GLP-1受体激动剂及其类似物减缓骨质疏松作用的研究进展

<正>目前,随着生活水平的改善,高脂肪饮食摄入增多,导致糖尿病的发病率持续上升,高血糖及其所致的各种并发症严重影响患者的生活质量。糖尿病基础上合并骨骼系统损害的全身代谢性骨病称为糖尿病性骨质疏松,是糖尿病导致的严重并发症之一^[1]。糖尿病患者易发生骨矿含量减少、骨密度降低的情况,但由于早期临床症状不明显而易被忽略。骨质疏松已成为糖尿病患者致骨折、致残的重要原因^[2]。胰高血糖素样肽(GLP)-1受体激动剂因其独特的作用优势,     

GLP-1在2型糖尿病诱发的阿尔茨海默病治疗中的作用

2型糖尿病是诱发阿尔茨海默病的高危因素.胰高血糖素样肽-1(GLP-1)可诱导胰岛β细胞再生和增殖,可以呈葡萄糖依赖性地促进胰岛素分泌.另外,GLP-1在治疗神经退行性病变中也有重要的作用,能降低脑内β淀粉样蛋白斑块沉积,减少氧化应激引起的神经细胞损伤,还可以调节突触的传递,增加突触的可塑性,刺激轴突生长,影响长时程增强,从而改善记忆并提高认知水平.     

GLP-1及其类似物心血管保护作用的机制

胰高血糖素样肽-1（GLP-1）作为肠促胰岛素,目前已广泛应用于2型糖尿病的治疗.GLP-1不仅具有降糖作用,还在抑制炎症反应、保护内皮细胞、改善心肌葡萄糖代谢、减少心肌梗死面积等方面发挥直接或间接的心血管保护效应,为心血管疾病的治疗提供了新的选择.     

营养物质刺激肠道L细胞分泌GLP-1的机制

在营养物质的刺激作用下,肠上皮的L细胞分泌胰高血糖素样肽-1( GLP-1),后者具有控制餐后血糖和食欲的重要作用.这些营养物质包括糖类物质、蛋白质、脂类物质,其中糖类物质刺激L细胞分泌GLP-1的机制包括ATP敏感的K通道(KATP通道)、钠-葡萄糖协同转运体(SGLT)1、味觉受体通路;蛋白质刺激L细胞分泌GLP-...     

GLP-1对胃肠道系统的作用

胰升糖素样肽1(GLP-1)是经食物刺激后由肠道L细胞分泌的一种肠肽类激素.本文就近期发表的研究同顾了GLP-1对胃排空、饱腹感和摄食的影响,同时评价了长效GLP-1类似物利拉鲁肽的临床应用优势和相关的胃肠道副作用.     

血浆GLP-1水平对2型糖尿病大鼠心肌收缩及舒张功能的影响

糖尿病心肌病(diabetic cardiomyopathy,DCM)是发生于糖尿病患者的一种特异性心肌疾病,其临床表现主要包括充血性心力衰竭、心绞痛等[1]。糖尿病心肌病患者临床检查多显示血糖和糖化血红蛋白增高、左室舒张功能的异常、窦性心动过速、24小时内心率变异性减弱或消失等现象,对社会和家庭都带来了严重的负担。GLP-1及其类似物具有十分重要的心血管保护作用,能显著增加心肌对葡萄糖     

GLP-1对胃肠道系统的作用

胰升糖素样肽1(GLP-1)是经食物刺激后由肠道L细胞分泌的一种肠肽类激素.本文就近期发表的研究同顾了GLP-1对胃排空、饱腹感和摄食的影响,同时评价了长效GLP-1类似物利拉鲁肽的临床应用优势和相关的胃肠道副作用.     

GLP-1对胃肠道系统的作用

胰升糖素样肽1(GLP-1)是经食物刺激后由肠道L细胞分泌的一种肠肽类激素.本文就近期发表的研究同顾了GLP-1对胃排空、饱腹感和摄食的影响,同时评价了长效GLP-1类似物利拉鲁肽的临床应用优势和相关的胃肠道副作用.     

胰高血糖素样肽-1受体激动剂对中枢神经系统的作用

胰高血糖素样肽-1受体(GLP-1R)激动剂通过GLP-1R刺激胰岛素分泌并改善胰岛细胞的状态,现已成为糖尿病领域研究热点.已证实GLP-1R在中枢神经系统有广泛表达,中枢应用GLP-1R激动剂后其可发挥保护神经细胞、调节食欲、调节认知功能等一系列作用,体现了其在中枢神经系统应用的潜质与价值.     

利拉鲁肽对胃肠道作用的机制探讨

利拉鲁肽是一种长效人胰升糖素样肽-1(GLP-1)的类似物,可通过提供药理学浓度的GLP-1与广泛分布于全身的GLP-1受体结合,发挥葡萄糖依赖性降糖作用、胰岛细胞功能保护作用、并具有抑制胃排空、降低食欲/增加饱腹感、减轻体重、保护心脏、降低血压等多种2型糖尿病治疗作用.但临床应用中发现,利拉鲁肽在良好发挥降糖减重等作用的同时,常常伴发一定的胃肠道不良反应.本文通过阐述GLP-1对胃肠道作用的可能机制、利拉鲁肽临床应用经验和有效应对方法等,以期帮助临床医师更全面了解上述问题,在实践中正确使用利拉鲁肽,并尽可能减少或避免相关不良反应.     

GLP-1: physiological effects and potential therapeutic applications

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone with the potential to change diabetes. The physiological effects of GLP-1 are multiple, and many seem to ameliorate the different conditions defining the diverse physiopathology seen in type 2 diabetes. In animal studies, GLP-1 stimulates beta-cell proliferation and neogenesis and inhibits beta-cell apoptosis. In humans, GLP-1 stimulates insulin secretion and inhibits glucagon and gastrointestinal secretions and motility. It enhances satiety and reduces food intake and has beneficial effects on cardiovascular function and endothelial dysfunction. Enhancing incretin action for therapeutic use includes GLP-1 receptor agonists resistant to degradation (incretin mimetics) and dipeptidyl peptidase (DPP)-4 inhibitors. In clinical trials with type 2 diabetic patients on various oral antidiabetic regimes, both treatment modalities efficaciously improve glycaemic control and beta-cell function. Whereas the incretin mimetics induce weight loss, the DPP-4 inhibitors are considered weight neutral. In type 1 diabetes, treatment with GLP-1 shows promising effects. However, several areas need clinical confirmation: the durability of the weight loss, the ability to preserve functional beta-cell mass and the applicability in other than type 2 diabetes. As such, long-term studies and studies with cardiovascular end-points are needed to confirm the true benefits of these new classes of antidiabetic drugs in the treatment of diabetes mellitus.     

Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia

Aims/hypothesis

Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1).

Methods

We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs).

Results

Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion.

Conclusions/interpretation

GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy.

Trial registration:

ClinicalTrials.gov NCT02550145

     

胰高糖素样肽-1及其类似物和二肽酰肽酶-Ⅳ抑制剂对胰岛功能的保护作用

胰岛β细胞功能受损是2型糖尿病发病的中心环节.随着病程的进展,多种机制参与导致β细胞功能进行性下降.胰高糖素样肽-1(GLP-1)是由肠道内分泌细胞L细胞分泌的肠促胰岛素,可以葡萄糖依赖性地增加胰岛素分泌、促进胰岛β细胞再生并抑制胰高糖素分泌.长效GLP-1类似物和二肽酰肽酶(DPP)-Ⅳ抑制剂能够减少内源性GLP-1在体内降解,从而更有效地保护胰岛β细胞功能,对于糖尿病的防治具有重要意义.