GLP-1在摄食和胃肠道生理功能中的作用

早期研究发现胰高血糖素样肽-1(GLP-1)作为一种肠道肽,具有葡萄糖依赖的胰岛素释放作用,后来在中枢神经系统中亦发现它的存在,消化道和脑中的GLP-1行使着多种生理功能,包括传递神经信号,调节摄食和饮水,调节体温和能量代谢,抑制胃肠分泌和运动,调节细胞的增殖和存活等.本文主要从GLP-1的合成与分泌,在脑中的分布,GLP-1对摄食和胃肠运动的影响,以及其临床应用潜力对它进行阐述.     

胰高血糖素样肽-1及其类似物的降糖机制

胰高血糖素样肽-1(GLP-1)是由肠道L细胞分泌的肠促胰岛素,对调节机体葡萄糖稳态有重要作用.GLP-1与其受体结合后,促进葡萄糖依赖的胰岛素分泌、胰岛β细胞增殖和分化并抑制其凋亡、延迟胃排空、增加外周组织对胰岛素的敏感性,但不引起体重增加和低血糖,从而保护了胰岛β细胞功能.在疾病早期应用此类药物后,受损的β细胞功能和β细胞数量有逆转的可能.GLP-1及其类似物必将成为治疗糖尿病的一个新亮点.     

胰高血糖素样肽-1与下丘脑食欲调节

下丘脑是神经内分泌中枢,也是食欲调节中枢.胰高血糖素样肽-1(GLP-1)是一种胃肠道激素,能够在下丘脑表达并对食欲中枢有调节作用.GLP-1作为一种厌食信号肽,通过促肾上腺皮质激素释放激素(CRH)通路、组胺神经元通路、神经肽和刺鼠相关蛋白(NPY/AgRP)以及前阿片黑皮质素原和可卡因-苯丙胺调节转录肽(POMC/CART)通路及AMP活化蛋白激酶(AMPK)介导的摄食负反馈信号通路参与调节摄食活动.针对GLP-1调节摄食作用机制的研究对肥胖、胰岛素抵抗和2型糖尿病的防治有重要的理论意义.     

基于增强采样构建的隐式马尔可夫状态模型分析GLP-1R激动剂对GLP-1R激活机制

目的 基于增强采样构建的隐式马尔可夫状态模型,分析胰高血糖素样肽1受体（GLP-1R）激动剂PF-06882961激活GLP-1R的机制。方法 从PDB数据库中下载GLP-1R晶体结构（PDBID:6X1A）,基于该晶体结构构建PF06882961与GLP-1R结合的高斯加速动力学（GaMD）体系,模拟PF06882961与GLP-1R结合的动力学轨迹。使用工具包Pyemma读取PF06882961与GLP-1R结合的GaMD动力学轨迹,构建马尔可夫模型。然后分别从一级结构[关键氨基酸残基间的αC间距（Glu247-His180;Glu364-Arg190）]和二级结构[关键α螺旋间扭转角（Val365-Pro358-Ala350;Arg380-Phe390-Met397）]两个层面对构建的马尔可夫模型中PF-06882961与GLP-1R复合物若干构象进行聚类分析,得出5个结构具有差异的PF-06882961与GLP-1R复合物宏观态构象（S1、2、3、4、5）,将其可视化后分析各个宏观态构象之间的结构差异,以明确PF-06882961激活GLP-1R的结构基础。结果 从二级结构层面...     

GLP-1受体激动剂心血管保护机制研究进展

随着胰高血糖素样肽-1( GLP-1)受体激动剂的广泛应用,越来越多的研究表明,此类药物能够通过调节血糖、血脂、血压,并通过抗炎、抗氧化应激等机制,发挥保护心肌、改善心肌梗死和心力衰竭等方面的效应.     

胰高血糖素样肽-1受体激动剂在心血管疾病中的研究进展

近年来新型降血糖药在心血管疾病治疗中获益显著。胰高血糖素样肽-1受体激动剂(GLP-1RA)是新一代降血糖药，除有较为明显的降糖作用外，还通过提高肠促胰岛素的活性在心血管系统中发挥保护作用。基础与临床研究表明，GLP-1RA具有抑制免疫反应、抑制平滑肌细胞增生和改善动脉粥样硬化形成等作用，在心血管临床研究中受到广泛关注。现对GLP-1RA在心血管疾病中直接或间接的影响进行综述，为临床防治提供理论基础。     

胰高血糖素样肽1的胰腺外作用研究进展

胰高血糖素样肽1(GLP-1)是体内重要的肠肽激素,在调节体内葡萄糖稳态中起重要作用.它通过促进胰岛素分泌、抑制胰高血糖素产生以及减慢餐后胃排空降低血糖.在胰腺外组织它也可通过调节葡萄糖代谢来参与全身血糖的调节.一方面通过激活磷脂酰肌醇3激酶、蛋白激酶B、蛋白激酶C、1型蛋白磷酸酶和丝裂原活化蛋白酶等增加糖原合酶a活性,促进糖原合成和糖利用.另一方面,在脂肪组织直接促进葡萄糖利用或增强胰岛素对葡萄糖的利用.此外,GLP-1还具有其它生物学作用包括舒张血管、保护血管内皮功能并激活垂体前叶激素分泌等.exendin-4是GLP-1的长效类似物,具有比GLP-1更持久的生物学活性和更强的降血糖作用,是一种治疗2型糖尿病的新型药物.     

胰高血糖素样肽-1受体激活在脑缺血中的神经保护作用

胰高血糖素样肽-1（glucagon-likepeptide1,GLP-1）是肠促胰岛素的重要成员。经口进食可刺激末端回肠和结肠L 细胞分泌GLP-1。 GLP-1与特异性受体GLP-1受体（ GLP-1 receptor, GLP-1R）结合后发挥促进葡萄糖依赖的胰岛素分泌、抑制胰高血糖素分泌和降低血浆胰高血糖素水平等作用。 GLP-1具有分子质量相对较小,可直接透过血脑屏障,且中枢和外周神经系统均有GLP-1R表达。 GLP-1可显著改善神经功能缺损和缩小梗死体积,其可能通过抑制炎症反应、氧化应激和细胞凋亡等机制发挥神经保护作用。文章就GLP-1的发现、生物学特性和在脑缺血中的神经保护作用进行了综述。     

胰高血糖素样肽-1对缺氧/复氧诱导的乳鼠心肌细胞损伤的影响

目的:研究胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)对缺氧/复氧(H/R)诱导的乳鼠心肌细胞损伤的影响及其可能的机制。方法:将体外培养乳鼠心肌细胞分为3组,即正常对照组、H/R组和GLP-1+H/R组。H/R损伤后,分别通过比色法、流式细胞术、荧光检测法测定上清液中乳酸脱氢酶(LDH)的活性、心肌细胞的凋亡率及半胱氨酸天冬氨酸特异性蛋白酶-3(caspase-3)的活性。结果:与正常对照组比较,H/R组LDH的活性、心肌细胞的凋亡率及caspase-3的活性均明显增高(P0.01);而与H/R组相比,GLP-1+H/R组LDH的活性、心肌细胞的凋亡率及caspase-3的活性则明显降低(P0.01)。结论:GLP-1可直接作用于心肌细胞,对H/R诱导的心肌细胞损伤产生一定的拮抗作用,其作用机制可能主要是通过抑制心肌细胞的凋亡所致;而GLP-1对心肌细胞凋亡的抑制作用,可能与其对caspase-3相关的凋亡或抗凋亡途径的调节有关。     

胰高血糖素样肽-1类似物改善肌肉萎缩的研究进展

胰高血糖素样肽-1(GLP-1)是由肠道L细胞分泌的一种肠促胰素,其主要功能是促进胰岛素分泌和抑制胰高血糖素分泌从而降低血糖,其制剂在临床上广泛用于糖尿病的治疗。近年来有研究发现,GLP-1类似物有改善肌肉萎缩的功能,该作用与抑制肌肉生长抑制素和肌萎缩因子表达、增强肌源性因子表达、改善骨骼肌微循环和胰岛素抵抗有关。     

Interaction of Benzodiazepines with Central Nervous Glycine Receptors: Possible Mechanism of Action

Interaction of 21 benzodiazepines with the glycine receptor in the brainstem and spinal cord of rat have been evaluated in terms of their displacement of [(3)H]strychinine binding. The rank order of potency of the 21 drugs in displacing specific [(3)H]strychinine binding correlates (p < 0.005) with their rank order of potency in a vareity of pharmacological and behavioral tests in humans and animals that predict clinical efficacy. There is a 50-fold variation in potency of the series of benzodiazepines with mean effective dose (ED(50)) values ranging from 19muM to > 1000 muM. Diazepam (Valium(R)) and chlordiazepoxide (Librium(R)) have ED(50)'s of 26 muM and 200 muM, respectively, whereas the ED(50) for glycine is 25 muM. The inhibitory effects of 10 of the agents in two other central nervous system membrane receptor assays, for the opiate receptor and the muscarinic cholinergic receptor, do not correlate with any of the in vivo pharmacologic and behavioral tests. The benzodiazepines may exert their antianxiety, anticonvulsant and muscle-relaxant effects by mimicking the effects of the neurotransmitter glycine at its central nervous system receptor sites.     

Ciliary neurotrophic factor prevents retrograde neuronal death in the adult central nervous system.

The neurocytokine ciliary neurotrophic factor (CNTF) was described originally as an activity that supports the survival of neurons of the chicken ciliary ganglia in vitro. The widespread expression of CNTF and its principal binding protein, CNTF receptor alpha, in the central and peripheral nervous systems suggests a broader trophic role for this peptide. In the present study, we report that CNTF prevents axotomy-induced cell death of neurons in the anteroventral and anterodorsal thalamic nuclei of the adult rat. Using the polymerase chain reaction, we also demonstrate the presence of CNTF and CNTF receptor alpha mRNA in these same thalamic nuclei. The coincidence of CNTF and its receptor in a population of neurons responding to the factor suggests a paracrine function for CNTF. The present findings establish that CNTF has significant effects on neurons of the central nervous system in vivo and demonstrate that neurocytokines can prevent cell death in the adult central nervous system.     

Central mineralocorticoid receptors, sympathetic activity, and hypertension

Recent evidence highlighting the presence of corticosteroid receptors in the central nervous system has prompted further investigation regarding their role in the pathogenesis of hypertension. The sympathetic nervous system, an important factor in the pathogenesis of hypertension, is influenced by sodium and volume status. Activation of central nervous system mineralocorticoid receptors is known to affect sympathetic activity, although the processes that underpin this phenomenon are incompletely understood. This article reviews some of the recent advances in this area, particularly mechanisms by which the mineralocorticoid receptor maintains selectivity for its ligand within the central nervous system, its role in salt appetite, and the possibility of local production of corticosteroids. In addition, the links between central mineralocorticoid receptor activation, stress, sympathetic activity, and hypertension are discussed.     

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of various nutrients to stimulate insulin secretion from pancreatic β‐cells glucose‐dependently. GIP and GLP‐1 undergo degradation by dipeptidyl peptidase‐4 (DPP‐4), and rapidly lose their biological activities. The actions of GIP and GLP‐1 are mediated by their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which are expressed in pancreatic β‐cells, as well as in various tissues and organs. A series of investigations using mice lacking GIPR and/or GLP‐1R, as well as mice lacking DPP‐4, showed involvement of GIP and GLP‐1 in divergent biological activities, some of which could have implications for preventing diabetes‐related microvascular complications (e.g., retinopathy, nephropathy and neuropathy) and macrovascular complications (e.g., coronary artery disease, peripheral artery disease and cerebrovascular disease), as well as diabetes‐related comorbidity (e.g., obesity, non‐alcoholic fatty liver disease, bone fracture and cognitive dysfunction). Furthermore, recent studies using incretin‐based drugs, such as GLP‐1 receptor agonists, which stably activate GLP‐1R signaling, and DPP‐4 inhibitors, which enhance both GLP‐1R and GIPR signaling, showed that GLP‐1 and GIP exert effects possibly linked to prevention or treatment of diabetes‐related complications and comorbidities independently of hyperglycemia. We review recent findings on the extrapancreatic effects of GIP and GLP‐1 on the heart, brain, kidney, eye and nerves, as well as in the liver, fat and several organs from the perspective of diabetes‐related complications and comorbidities.     

Distribution of G-protein-coupled receptor (GPCR)135 binding sites and receptor mRNA in the rat brain suggests a role for relaxin-3 in neuroendocrine and sensory processing

G-protein-coupled receptor 135 (GPCR135), a former orphan GPCR also known as SALPR, has recently been shown to be modulated by relaxin-3 (R3). In addition to GPCR135, R3 has been shown to be an agonist for GPCR142 (which is a pseudogene in the rat) and to activate LGR7, which is primarily the receptor for relaxin-1/2. The interaction of R3 with LGR7 has confounded the autoradiographic study of the GPCR135 distribution in the rat CNS due to significant expression of LGR7 in the brain. R3/I5, a chimera of the B-chain of R3 bonded to the A-chain of INSL-5, is a specific GPCR135 agonist which is highly selective for GPCR135 over LGR7. [(125)I]R3/I5 specifically binds to sites on rat brain sections with a pharmacology matching results from membrane preparations of recombinant GPCR135 receptors. Autoradiographic studies show the GPCR135 receptor density is most prominent in areas such as the olfactory bulb, sensory cortex, amygdala, thalamus, paraventricular nucleus, supraoptic nucleus, inferior and superior colliculus. The GPCR135 mRNA distribution generally overlaps the pattern of GPCR135 binding sites shown by autoradiography using [(125)I]R3/I5. The nucleus incertus, which has been implicated in the extrapituitary actions of corticotropin-releasing hormone, is the primary source of R3 in the rat central nervous system and expresses GPCR135 receptors. These binding autoradiography and in situ hybridization data suggest that GPCR135 plays an important role in the central processing of sensory signals in rats, are consistent with a putative role for R3/GPCR135 as modulators of stress responses, and confirm the identity of R3 as the central nervous system ligand for GPCR135.     

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

Aims/hypothesis  

Modulation of central nervous system (CNS) and extra-CNS cannabinoid receptor type 1 (CB1R) affects metabolic conditions, independently of weight loss. Here we examined the relative contributions of acute CNS and extra-CNS CB1R modulation on insulin sensitivity using pharmacological gain- and loss-of-function of CB1R in mice.     

Characterization and immunohistochemical visualization of the vasotocin VT2 receptor in the pituitary gland of the chicken, Gallus gallus

Arginine vasotocin is a neurohypophysial hormone in lower vertebrates including birds. Its actions are mediated through G-protein coupled receptors that belong to the vasopressin/oxytocin receptor family. Our laboratory recently cloned a vasotocin receptor, designated the VT2 receptor (VT2R), which shares high sequence identity at both the nucleotide and amino acid level with the mammalian V1b vasopressin receptor (V1bR). In the present study, we report development and use of an antibody to the VT2R to obtain anatomical evidence for testing the hypothesis that the VT2R is the avian homolog of the mammalian V1bR. Results verified the specificity of the antibody and demonstrated a receptor distribution occurring predominantly in the cephalic lobe of the pars distalis and co-localizing with adrenocorticotropin in corticotrophs. With respect to VT2R distribution and cell-type localization in pituitary gland, evidence presented support its similarity with the mammalian V1bR. In contrast to the mammalian V1bR, VT2R expression was not observed in chicken brain. Further research will be required to determine which receptor/s in the arginine vasotocin/mesotocin family are expressed in brain and mediate regulatory functions of vasotocin in the central nervous system.     

Synaptic relationship between substance P and the substance P receptor: light and electron microscopic characterization of the mismatch between neuropeptides and their receptors.

Light microscopic studies have demonstrated significant mismatches in the location of neuropeptides and their respective binding sites in the central nervous system. In the present study we used an antiserum raised against a synthetic peptide corresponding to the carboxyl-terminal tail of the substance P (SP) receptor (SPR) to further explore the relationship between a neuropeptide and its receptor. Light microscopy revealed an excellent correlation between the patterns of SPR immunoreactivity and of 125I-labeled SPR-binding sites in the central nervous system. The SPR appeared to be exclusively expressed by neurons; in fact, the SPR decorates the somatic and dendritic surface of neurons, producing Golgi-like images. Electron microscopic analysis in cortex, striatum, and spinal cord revealed that approximately 70% of the surface membrane of immunoreactive neurons is SPR laden. Simultaneous electron microscopic labeling of SP and SPR demonstrated significant mismatch at the synaptic level. Although some SP terminals contacted SPR-immunoreactive membrane, no more than 15% of the SPR-laden membrane apposed synaptic terminals. These results suggest that in contrast to more "classical" central and peripheral nervous system synapses, wherein the receptor immediately apposes the site of neurotransmitter storage and release, much of the surface of SPR-expressing neurons can be targeted by SP that diffuses a considerable distance from its site of release.     

GLP‐1 receptor agonist attenuates endoplasmic reticulum stress‐mediated β‐cell damage in Akita mice

Aims/Introduction: Endoplasmic reticulum (ER) stress is one of the contributing factors in the development of type 2 diabetes. To investigate the cytoprotective effect of glucagon‐like peptide 1 receptor (GLP‐1R) signaling in vivo, we examined the action of exendin‐4 (Ex‐4), a potent GLP‐1R agonist, on β‐cell apoptosis in Akita mice, an animal model of ER stress‐mediated diabetes. Materials and Methods: Ex‐4, phosphate‐buffered saline (PBS) or phlorizin were injected intraperitoneally twice a day from 3 to 5 weeks‐of‐age. We evaluated the changes in blood glucose levels, bodyweights, and pancreatic insulin‐positive area and number of islets. The effect of Ex‐4 on the numbers of C/EBP‐homologous protein (CHOP)‐, TdT‐mediated dUTP‐biotin nick‐end labeling (TUNEL)‐ or proliferating cell nuclear antigen‐positive β‐cells were also evaluated. Results: Ex‐4 significantly reduced blood glucose levels and increased both the insulin‐positive area and the number of islets compared with PBS‐treated mice. In contrast, there was no significant difference in the insulin‐positive area between PBS‐treated mice and phlorizin‐treated mice, in which blood glucose levels were controlled similarly to those in Ex‐4‐treated mice. Furthermore, treatment of Akita mice with Ex‐4 resulted in a significant decrease in the number of CHOP‐positive β‐cells and TUNEL‐positive β‐cells, and in CHOP mRNA levels in β‐cells, but there was no significant difference between the PBS‐treated group and the phlorizin‐treated group. Proliferating cell nuclear antigen staining showed no significant difference among the three groups in proliferation of β‐cells. Conclusions: These data suggest that Ex‐4 treatment can attenuate ER stress‐mediated β‐cell damage, mainly through a reduction of apoptotic cell death that is independent of lowered blood glucose levels. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00075.x , 2010)