眼针疗法对D-IBS模型大鼠结肠VIPR1表达的影响

目的 观测眼针对腹泻型肠易激综合征(D-IBS)模型大鼠血清、结肠组织中血管活性肠肽(VIP)含量及结肠组织VIP受体1(VIP-Rl)表达的变化,探讨眼针治疗D-IBS的作用机制.方法 30只雄性SPF级大鼠,分为对照组、IBS模型组和眼针组,采用慢性应激与束缚相结合的方法复制D-IBS模型后,进行眼针治疗7d.应用ELISA方法检测VIP含量；采用免疫组化、RT-PCR方法检测VIP-R1表达.结果 与对照组比较,模型组血清、结肠组织中VIP含量及VIP-R1表达明显增高和上调(P ＜0.01,P＜0.05)；与模型组比较,眼针组血清、结肠组织中VIP含量及VIP-R1表达明显下降和下调.结论 眼针治疗D-IBS的机制之一可能与抑制血清、结肠组织VIP释放、下调VIP-R1表达有关.     

从肠肌间神经丛抑制性神经递质的改变探讨IBS不同亚型的发病机制

目的:检测腹泻型IBS(D-IBS)和便秘型IBS(C-IBS)动物模型肠肌间神经丛的抑制性神经递质一氧化氮(NO)的差异,来探讨肠肌间神经丛神经递质的改变对IBS亚型的影响．方法:采用乙酸灌肠加束缚应激的方法造成D-IBS动物模型,同时设立灌肠对照和空白对照．采用冰水每日灌胃共14 d的方法造成C-IBS动物模型,同时设立灌胃对照和空白对照．检测各组大鼠粪便性状、内脏敏感性及肠肌间神经丛抑制性神经递质No的含量．结果:在高容量球囊扩张时,D-IBS组大鼠的腹肌收缩次数比C-IBS组及灌肠、空白对照组均明显增多(1．2 mL:7．22±2．01 vs 2．77±0．78,2．89±1．17,3．59±1．08; 1．6 mL:8．11±1．94 vs 2．89±1．67,2．44±1．42, 2．89±1．22,P<0．05)．在低容量球囊扩张时,C-IBS组大鼠的腹肌收缩次数比对照组及D-IBS组明显减少(0．4 mL:0．44±0．22 vs 2．44±0．67;0．8 mL:1．56±0．74 vs 6．31±1．74,P<0．05)．C-IBS组和灌胃对照组的粪粒数、粪便湿重及粪便含水量均小于空白对照组(2．00±0．66, 2.33±0．50 vs 3．67±1．00;0．80±0．32,1．69±0．49 vs 2．14±0．27;39．24±3．11,40．67±2．84 vs 48．38±2．79, P<0．05);D-IBS组粪便湿重和粪便含水量均高于灌肠和空白对照组(2.31±0．72 vs 1．52±0．58,1．57±0．56, P<0．05;65．31±3．31 vs 53．41±2．73,55．78±3．99． P<0．05)．C-IBS组首次排黑便时间比灌胃和空白对照组明显延长(277．89±25．08 vs 205．44±15．74, 189．22±18．45,P<0．05)．结肠组织学分析显示各组大鼠均无明显结肠炎性表现．C-IBS组NO阳性的神经元细胞数显著多于D-IBS组和对照组(303．50±14．43 vs 200．89±16．67,185．78±16．66,P<0．01),而D-IBS组和对照组NO阳性的神经元细胞数无显著差异(P>0．05)．结论:抑制性神经递质NO的数量的增加与IBS不同亚型、内脏敏感性及动力异常相关,提示NO的改变与 IBS不同亚型发病机制有一定关系．     

肠易激综合征模型大鼠5-羟色胺7受体的表达及作用

目的 观察5-羟色胺7受体在肠易激综合征(IBS)不同亚型模型大鼠大脑和消化道组织中表达和分布的差异,探讨其在IBS发病中的作用.方法 45只成年SD大鼠分均为对照组、腹泻型IBS(IBS-D)组和便秘型IBS(IB-C)组.乙酸加束缚应激法制备IBS-D模型,冰水灌胃法制备IBS-C模型.免疫组化法和实时定量PCR法检测各组大鼠大脑、空肠、回肠、近端结肠、远端结肠中5-HT7受体的分布及表达差异.放射免疫法测定以上各组织中环磷酸腺苷(cAMP)含量.结果 免疫组化结果 显示,IBS-C组和IBS-D组海马及下丘脑、IBS-C组回肠、近端结肠、远端结肠5-HT7受体表达强于对照组(P＜0.05).实时定量PCR结果 显示,IBS-C和IBS-D组海马和下丘脑、IBS-C组回肠、近端结肠及远端结肠5-HT7受体mRNA明显高于对照组(P＜0.05).IBS-C和IBS-D组海马和下丘脑、IBS-C组近端结肠和远端结肠cAMP含量显著高于对照组(P＜0.05).结论 两组大鼠脑组织及IBS-C大鼠结肠5-HT7受体表达及cAMP水平明显增高,可能与IBS-C胃肠动力障碍和内脏感觉异常有关.     

肠易激综合征患者血浆脑肠肽水平的变化

脑肠肽作为一类具有神经递质和激素双重功能的小分子多肽,在肠易激综合征（IBS）的发病机制中起重要作用.目的：研究血管活性肠肽（VIP）,神经肽Y（NPY）和神经降压素（NT）水平在IBS患者血浆中的变化及其临床意义.方法：根据RomeⅡ标准纳入IBS患者36例,其中腹泻为主型IBS（D-IBS）24例,便秘为主型IBS（C-IBS）12例,同时纳入正常对照者10名.采用放射免疫测定分别检测受试者血浆VIP、NPY和NT水平.结果：D-IBS患者血浆VIP水平显著高于正常对照组（P＜0.05）,而C-IBS患者血浆VIP水平与正常对照组比较无显著差异（P＞0.05）;D-IBS和C-IBS患者血浆NPY水平均显著低于正常对照组（P＜0.05和P＜0.01）,其中C-IBS患者又显著低于D-IBS患者（P＜0.05）;D-IBS和C-IBS患者血浆NT水平均显著高于正常对照组（P＜0.05）,但两亚型间比较无显著差异（P＞0.05）.结论：IBS患者血浆脑肠肽水平与腹泻或便秘症状有一定的联系,表现为D-IBS和C-IBS患者的血浆NT水平均显著升高,而NPY和VIP水平因IBS亚型的不同而有差异.脑肠肽作为调节胃肠运动功能和感觉功能的重要因素,可能与IBS的发生、发展有必然的内在联系.     

胃旁路手术治疗2型糖尿病模型大鼠的机制

目的 探讨胃旁路术(GBP)对2型糖尿病(非胰岛素依赖型糖尿病,NIDDM)大鼠模型治疗作用的可能机制.方法 将60只已成功建模的SD成年雄性2型糖尿病大鼠随机分为胃旁路术组(A组)和假手术组(Sham-A组),每组30只.观察、记录所有SD大鼠手术前后体重、空腹血糖(FPG)水平、胰岛素(FINS)水平,计算胰岛素敏感指数(IAI)=1/FPG×FINS);ELISA法检测手术前后血浆胰高血糖素样肽-1(GLP-1)、葡萄糖依赖性促胰岛素激素(GIP)的水平,RT-PCR检测胰腺组织胰高血糖素样肽-1受体(GLP-1R)mRNA、葡萄糖依赖性促胰岛素激素受体(GIPR) mRNA表达变化.结果 GBP术后8wA组糖尿病大鼠的空腹血糖由术前的(20.05±3.50) mmol/L下降至(5.85±0.72) mmol/L(P ＜0.05),且长期维持在较低水平;GBP术后8wA组糖尿病大鼠的空腹胰岛素水平由术前的(7.55±3.15)μU/ml升高至(14.85±2.52)μU/ml(P＜0.05);GBP术后8wA组糖尿病大鼠的空腹胰岛素敏感指数由术前的(0.32±0.12)下降至(0.12±0.06)(P＜0.05).空腹血清GLP-1由术前的(16.86±0.85) pmol/L上升至(35.58±2.15) pmol/L(P ＜0.05),经25％葡萄糖灌胃30 min后更加明显;空腹血清GIP由术前的(7.65±0.75)pmoL/L下降至(4.28±0.08) pmol/L(P＜0.05),经25％葡萄糖灌胃30 min后更加明显.胰腺GLP-1R mRNA表达由术前的(1.01±0.02)倍上升至(5.38±0.65)倍(P＜0.05);胰腺GIP mRNA术前术后无明显变化.结论 GBP对SD大鼠2型糖尿病模型具有明显的治疗作用;其可能机制是过早进入空肠下段的食物,促进GLP-1分泌、减少GIP分泌,同时促进GLP-1R高表达,进而促进胰岛素分泌和(或)增加胰岛素敏感性.     

肠易激综合征患者5-HT阳性细胞与SERT表达的关系

[目的]研究肠易激综合征(IBS)患者中5-HT阳性细胞与5-羟色胺转运体(SERT)的表达及二者之间的关系。[方法]分别应用免疫组织化学方法和原位杂交方法检测IBS不同亚型[腹泻型IBS(D-IBS)、便秘型IBS(CIBS)、交替型IBS(A-IBS)]患者结肠黏膜5-HT阳性细胞和SERT的表达,以结肠息肉或胃息肉切除术后复查者60例作为对照组。[结果]5-HT阳性细胞在D-IBS组、A-IBS组、对照组、C-IBS组中的表达率依次降低(χ~2=13.331,P0.05)。而SERT mRNA在D-IBS组、A-IBS组、对照组、C-IBS组中的阳性表达率依次升高(χ~2=8.341,P0.05)。[结论]SERT影响5-HT的调控从而产生IBS不同躯体症状。     

疏肝健脾方对腹泻型肠易激综合征大鼠的治疗作用及对肥大细胞、5-HT通路的影响

[目的]探讨疏肝健脾方对腹泻型肠易激综合征(diarrhea-predominant pattern irritable bowel syndrome,D-IBS)大鼠的治疗作用及肥大细胞、5-HT通路的影响。[方法]1日龄SD雄性大鼠随机分为正常组、模型组、疏肝健脾方组。采用母婴分离联合束缚应激方法建立D-IBS大鼠模型。造模成功后,疏肝健脾方组给予疏肝健脾方灌胃(2.33g·100g~(-1)·d~(-1)),正常组和模型组则给予等体积的生理盐水灌胃。灌胃结束后,测定各组大鼠粪便含水量、直结肠球囊扩张刺激时腹壁撤退反射(abdominal withdrawal reflex,AWR)评分及腹外斜肌肌电(electromyography,EMG)积分变化率。并分别采用甲苯胺蓝染色检测结肠肥大细胞表达,酶联免疫法(ELISA)测定结肠5-HT水平,蛋白免疫印记法(Western blot,WB)检测结肠5-HT3R(5-hydroxytryptamine receptor 3,5-HT3R)、5-HT4R(5-hydroxytryptamine receptor 4,5-HT4R)蛋白表达。[结果]疏肝健脾方组大鼠粪便含水量较模型组降低(P0.05);直结肠内球囊压力在40、60、80mmHg(1mmHg=0.133kPa)时,AWR评分及EMG积分变化率较模型组均降低(P0.05);疏肝健脾方组结肠肥大细胞数目、5-HT含量、5-HT3AR及5-HT3BR蛋白表达较模型组均降低(P0.05),5-HT4R蛋白表达较模型组升高(P0.05)。[结论]疏肝健脾方对D-IBS大鼠有较好治疗作用,其作用机制可能与降低结肠肥大细胞数目、5-HT的含量、5-HT3AR及5-HT3BR的表达,升高5-HT4R的表达有关。     

电针刺激足三里对内脏高敏感大鼠的影响及其机制

背景:内脏高敏感是肠易激综合征(IBS)的重要发病机制之一,电针刺激足三里治疗IBS正逐渐应用于临床,然而其对内脏敏感性的影响及其作用机制尚不十分清楚。目的:研究电针刺激足三里对大鼠内脏感觉的影响以及近端结肠、远端结肠和丘脑组织中μ阿片受体蛋白表达的变化,以探讨μ阿片受体在电针治疗IBS中的作用。方法:32只Sprague-Dawley大鼠随机分为正常对照组(NC组)、单纯模型组(M组)、模型+电针组(MEA组)和模型+假电针组(MSE组)。采用直肠灌注乙酸制备内脏高敏感模型。电针(假电针)治疗前后,大鼠行结直肠扩张后记录腹壁肌电。采用蛋白质印迹法检测各组大鼠近端结肠、远端结肠和丘脑组织中μ阿片受体的蛋白表达。结果:与电针刺激前相比,电针刺激后MEA组大鼠在相同结直肠扩张压力(20、40、60、80 mm Hg)下腹外斜肌放电次数均明显减少(P0.001):而MSE组腹外斜肌放电次数无明显差异(P0.05)。与M组相比,MEA组近端结肠、远端结肠和丘脑组织中μ阿片受体蛋白表达明显增加(P0.05),而MSE组无明显差异(P0.05)。结论:电针刺激足三里可降低大鼠内脏高敏感性.其作用机制可能通过上调中枢和外周μ阿片受体蛋白表达而实现的。     

胰高血糖素样肽-1对糖尿病大鼠胃排空的非受体通路的影响

目的探讨室旁核(Paraventricular nucleus,PVN)内胰高血糖素样肽-1(Glucagon-like pepetide-1,GLP-1)是否存在非受体通路参与糖尿病大鼠胃排空的中枢调节。方法 40只雄性Wistar大鼠随机分为正常对照组(NC组)、糖尿病组(DM组)、GLP-1(7-36)干预组(GLP组)、Exendin(9-39)联合GLP-1干预组(E-G组)及Exendin(9-39)干预组(Exendin组)。制备糖尿病大鼠模型,PVN埋置套管并给予GLP-1(7-36)或Exendin(9-39)等药物,2周后甲基纤维素-酚红溶液测胃排空;实时荧光定量分析法检测PVN区GLP-1受体(GLP-1R)mRNA表达情况。结果注射STZ 2周后,GLP组及E-G组胃排空率较DM组、Exendin组均明显降低(P均0.05),但高于NC组(P0.05);GLP组及E-G组的下丘脑GLP-1R mRNA表达较DM组、NC组、Exendin组均明显增高(P均0.05)。GLP组胃排空率和空腹血糖较E-G组降低(P0.05);下丘脑GLP-1R mRNA表达GLP组与E-G组比较差异无统计学意义(P0.05)。结论室旁核注射GLP-1可减缓糖尿病大鼠早期的胃排空,推测GLP-1影响胃排空的中枢作用机制除促进GLP-1受体表达增加外,非受体作用通路亦发挥重要作用。     

腹泻型肠易激综合征大鼠模型的评价研究

[目的]对母婴分离联合束缚应激法建立的腹泻型肠易激综合征(Diarrhea-predominant pattern irritable bowel syndrome,D-IBS)大鼠模型进行评价。[方法]16只2日龄SD大鼠随机分为正常组(8只)和模型组(8只)。模型组大鼠第2~21日龄,每天将新生期大鼠与哺乳期母鼠分离3h;第50~59日龄每天予束缚应激刺激。正常组不予任何干预,直至大鼠60日龄。造模结束后,检测各组大鼠体重变化、粪便含水量、结肠球囊扩张刺激时大鼠腹壁撤退反射(Abdominal withdrawal reflex,AWR)评分及腹外斜肌肌电(Electromyography,EMG)积分变化率。[结果]模型组大鼠体重低于正常组(P0.05),粪便含水量明显高于正常组(P0.05);与正常组比较,在结肠气囊压力为40mmHg、60mmHg、80mmHg时,模型组大鼠AWR评分及EMG积分变化率均显著升高(P0.05);2组大鼠结肠黏膜均无明显病理改变。[结论]采用母婴分离联合束缚应激的方法建立D-IBS大鼠模型可在一定程度上模拟D-IBS的腹泻症状及内脏高敏感的状态。     

Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L-cells in response to nutrients. GLP-1 lowers blood glucose levels by stimulating insulin secretion from pancreatic beta-cells in a glucose-dependent manner. In addition, GLP-1 slows gastric emptying, suppresses appetite, reduces plasma glucagon, and stimulates glucose disposal, which are beneficial for glucose homeostasis. Therefore, incretin-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase IV, an enzyme which inactivates GLP-1, have been developed for treatment of diabetes. This review outlines our knowledge of the actions of GLP-1 on insulin secretion and biosynthesis, beta-cell proliferation and regeneration, and protection against beta-cell damage, as well as the involvement of recently discovered signaling pathways of GLP-1 action, mainly focusing on pancreatic beta-cells.     

人胰高血糖素样肽-1类似物:利拉鲁肽

胰高血糖素样肽-1(GLP-1)是一种肠促胰岛素,具有促进胰岛素释放、延缓胃排空、减低体重和降低食欲等生理作用.然而,大然的GLP-1很不稳定.可被二肽基肽酶-Ⅳ(DPP-Ⅳ)降解,半衰期仅为1～2 min.若采用天然GLP-1来降低血糖,需持续静脉输注或持续皮下注射,临床可行性较差.面对这种情况,人们不断探索,研发具有长效作用的人GLP-1类似物.本文着重论述此类药物的代表药物利托鲁肽(liraglutide).它的分子结构独特,通过和白蛋白结合,既保留了天然GLP-1的功效义延长了作用时间,可每日一次注射.临床应用中,它能安全、有效的控制糖代谢,改善胰岛β细胞功能,降低体重和收缩压.正是这种治疗的多效性,给2型糖尿病患者的治疗带来了新希单.     

Enhanced glucagon-like peptide-1 secretion in a patient with glucagonoma: Implications for glucagon-like peptide-1 secretion from pancreatic α cells in vivo

We examined GLP-1 secretion from the pancreas of a patient with glucagonoma and pancreatic resection by measuring GLP-1 after meal ingestion or selective arterial calcium injection, and immunohistochemical analysis. Our findings support the notion that GLP-1 is secreted from pancreatic α cells in humans.     

胰升糖素样肽-1的研究进展

胰升糖素样肽-1(GLP-1)是由肠道内分泌L细胞分泌的肠促胰岛素,具有促进胰岛素分泌、胰岛细胞生长、增殖和分化并抑制胰岛β细胞凋亡等多种作用,可用来预防和治疗糖尿病,辅助进行胰岛细胞移植,且不引起体重增加和低血糖。但GLP-1可很快被二肽基肽酶Ⅳ降解,限制了其临床应用。目前对长效的GLP-1类似物、二肽基肽酶Ⅳ抑制剂和GLP-1基因治疗的研究已成为热点。     

胰高血糖素样肽-1的心脏保护作用

胰高血糖素样肽-1( GLP-1)是由肠道内分泌L细胞分泌的一种重要的肠促胰岛素,具有促进胰岛素分泌、增加葡萄糖利用、降低血糖等生物学作用.研究显示,GLP-1具有明显的心脏保护作用,主要通过抑制心肌细胞凋亡、改善心肌收缩力、促进心肌葡萄糖的利用等直接或间接发挥其心脏保护作用,并逐渐应用于临床.进一步深入探讨GLP-1的心脏保护作用机制有助于临床上为心血管疾病患者提供新的治疗思路.     

Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure

BACKGROUND & AIMS: Gut-derived peptides including ghrelin, cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide (GLP-1), and GLP-2 exert overlapping actions on energy homeostasis through defined G-protein-coupled receptors (GPCRs). The proglucagon-derived peptide (PGDP) oxyntomodulin (OXM) is cosecreted with GLP-1 and inhibits feeding in rodents and humans; however, a distinct receptor for OXM has not been identified. METHODS: We examined the mechanisms mediating oxyntomodulin action using stable cell lines expressing specific PGDP receptors in vitro and both wild-type and knockout mice in vivo. RESULTS: OXM activates signaling pathways in cells through glucagon or GLP-1 receptors (GLP-1R) but transiently inhibits food intake in vivo exclusively through the GLP-1R. Both OXM and the GLP-1R agonist exendin-4 (Ex-4) activated neuronal c-fos expression in the paraventricular nucleus of the hypothalamus, the area postrema, and the nucleus of the solitary tract following intraperitoneal (i.p.) injection. However, OXM transiently inhibited food intake in wild-type mice following intracerebroventricular (i.c.v.) but not i.p. administration, whereas Ex-4 produced a more potent and sustained inhibition of food intake following both i.c.v. and i.p. administration. The anorectic effects of OXM were preserved in Gcgr(-/-) mice but abolished in GLP-1R(-/-) mice. Although central Ex-4 and OXM inhibited feeding via a GLP-1R-dependent mechanism, Ex-4 but not OXM reduced VO2 and respiratory quotient in wild-type mice. Conclusions: These findings demonstrate that structurally distinct PGDPs differentially regulate food intake and energy expenditure by interacting with a GLP-1R-dependent pathway. Hence ligand-specific activation of a common GLP-1R increases the complexity of gut-central nervous system pathways regulating energy homeostasis and metabolic expenditure.     

Efficacy and safety of high-dose glucagon-like peptide-1, glucagon-like peptide-1/glucose-dependent insulinotropic peptide,and glucagon-like peptide-1/glucagon receptor agonists in type 2 diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms ‘glucagon-like peptide-1 receptor agonist’, ‘glucagon receptor agonist’, ‘glucose-dependent insulinotropic peptide’, ‘dual or co-agonist’, and ‘tirzepatide’. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose- and weight-lowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.     

Characterization of glucagon-like peptide-1 receptor-binding determinants

Glucagon-like peptide 1 (GLP-1) is a potent insulinotropic hormone currently under study as a therapeutic agent for type 2 diabetes. Since an understanding of the molecular mechanisms leading to high-affinity receptor (R) binding and activation may facilitate the development of more potent GLP-1R agonists, we have localized specific regions of GLP-1R required for binding. The purified N-terminal fragment (hereafter referred to as NT) of the GLP-1R produced in either insect (Sf9) or mammalian (COS-7) cells was shown to bind GLP-1. The physical interaction of NT with GLP-1 was first demonstrated by cross-linking ((125)I-GLP-1/NT complex band at approximately 28 kDa) and secondly by attachment to Ni(2+)-NTA beads. The GLP-1R NT protein attached to beads bound GLP-1, but with lower affinity (inhibitory concentration (IC(50)): 4.5 x 10(-7) M) than wild-type (WT) GLP-1R (IC(50): 5.2 x 10(-9)M). The low affinity of GLP-1R NT suggested that other receptor domains may contribute to GLP-1 binding. This was supported by studies using chimeric glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptors. GIP(1-151)/GLP-1R, but not GIP(1-222)/GLP-1R, exhibited specific GLP-1 binding and GLP-1-induced cAMP production, suggesting that the region encompassing transmembrane (TM) domain 1 through to TM3 was required for binding. Since it was hypothesized that certain charged or polar amino acids in this region might be involved in binding, these residues (TM2-TM3) were analyzed by substitution mutagenesis. Five mutants (K197A, D198A, K202A, D215A, R227A) displayed remarkably reduced binding affinity. These studies indicate that the NT domain of the GLP-1R is able to bind GLP-1, but charged residues concentrated at the distal TM2/extracellular loop-1 (EC1) interface (K197, D198, K202) and in EC1 (D215 and R227) probably contribute to the binding determinants of the GLP-1R.     

Impact of glucagon-like peptide-1 on endothelial function

Cardiovascular (CV) disease is the major cause of mortality and morbidity in individuals with diabetes. Individuals with diabetes often have a variety of factors such as hyperglycaemia, dyslipidaemia, hypertension, insulin resistance and obesity, which increase their risks of endothelial dysfunction and CV disease. The incretin hormones, such as glucagon-like peptide-1 (GLP-1), induce the glucose-dependent secretion of insulin, improve beta-cell function and induce slowing of gastric emptying and feelings of satiety – which result in reduced food intake and weight loss. Therapeutic treatments targeting the incretin system, such as GLP-1 receptor agonists, offer the potential to address beta-cell dysfunction (one the underlying pathogenic mechanisms of type 2 diabetes), as well as the resulting hyperglycaemia. Initial evidence now suggests that incretins could have beneficial effects on endothelial function and the CV system through both indirect effects on the reduction of hyperglycaemia and direct effects mediated through GLP-1 receptor–dependent and –independent mechanisms. If these initial findings are confirmed in larger clinical trials, GLP-1 receptor antagonists could help to address the major CV risks faced by patients with diabetes.