钠葡萄糖转运子2研究进展

钠葡萄糖转运子2(sodium-dependent glucose transporters,SGLT2)是一种主要表达于肾脏近曲小管的低亲和力转运蛋白,在肾脏葡萄糖的重吸收中有着重要的作用。SGLT2竞争性抑制药可增加尿糖排泄、能量消耗,从而可以有效地降低血糖,成为糖尿病治疗的又一个靶点。随着研究的深入,不断有新型的SGLT2抑制药问世。本文就SGLT家族的生物学特性、各种SGLT2抑制药的特点、临床疗效、安全性及在糖尿病治疗中的应用前景进行探讨。     

吸烟2型糖尿病大鼠葡萄糖转运子4的表达

目的了解葡萄糖转运子4在吸烟2型糖尿病大鼠骨骼肌组织中的表达,探讨吸烟对2型糖尿病发生发展的作用。方法以健康成年Wistar大鼠为研究对象,随机分为正常对照组、2型糖尿病非吸烟组及2型糖尿病吸烟组。正常对照组予普通饲料喂养,2型糖尿病吸烟组及2型糖尿病非吸烟组给予高糖高脂饲料喂养。7周时静脉注射链脲佐菌素诱导2型糖尿病模型。8周时2型糖尿病吸烟组大鼠关进"被动吸烟箱"内,12周时检测三组血清胰岛素及血糖等指标进行比较。实验12周时三组大鼠均处死,PCR法检测葡萄糖转运子4在骨骼肌组织中的表达。结果葡萄糖转运子4在2型糖尿病吸烟组及2型糖尿病非吸烟组骨骼肌组织中的表达均明显低于正常对照组。葡萄糖转运子4在吸烟2型糖尿病大鼠骨骼肌组织中的表达明显低于2型糖尿病非吸烟组。结论吸烟可能通过下调葡萄转运子4的表达增加胰岛素抵抗,促进2型糖尿病的发生和发展。     

食管鳞癌组织中葡萄糖转运蛋白-1表达的临床意义

目的探讨葡萄糖转运蛋白-1（GLUT-1）的表达与食管鳞癌发生、发展的关系。方法对95例食管癌患者的手术切除标本及胃镜活检标本采用免疫组化S—P法检测GLUT-1表达水平。结果GLUT-1在食管鳞癌组织、癌旁不典型增生组织及正常食管组织中的阳性表达率、不同浸润程度时的表达率、临床病理分型的表达率、淋巴结转移的表达率之间差异有统计学意义（P〈0．05）。结论GLUT-1在食管鳞癌的发生、发展中具有重要作用，有可能成为临床食管鳞癌诊断和判断预后的一个重要指标。     

钠-葡萄糖协同转运蛋白2抑制剂治疗多囊卵巢综合征的研究进展

多囊卵巢综合征(PCOS)是育龄妇女常见的异质性内分泌疾病。PCOS患者心血管疾病、糖尿病、高尿酸血症、肥胖、血脂异常及其他代谢综合征的发生风险增加。胰岛素抵抗(IR)作为PCOS代谢紊乱中心环节,其改善对于PCOS治疗意义重大。近年发现钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂是增加尿糖排泄的非胰岛素依赖性降血糖药,可改善PCOS患者IR与代谢,减轻患者体质量,保护多器官,降低PCOS心血管损伤、代谢综合征、血脂异常、肾病、肝脏代谢性疾病发生风险。该文就SGLT2抑制剂通过改善IR对PCOS患者代谢及心血管功能的作用及可能的机制进行综述。     

小分子钠-葡萄糖协同转运蛋白2抑制剂的研究进展

慢性高血糖是2型糖尿病(T2DM)的主要特征。钠-葡萄糖协同转运蛋白2(sodium-glucose cotransporter 2,SGLT2)是位于肾脏上的一种转运蛋白,它可以介导原尿中葡萄糖的重吸收,对维持人体血糖平衡起着关键性的作用。SGLT2抑制剂可以在近曲小管减少肾对葡萄糖的重吸收,增加尿液中葡萄糖的排泄量,从而降低血糖。本文就不同类型的SGLT2抑制剂的研究进展进行综述。     

葡萄糖转运蛋白-1的生物特性及临床意义

葡萄糖转运蛋白是细胞膜上的跨膜糖蛋白，介导细胞内外的葡萄糖以易化扩散的方式相互转运，是目前研究最为彻底的易化扩散转运体。葡萄糖的易化转运体家族到目前为止已有6种葡萄糖转运蛋白被鉴定，分别命名为葡萄糖转运蛋白-1～5（Glut-1～5）和葡萄糖转运蛋白-7（Glut-7），它们各自的功能取决于细胞的类型与代谢状态。现将Glut-1的生物特性及临床意义综述如下。     

别嘌醇改善果糖诱导的大鼠高尿酸血症与调节肠道葡萄糖转运子表达的关系研究

目的观察别嘌醇和苯溴马隆对高果糖饮水诱导的高尿酸血症(hyperuricemia,HUA)大鼠血尿酸水平、肝脏黄嘌呤氧化酶活性以及肠道果糖转运子(glucose transporter,GLUT)2和5表达的影响。方法 Wistar大鼠连续饮用10%果糖水8周以制备高尿酸血症大鼠模型,其中从第5周开始分别给予大鼠灌胃5 mg·kg~(-1)别嘌醇或10 mg·kg~(-1)苯溴马隆,共4周。磷钨酸法检测大鼠血尿酸水平,比色法检测肝脏XOD活性,Western blot法和免疫组化染色法检测肠道GLUT2和GLUT5的表达。结果别嘌醇明显降低果糖诱导的HUA大鼠血尿酸水平(P<0.01)和肝脏XOD活性(P<0.01),减少了HUA大鼠肠道GLUT5的表达(P<0.01),但对肠道GLUT2的表达无明显影响。与此同时,苯溴马隆也明显降低了果糖诱导的HUA大鼠血尿酸水平(P<0.01),但对HUA大鼠肝脏XOD活性、肠道GLUT2和GLUT5的表达均无明显影响。结论别嘌醇可明显降低果糖诱导的HUA大鼠血尿酸水平,其机制与抑制肝脏XOD活性以减少尿酸产生,抑制GLUT5表达以减少肠道果糖转运吸收,最终减少果糖代谢产生尿酸相关。     

缺氧诱导因子-1α过表达通过葡萄糖转运载体-4介导缺氧大鼠骨髓间充质干细胞对葡萄糖的摄取

目的探讨缺氧诱导因子-1α(HIF-1α)基因转染是否提高骨髓间充质干细胞(MSC)缺氧状态下的葡萄糖摄取能力以及这种能力是否与葡萄糖转运载体-4(GLUT-4)的表达和易位有关。方法将MSCs分为常氧非转染组(即对照组)、常氧转染组、缺氧非转染组和缺氧转染组,分别于常氧(5%CO_2,37℃)和缺氧(94%N_2、1%O_2和5%CO_2,37℃)条件下孵育8 h。放射同位素法检测~3H-G摄取量,免疫细胞化学和Western-blot检测GLUT-4的表达。结果①与缺氧非转染组相比,缺氧转染组显著提高细胞摄取~3H-G量(P<0.01),但二者均显著低于对照组和常氧转染组对~3H-G的摄取(P<0.01);②与缺氧非转染组相比,缺氧转染组显著提高细胞和细胞膜GLUT-4蛋白的表达(P<0.01),2组均显著低于对照组GLUT-4蛋白的表达和移位(P<0.01);③~3H-G摄取量与细胞膜中GLUT-4表达呈正相关(r=0.437,P=0.001)。结论 HIF-1α基因提高MSCs的葡萄糖摄取能力,此机制与HIF-1α基因提高GLUT-4的表达和易位相关。     

治疗糖尿病新药:钠-葡萄糖协同转运蛋白抑制剂dapagliflozin

钠-葡萄糖协同转运蛋白2(SGLT-2)是一种跨膜蛋白,主要分布在肾脏近曲小管,将葡萄糖从肾小管液转运入肾小管细胞内,约占肾脏重吸收葡萄糖的90%。SGLT-2抑制剂是治疗糖尿病的新药,可降低SGLT-2活性,减少肾脏对葡萄糖的重吸收量,增加尿糖排出,从而降低血糖。已有的临床试验表明SGLT-2抑制剂dapagliflozin治疗糖尿病有效且安全,患者耐受性良好。SGLT-2抑制剂很可能是未来糖尿病治疗的一个新的突破口。     

葡萄糖转运体1研究进展

葡萄糖转运体(glucose transporter,GLUT)家族是葡萄糖转运的主要媒介,目前发现有13个成员。其中GLUT1以异构体的形式广泛表达于多种细胞,是介导葡萄糖经过血脑屏障的主要转运体。疾病可以改变GLUT1介导的葡萄糖转运过程,糖转运受到干扰能使脑功能受损,甚至导致脑死亡。近来研究显示,GLUT1能介导一些神经活性药物的转运,如糖基化的神经肽、低分子量肝素及D-葡萄糖衍生物等。因此,依赖于葡萄糖转运体的葡萄糖运载方法有可能是一个选择性药物运输系统,通过此高效转运系统,可调节药物进入大脑。     

经基因分析确诊的原发性范可尼综合征一例报告

摘要：原发性范可尼综合征是一类罕见的遗传病,由于HNF4A等基因缺陷导致近端肾小管功能障碍,重吸收受阻引发营养物质丢失及电解质紊乱,从而以多饮、多尿、生长发育落后、佝偻病为主要表现。对于原发性范可尼综合征的临床与遗传学研究,国内仅有数例病例报道,尚少见遗传学确诊病例报道。本文患者经临床、生化、影像学及HNF4A基因分析,发现HNF4A基因存在c.187C>T（p.R63W）的杂合突变,未在患者父母中检出,经临床及遗传学确诊为原发性范可尼综合征。给予患者左卡尼汀、辅酶Q10、纠酸、保肝、护肾、补充维生素D、改善线粒体功能等治疗并进行随访,患者临床症状有所好转。     

Mechanistic evaluation of the effect of sodium-dependent glucose transporter 2 inhibitors on delayed glucose absorption in patients with type 2 diabetes mellitus using a quantitative systems pharmacology model of human systemic glucose dynamics

Sodium-dependent glucose transporter (SGLT) 2 is specifically expressed in the kidney, while SGLT1 is present in the kidneys and small intestine. SGLT2 inhibitors are a class of oral antidiabetic drugs that lower elevated plasma glucose levels by promoting the urinary excretion of excess glucose through the inhibition of renal glucose reuptake. The inhibition selectivity for SGLT2 over SGLT1 (SGLT2/1 selectivity) of marketed SGLT2 inhibitors is diverse, while SGLT2/1 selectivity of canagliflozin is relatively low. Although canagliflozin suppresses postprandial glucose levels, the degree of contribution for SGLT1 inhibition to this effect remains unproven. To analyze the effect of SGLT2 inhibitors on postprandial glucose level, we constructed a novel quantitative systems pharmacology (QSP) model, called human systemic glucose dynamics (HSGD) model, integrating intestinal absorption, metabolism, and renal reabsorption of glucose. This HSGD model reproduced the postprandial plasma glucose concentration–time profiles during a meal tolerance test under different clinical trial conditions. Simulations after canagliflozin administration showed a dose-dependent delay of time (T_max,glc) to reach maximum concentration of glucose (C_max,glc), and the delay of T_max,glc disappeared when inhibition of SGLT1 was negated. In addition, contribution ratio of intestinal SGLT1 inhibition to the decrease in C_max,glc was estimated to be 23%–28%, when 100 and 300 mg of canagliflozin are administered. This HSGD model enabled us to provide the partial contribution of intestinal SGLT1 inhibition to the improvement of postprandial hyperglycemia as well as to quantitatively describe the plasma glucose dynamics following SGLT2 inhibitors.     

Hydrophilic anti-migraine triptans are substrates for OATP1A2, a transporter expressed at human blood-brain barrier

1. OATP1A2 is expressed in the luminal membrane of human blood-brain barrier (BBB). The human tissue with the highest OATP1A2 mRNA expression is the brain.

2. We have established a robust BacMam2-OATP1A2 transduced HEK293 system. Among the 36 central nervous system (CNS) marketed drugs tested, hydrophilic triptans, 5-HT_1B/1D receptor agonists for the treatment of migraine attacks, were identified as OATP1A2 substrates. Kinetics (K_m and V_max) were determined for six marketed triptans.

3. Structure-activity relationship (SAR) obtained from 18 triptan structural analogs revealed that the positively charged basic amine atom was essential for efficient OATP1A2-mediated triptan uptake and uptake rate was in the order of tertiary > secondary > primary.

4. Preliminary quantitative SAR analysis of the triptan analogs demonstrated positive correlation between OATP1A2-mediated uptake rate and van der Waals volume (vdw_vol).

5. OATP1A2 was specifically expressed on the apical side of MDCKII monolayer after BacMam2-OATP1A2 transduction and can facilitate transport of triptans across the MDCKII monolayer from apical to basolateral side. Involvement of OATP1A2 for brain penetration of triptans in human requires further investigation.

     

Chronic restraint stress induces intestinal inflammation and alters the expression of hexose and lipid transporters

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二甲双胍与罗格列酮对2型糖尿病大鼠GLUT4表达的比较

目的比较二甲双胍与罗格列酮对2型糖尿病大鼠骨骼肌葡萄糖转运蛋白4(GLUT4)mRNA表达的影响.方法以低剂量链脲佐菌素(STZ)加高热量饲料喂养制作模型,灌胃给药4周,检测糖耐量、空腹血清胰岛素(Ins)及骨骼肌GLUT4 mRNA表达量的变化.结果造模后大鼠注射葡葡糖后30,60,120min血糖显著升高,空腹Ins无明显变化,骨骼肌GLUT4 mRNA表达量显著降低.两药均可使注糖后120min血糖下降;罗格列酮尚可降低空腹血糖.二甲双胍可使骨骼肌GLUT4 mRNA表达量明显升高,但罗格列酮对骨骼肌GLUT4 mRNA表达的降低无影响.结论本造模方法可导致大鼠产生类似2型糖尿病的变化,两药均可改善此模型糖耐量异常,二甲双胍的作用与增强骨骼肌GLUT4基因表达有关,而罗格列酮的作用可能与其它环节有关.     

一个导致Allan-Herndon-Dudley综合征的 SLC16A2基因新突变

摘要：Allan-Herndon-Dudley综合征（AHDS）为具有特异性的临床表现及甲状腺功能改变的罕见遗传病。系因 SLC16A2致病变异导致特异性甲状腺素转运蛋白MCT8缺陷而致病。本文报告1例全面发育迟缓、肌张力障碍、甲状 腺功能异常患儿,经二代测序发现其SLC16A2基因4号内含子存在c.1170+1G>A半合子突变,综合分析该变异为致 病突变,数据库中未检索到该变异的既往报道。该变异丰富了SLC16A2基因致病突变谱。     

Active absorption of ginsenoside Rg1 in vitro and in vivo: the role of sodium‐dependent glucose co‐transporter 1

Objectives Our previous study suggested that adrenaline (epinephrine) could be an effective absorption enhancer for ginsenoside Rg1 (Rg1). This study focused on the transport mechanism of Rg1 and the role of sodium‐dependent glucose co‐transporter 1 in the regulation of Rg1 uptake after exposure to adrenaline. Methods Caco‐2 cells were used as an in‐vitro model to assess the absorption mechanism of Rg1. Also the effect of D‐glucose on adrenaline‐induced absorption of Rg1 was investigated in vivo in rats. Key findings Results showed that the uptake of Rg1 was temperature‐dependent. The transport from the basolateral side to the apical side was significantly lower compared with that from the apical to the basolateral side (P < 0.01). The transport of Rg1 was concentration dependent (Km was 41.60 mM, Vmax was 353.75 mol/cm²/min). Cells incubated with D‐glucose‐free medium exhibited significantly greater Rg1 uptake (+ 62.6%) compared with cells in D‐glucose‐containing medium. The data indicated that sodium‐dependent glucose co‐transporter 1 was involved in the transport of Rg1. Adrenaline‐induced uptake of Rg1 was significantly inhibited in the presence of phlorizin and the absence of Na⁺. In the in‐vivo study in rats, it was found that after co‐administration with D‐glucose, the adrenaline‐induced absorption of Rg1 was inhibited. The area under the concentration‐time curve (AUC_0→∞) value was significantly decreased from 64.57 ± 27.08 to 1.37 ± 0.42 μg/ml h (P < 0.001). Conclusions The data suggested that adrenaline enhanced the absorption of Rg1 by regulating sodium‐dependent glucose co‐transporter 1.     

基于Oncomine和TCGA数据库分析SLC2A1基因在肺腺癌中的表达意义

目的阐明SLC2A1基因在肺腺癌中的表达及临床意义。方法通过检索Oncomine和TCGA等生物信息数据库中有关SLC2A1的信息,并对所获取的数据资料挖掘并进行二次分析,对SLC2A1在肺腺癌中的作用进行荟萃分析。结果 Oncomine数据库中共收集了448项不同类型SLC2A1的研究结果,关于在肿瘤与对照组织中SLC2A1表达有统计学差异的结果有47项,其中SLC2A1表达增高的有43项,表达降低的有4项。肺腺癌中高表达的研究有8项、低表达的有0项。共有8项研究数据集涉及SLC2A1在肺腺癌组织和正常组织中的表达,包括786例样本。在数据库中综合比较这8项研究成果,发现与对照组相比,SLC2A1在肺腺癌中的表达高于正常组织(P0.05)。另外,免疫组织化学显示SLC2A1在肺腺癌组织中表达较强或中等,而在正常组织中表达较弱或呈阴性。TCGA数据库中挖掘的结果也同样显示高表达SLC2A1的患者总体死亡率较高,低表达SLC2A1的患者预后较好(P0.05)。结论基于公共数据库中肿瘤相关的基因信息,提示SLC2A1的m RNA水平在肺腺癌组织中呈现高表达,并与肺腺癌预后相关,其有望成为肺腺癌药物治疗的重要治疗靶点。     

The proton-coupled amino acid transporter, SLC36A1 (hPAT1), transports Gly-Gly, Gly-Sar and other Gly-Gly mimetics

BACKGROUND AND PURPOSE

The intestinal proton-coupled amino acid transporter, SLC36A1, transports zwitterionic α-amino acids and drugs such as vigabatrin, gaboxadol and δ-aminolevulinic acid. We hypothesize that SLC36A1 might also transport some dipeptides. The aim of the present study was to investigate SLC36A1-mediated transport of Gly-Gly and Gly-Gly mimetics, and to investigate Gly-Sar transport via SLC36A1 and the proton-coupled dipeptide/tripeptide transporter, SLC15A1 in Caco-2 cells.

EXPERIMENTAL APPROACH

Transport of a compound via SLC36A1 was determined by its ability to induce an increase in the inward current of two-electrode voltage clamped SLC36A1 cRNA-injected Xenopus laevis oocytes. SLC36A1-mediated l-[³H]Pro uptake in Caco-2 cells was measured in the absence and presence of Gly-Gly or Gly-Sar. In addition, apical [¹⁴C]Gly-Sar uptake was measured in the absence and presence of the SLC36A1 inhibitor 5-hydroxy-l-tryptophan (5-HTP) or the SLC15A1 inhibitor l-4,4′-biphenylalanyl-l-proline (Bip-Pro).

KEY RESULTS

In SLC36A1-expressing oocytes, an inward current was induced by Gly-Sar, Gly-Gly, δ-aminolevulinic acid, β-aminoethylglycine, δ-aminopentanoic acid, GABA, Gly and Pro, whereas Val, Leu, mannitol, 5-HTP and the dipeptides Gly-Ala, Gly-Pro and Gly-Phe did not evoke currents. In Caco-2 cell monolayers, the apical uptake of 30 mM Gly-Sar was inhibited by 20 and 22% in the presence of 5-HTP or Bip-Pro, respectively, and by 48% in the presence of both.

CONCLUSION AND IMPLICATIONS

Our results suggest that whereas Gly-Gly amid bond bioisosteres are widely accepted by the hPAT1 carrier, dipeptides in general are not; and therefore, Gly-Sar might structurally define the size limit of dipeptide transport via SLC36A1.