly improve with relief from glucose toxicity. Furthermore, whole‐body energy metabolism changes to relative glucose deficiency and triggers increased lipolysis in fat cells, and fatty acid oxidation and then ketone body production in the liver during treatment with SGLT2 inhibitors. In addition, SGLT2 inhibitors have profound hemodynamic effects including diuresis, dehydration, weight loss and lowering blood pressure. The most recent findings on SGLT2 inhibitors come from results of the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes trial. SGLT2 inhibitors exert extremely unique and cardio‐renal protection through metabolic and hemodynamic effects, with long‐term durability on the reduction of blood glucose, bodyweight and blood pressure. Although a site of action of SGLT2 inhibitors is highly specific to inhibit renal glucose reabsorption, whole‐body energy metabolism, and hemodynamic and renal functions are profoundly modulated during the treatment of SGLT2 inhibitors. Previous studies suggest multifactorial clinical benefits and safety concerns of SGLT2 inhibitors. Although ambivalent clinical results of this drug are still under active discussion, the present review summarizes promising recent evidence on the cardio‐renal and metabolic benefits of SGLT2 inhibitors in the treatment of type 2 diabetes.     

Spontaneous regression of hepatocellular carcinoma with reduction in angiogenesis‐related cytokines after treatment with sodium‐glucose cotransporter 2 inhibitor in a cirrhotic patient with diabetes mellitus

Spontaneous regression of hepatocellular carcinoma (HCC) is a rare event, and the pathogenesis remains unclear. Here, we present a case of spontaneous regression of HCC after treatment with sodium‐glucose cotransporter 2 inhibitor (SGLT2i) in a cirrhotic patient with diabetes mellitus (DM). A 68‐year‐old man regularly visited our hospital for follow‐up of HCC after treatment with transcatheter arterial chemoembolization, and management of liver cirrhosis and type 2 DM. Contrast‐enhanced computed tomography scan showed a hypervascular tumor in the liver and elevated serum α‐fetoprotein levels, indicating the recurrence of HCC. Simultaneously, the hemoglobin A1c value increased to 8.0%; therefore, he was treated with SGLT2i (canagliflozin 100 mg/day). Ten weeks after the initiation of SGLT2i treatment, he was admitted to our hospital for treatment of recurrent HCC. However, the hypervascular tumor had disappeared, and the elevated serum α‐fetoprotein level had decreased to normal limits, indicating spontaneous regression of HCC. In addition, an angiogenesis array analysis revealed downregulated protein expression of matrix metalloproteinase‐8, angiopoietin‐1/2, platelet‐derived growth factor‐AA, and prolactin at 10 weeks after SGLT2i treatment. In this report, we first describe a case of spontaneous regression of HCC with reduction in angiogenesis‐related cytokines after SGLT2i treatment.     

Sodium glucose cotransporter 2 inhibitors: New horizon of the heart failure pharmacotherapy

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have gained momentum as the latest class of antidiabetic agents for improving glycemic control. Large-scale clinical trials have reported that SGLT2 inhibitors reduced cardiovascular outcomes, especially hospitalization for heart failure in patients with type 2 diabetes mellitus who have high risks of cardiovascular disease. Accumulating evidence has indicated that beneficial effects can be observed regardless of the presence or absence of type 2 diabetes mellitus. Accordingly, the Food and Drug Administration approved these agents specifically for treating patients with heart failure and a reduced ejection fraction. It has been concluded that canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin can be recommended for preventing hospitalization associated with heart failure in patients with type 2 diabetes and established cardiovascular disease or those at high cardiovascular risk. In the present review, we explore the available evidence on SGLT2 inhibitors in terms of the cardioprotective effects, potential mechanisms, and ongoing clinical trials that may further clarify the cardiovascular effects of the agents.     

Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA‐REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte‐free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte‐free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2‐fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.     

心肌梗死后左室重构发病机制进展

急性心肌梗死(AMI)是威胁人类健康的重大疾病,心肌梗死(MI)后30 min,部分心肌细胞即发生不可逆的坏死,因此,MI有效救治的时间窗极为短暂,许多患者不能够得到及时有效的治疗,使得MI后心力衰竭(HF)的发生率仍然居高不下。最新调查研究表明,MI后1年HF的发生率约为14.2%。因MI后HF再次入院的患者,1年死亡率高达为45.5%。MI后HF的主要原因是部分心肌细胞坏死,左室重构,心脏扩张,继而引发HF。目前,MI后左室重构的机制尚未完全阐明。本文介绍了AMI后左室重构的发病机制主要进展。     

Sodium–glucose cotransporter inhibition: therapeutic potential for the treatment of type 2 diabetes mellitus

Results from randomized controlled trials have demonstrated that the risk of microvascular complications can be reduced by intensive glycaemic control in patients with type 2 diabetes mellitus (T2DM). However, only about half of patients with diagnosed diabetes achieve recommended glycaemic goals. New therapies with complementary mechanisms of action that are independent of insulin secretion or action may provide additional therapeutic options to enable patients to achieve glycaemic control. The kidney plays an important role in glucose homeostasis, primarily by the reabsorption of filtered glucose. The sodium–glucose cotransporter 2 (SGLT2), located in the proximal convoluted tubule, is responsible for the majority of glucose reabsorption by the kidney. SGLT2 inhibitors offer a novel approach to treat T2DM and reduce hyperglycaemia by increasing urinary excretion of glucose. Dapagliflozin, an SGLT2 inhibitor recently approved in Europe for the treatment of T2DM, improves glycaemic control in patients with T2DM when used as monotherapy or when added to other diabetes medications, such as metformin, sulfonylureas, pioglitazone, and insulin. As a class, SGLT2 inhibitors are well tolerated and have a low propensity to cause hypoglycaemia. An increase in signs, symptoms, and other events suggestive of genital and, in some studies, urinary tract infections has been reported with SGLT2 inhibitors. Results from ongoing and future clinical trials will help define the role for this new class of investigational compounds, with its unique mechanism of action, as a treatment option for reducing hyperglycaemia in patients with T2DM. Copyright © 2013 John Wiley & Sons, Ltd.     

舒张性心力衰竭早期防治专家建议

舒张性心力衰竭(DHF)已经成为一个公共健康问题,其发病主要涉及心血管代谢危险因素(CMRF)人群。对于DHF早期诊断,本专家组建议推荐超声心动图测量左室舒张功能指标和检测利钠肽水平;在治疗高血压、高脂血症、2型糖尿病(T2D)及肥胖等CMRF时,推荐应用SGLT2抑制剂、二甲双胍、GLP-1受体激动剂和他汀等药物进行心外膜脂肪组织(EAT)聚集的早期干预,预防DHF。