类胰高血糖素肽—1免疫活性细胞在大鼠胃肠道的分布

目的 为了探讨类胰高血糖素肽—1(Glucagon—like peptide—1,GLP—1)在大鼠的胃肠道中的分布情况。方法 应用免疫组织化学ABC法,观察了6只Wistor大鼠胃肠道中GLP—1免疫活性细胞分布情况。结果 大鼠胃肠道中GLP—1免疫活性细胞密度最大的是回肠,其次是结肠和直肠。结论 GLP—1免疫活性细胞主要分布在小肠远端。     

灵芝多糖抗肿瘤靶向作用机制研究进展

灵芝在中国已有2000多年的药用历史, 大量的民间实践证明灵芝对多种疾病具有明显的疗效, 其主要药效成分为(ganoderma lucidum polysaccharides, GLP), GLP存在于灵芝属真菌的菌丝体和子实体中, 由肽多糖、葡聚糖、杂多糖等组成的混合物, 是灵芝的主要有效成分之一, 尤其GLP药理活性广泛;具有提高机体免疫功能、抗肿瘤等作用.     

肠促胰岛素用于2型糖尿病治疗的研究进展

肠促胰岛素如抑胃多肽(GIP)和胰高血糖素样肽1(GLP1)可以调节β细胞增殖和细胞防御,在β细胞刺激的胰岛素分泌上发挥重要作用。GLP1可抑制胃排空、分泌和食物摄入,运用于2型糖尿病患者可明显降低餐后血糖,且发生低血糖风险小,尤其适用于老年糖尿病患者。天然GLP1在体内迅速被DPPIV降解,目前已有抗降解、长效的GLP1R配体用于临床研究。DPPIV抑制剂可以发挥降糖作用。     

谷氨酰胺二肽肠外营养对大鼠移植小肠的营养作用—小肠粘膜的形…

研究采用１８只接受印种近段空肠异体移植的Ｗｉｓｔａｒ大鼠，随机分组，分别给于常规全肠外营养和含３％丙氨酰－谷氨酰胺吐肽的全肠外营养，持续１０天。我镜、电镜和组织化学等技术对两组大鼠的移植小肠进行形态学的对比研究。研究表明：附加３％丙氨酰－谷氨酰胺二肽的全肠外营养可较好的维持移植小肠粘膜上皮吸收细胞超微结构的正常形态和结构的完整性，防止肠粘膜萎缩，改善其吸收功能。     

联合应用生长激素和谷氨酰胺对短肠大鼠小肠粘膜形态结构的影响——光镜、扫描电镜和透射电镜观察

目的探讨联合应用生长激素和谷氨酰胺对小肠粘膜的营养作用.材料和方法研究选用40只手术成功的SD短肠大鼠,按2×2析因实验设计随机分为四组,分别给予常规全肠外营养、附加谷氨酰胺、附加生长激素及附加谷氨酰胺和生长激素全肠外营养,持续6天.应用光镜和电镜技术对残留小肠进行形态学对比研究.结果单用谷氨酰胺和生长激素均可不同程度增加小肠粘膜的粘膜厚度、肠腺深度、绒毛高度和表面积(P＜0.01),维持肠粘膜上皮吸收细胞超微结构的正常形态,但联用谷氨酰胺和生长激素的效果优于各自单独使用(P＜0.01).结论研究表明联合应用谷氨酰胺和生长激素能够更有效的防止小肠粘膜萎缩,维持其上皮吸收细胞超微结构的正常形态和结构完整性,为临床谷氨酰胺和生长激素的联合应用提供实验依据.     

小胶质细胞阻断A1型星形胶质细胞转化在帕金森病模型中具有神经保护作用

<正>在多种神经系统疾病中,被经典炎症介质活化的小胶质细胞可以使星形胶质细胞转化为具有神经毒性的A1表型。开发抑制A1反应性星形胶质细胞形成的药物可以用来治疗这些尚无明确有效疗法的疾病。胰高血糖素样肽1受体(glucagon-like peptide-1 receptor,GLP1R)激动剂已被认为是神经系统疾病如阿尔茨海默病和帕金森病的潜在神经保护剂,但其神经保护作用的机制尚不明确。Yun等研究了一种强效、能透过血脑屏障的长效GLP1R激动剂NLY01,该药能保护α-突触核蛋白预成形     

谷氨酰胺对氟尿嘧啶引起大鼠小肠结构和色氨酸吸收功能改变的保护作用

为探讨谷氨酰胺对化疗大鼠小肠结构和吸收色氨酸功能的保护作用，通过胃管连续两天给予大鼠氟尿嘧啶125mg/(kg.d)，观察谷氨酰胺对氟尿嘧啶引起的大鼠肠道结构损伤，色氨酸吸收功能障碍及每日饮食量改变的影响，可见谷氨酰胺明显减轻氟尿嘧啶引起的大鼠小肠结构损伤，增加其每日饮食量和小肠对色氨酸的吸收，升高其动脉血谷氨酰胺浓度，谷氨酰胺对氟尿嘧啶引起的大鼠小肠结构损伤和吸收功能的改变有明显的保护作用。     

人BDNF成熟肽基因克隆及序列分析(英文)

为研究人脑源性神经营养因子在大肠杆菌中的表达及其在治疗 Alzheimer病中的作用 ,本文作者等克隆了其成熟肽基因并进行了序列分析。提取健康成人末梢血白细胞基因组 DNA作为模板 ,应用 PCR技术扩增人脑源性神经营养因子成熟肽基因片段 ,并将其插入 p GEM-T质粒。限制性内切酶鉴定重组质粒并进行序列测定和分析。与 Gen Bank提供的已知序列(M61181)比较 ,所克隆的人脑源性神经营养因子成熟肽基因片段长 3 5 7bp,序列完全相同。人脑源性神经营养因子成熟肽基因的克隆 ,为其在原核细胞中的表达、抗体的制备及神经系统疾病的治疗奠定了基础     

联合应用生长激素和谷氨酰胺对短肠大鼠小肠粘膜吸收功能的影响

目的 :探讨联合应用生长激素和谷氨酰胺对短肠大鼠小肠粘膜吸收功能的影响。材料和方法 :研究选用 40只手术成功的SD短肠大鼠 ,按 2× 2析因实验设计随机分为四组 ,分别给予常规全肠外营养、附加谷氨酰胺、附加生长激素及附加谷氨酰胺和生长激素全肠外营养 ,持续 6天。应用生化酶学的方法测定各组小肠粘膜上皮Na+ ,K+ ATPase的活性。结果 :谷氨酰胺组小肠粘膜Na+ ,K+ ATPase的活性较常规组明显增高 ;生长激素组Na+ ,K+ ATPase的活性无明显增高 ;而联合应用谷氨酰胺和生长激素组小肠粘膜上皮Na+ ,K+ ATPase的活性较常规组亦有显著性增高。结论 :研究表明联合应用谷氨酰胺和生长激素能够有效的增加小肠粘膜上皮Na+ ,K+ AT Pase的活性 ,从而提高其吸收功能。     

脾肝体积比与血清内皮素水平的关系

内皮素(ET)是由内皮细胞合成和分泌的生物活性肽,有强烈的收缩血管和升高血压的作用,并与肿瘤的生长侵袭转移有关。目前已发现ET有ET-1、ET-2、ET-3和血管小肠收缩肽4种异构肽,这4个异构肽在生物活性上有一定程度的差异,大部分作用是由其亚型ET-1介导。肝硬化发展到一定程度会出现脾脏纤维化,体积增大,功能亢进。本文着重探讨脾肝体积比这一相对性的形态学指标与ET-1的关系。     

Peripheral glucagon-like peptide-1 (GLP-1) and satiation

Peripheral GLP-1 is produced by post-translational processing of pro-glucagon in enteroendocrine L-cells and is released in response to luminal nutrient (primarily carbohydrate and fat) stimulation. GLP-1 is well known for its potent insulinotropic and gluco-regulatory effects. GLP-1 receptors (GLP-1R) are expressed in the periphery and in several brain areas that are implicated in the control of eating. Both central and peripheral administration of GLP-1 have been shown to reduce food intake. Unresolved, however, is whether these effects reflect functions of endogenous GLP-1. Data collected in our laboratory indicate that in chow-fed rats: 1) Remotely controlled, intra-meal intravenous (IV) or intraperitoneal (IP) GLP-1 infusions selectively reduce meal size; 2) hindbrain GLP-1R activation is involved in the eating-inhibitory effect of IV infused GLP-1, whereas intact abdominal vagal afferents are necessary for the eating-inhibitory effect of IP, but not IV, infused GLP-1; 3) GLP-1 degradation in the liver prevents a systemic increase in endogenous GLP-1 during normal chow meals in rats; and 4) peripheral or hindbrain GLP-1R antagonism by exendin-9 does not affect spontaneous eating. Also, although our data indicate that peripheral GLP-1 can act in two different sites to inhibit eating, they argue against a role of systemic increases in endogenous GLP-1 in satiation in chow-fed rats. Therefore, further studies should examine whether a local paracrine action of GLP-1 in the intestine or and endocrine action in the hepatic-portal area is physiologically relevant for satiation.     

Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: Role of peripherally secreted and centrally produced peptides

The scientific understanding of preproglucagon derived peptides has provided people with type 2 diabetes with two novel classes of glucose lowering agents, the dipeptidyl peptidase IV (DPP-IV) inhibitors and GLP-1 receptor agonists. For the scientists, the novel GLP-1 agonists, and DPP-IV inhibitors have evolved as useful tools to understand the role of the preproglucagon derived peptides in normal physiology and disease. However, the overwhelming interest attracted by GLP-1 analogues as potent incretins has somewhat clouded the efforts to understand the importance of preproglucagon derived peptides in other physiological contexts. In particular, our neurobiological understanding of the preproglucagon expressing neuronal pathways in the central nervous system as well as the degree to which central GLP-1 receptors are targeted by peripherally administered GLP-1 receptor agonists is still fairly limited. The role of GLP-1 as an anorectic neurotransmitter is well recognized, but clarification of the neuronal targets and physiological basis of this response is further warranted, as is the mapping of GLP-1 sensitive neurons involved in a variety of neuroendocrine and behavioral responses. Further recent evidence points to GLP-1 as a central neuropeptide with neuroprotective capabilities potentially mitigating a wide array of neurodegenerative conditions. It is the aim of the present review to summarize our current understanding of preproglucagon derived peptides as neurotransmitters in the central nervous system.     

The physiology of glucagon-like peptide 1

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.     

Glucagon-like peptide 1 and gastric inhibitory polypeptide: potential applications in type 2 diabetes mellitus

Although the insulinotropic actions of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been known for almost 2 decades, the incretin hormones have not yet become available for clinical application. This can be explained by their unfavourable pharmacological properties. Both hormones are rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP IV), yielding biologically inactive fragments. There have been several attempts to make use of the antidiabetogenic potential of the incretin hormones. Various analogues of GLP-1 and GIP have been generated in order to achieve resistance to DPP IV degradation. The natural GLP-1 receptor agonist exendin-4, found in the saliva of the Gila monster, has a longer biological half-life after subcutaneous injection than GLP-1, and inhibition of DPP IV using, for example, pyrrolidine derivatives provides elevated concentrations of intact, biologically active GIP and GLP-1 endogenously released from the gut. A continuous intravenous infusion of native GLP-1 for a limited time may be suitable in certain clinical situations. Numerous clinical studies are currently underway to evaluate these approaches. Therefore, an antidiabetic treatment based on incretin hormones may become available within the next 5 years.     

Nutritional regulation of glucagon-like peptide-1 secretion

Glucagon-like peptide-1 (GLP-1), released from L- cells in the intestinal epithelium, plays an important role in postprandial glucose homeostasis and appetite control. Following the recent therapeutic successes of antidiabetic drugs aimed at either mimicking GLP-1 or preventing its degradation, attention is now turning towards the L-cell, and addressing whether it would be both possible and beneficial to stimulate the endogenous release of GLP-1 in vivo . Understanding the mechanisms underlying GLP-1 release from L-cells is key to this type of approach, and the use of cell line models has led to the identification of a variety of pathways that may underlie the physiological responses of L-cells to food ingestion. This review focuses on our current understanding of the signalling mechanisms that underlie L-cell nutrient responsiveness.     

Intracerebroventricular injection of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibits feeding in chicks

Previous research has indicated an involvement of glucagon superfamily peptides in the regulation of feeding in the domestic chick brain. However the possible roles of vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP) have not yet been investigated. We therefore examined the effect of intracerebroventricular (ICV) injections of VIP or PACAP on food intake in chicks. ICV injection of both VIP and PACAP significantly inhibited food intake over 4 h at doses ranging from 12 to 188 pmol. Subsequently, we compared the anorexic effect the glucagon superfamily peptides VIP, PACAP, growth hormone-releasing factor (GRF) and glucagon-like peptide-1 (GLP-1) after ICV injection at an equimolar dose (12 pmol). All four peptides significantly inhibited food intake, although the anorexic effects of VIP and PACAP were weaker than those of GRF and GLP-1. These findings support the hypothesis that glucagon superfamily peptides play an important role in the regulation of appetite in the chick brain.     

Use of satiety peptides in assessing the satiating capacity of foods

Foods differ in their satiating capacity. Satiety peptides may help to provide evidence for biological mechanisms behind these differences. The aim of this paper was to discuss the physiological relevance of three individual appetite peptides, i.e. CCK, GLP-1 and PYY, in assessing the satiating capacity of foods. A literature research was conducted on CCK, GLP-1, PYY and satiety; effective exogenous infusion studies and endogenous production studies, i.e. changes induced by foods, were identified. The relative changes in blood concentrations in these studies were compared in order to assess an indication of the physiological relevance of the peptides. Relative changes in the two types of studies investigating CCK overlapped, i.e. increases in serum were 3 to 14-fold in effective exogenous studies (n=7) and 2 to 8-fold in endogenous production studies (n=9). The relative changes in GLP-1 and PYY did not overlap; GLP-1: 4 to 16 fold in effective exogenous studies (n=4) and no effect to 4 fold in endogenous production studies (n=38). PYY: 3 to 11-fold in effective exogenous studies (n=14) and no effect to 2-fold in endogenous production studies (n=10). GLP-1 and PYY show effects on satiety at supra-physiological dosages, they are not likely to contribute individually to a difference in satiating capacity of foods and can therefore not be interpreted in isolation. The effects of CCK are likely to be in the physiological range and therefore may have an individual contribution to a difference in satiating capacity between foods.     

The Correlation Between Intestinal Gonadotropin-Releasing Hormone (GnRH) and Proglucagon in Hyperlipidemic Rats and Goto-Kakizaki (GK) Rats

Our experiment investigated the mRNA expression of intestinal gonadotropin-releasing hormone (GnRH), proglucagon (PG), and glucagon-like peptide 1 receptor (GLP-1R) in the jejunum, ileum, and colon of rats fed with high-fat diet and Goto-Kakizaki (GK) rats and revealed the physiological role of intestinal GnRH. We found that the GnRH and PG mRNA levels in high-cholesterol (HCh) diet were higher than in the control. However, the GnRH receptor (GnRHR) and GLP-1R mRNA levels did not differ significantly between HCh and control. The GnRH, PG, and GLP-1R mRNA levels in GK rats were lower, respectively, than those in control rats, while the GnRHR levels did not differ significantly between GK rats and control rats. There were no difference in GnRH, PG, GnRHR, and GLP-1R mRNA levels in the ileum and colon tissue between HCh and control rats. The GnRH mRNA levels of GK rats were lower than those in control rats; however, the PG, GLP-1R, and GnRHR levels did not differ significantly between GK and control rats. The GLP-1R mRNA levels of GK rats were lower than those in control rats. The GnRH mRNA expression showed positive correlation with PG mRNA expression in different intestinal sections. The GnRH level in the jejunum showed a significant effect on blood glucose level, while the PG level in the jejunum showed a significant effect on insulin level. This may imply that, compared with the ileum and colon, the jejunum had greater impact on glucose metabolism; furthermore, GnRH might interact with intestinal GLP-1 and GLP-2 through the paracrine and autocrine ways and then regulate glucose metabolism and insulin secretion.     

Thymoquinone activates imidazoline receptor to enhance glucagon-like peptide-1 secretion in diabetic rats

IntroductionThymoquinone (TQ) is one of the principal bioactive ingredients proven to exhibit anti-diabetic effects. Recently, glucagon-like peptide-1 (GLP-1) has been found to be involved in antidiabetic effects in rats. The aim of this study was to evaluate the mediation of GLP-1 in the antidiabetic effect of TQ and to understand the possible mechanisms.Material and methodsNCI-H716 cells and CHO-K1 cells were used to investigate the effects of TQ on GLP-1 secretion in vitro. In type 1 diabetic rats, the changes in plasma glucose and GLP-1 levels were evaluated with TQ treatment.ResultsThe direct effect of TQ on imidazoline receptors (I-Rs) was identified in CHO-K1 cells overexpressing I-Rs. Additionally, in the intestinal NCI-H716 cells that may secrete GLP-1, TQ treatment enhanced GLP-1 secretion in a dose-dependent manner. However, these effects of TQ were reduced by ablation of I-Rs with siRNA in NCI-H716 cells. Moreover, these effects were inhibited by BU224, the imidazoline I2 receptor (I-2R) antagonist. In diabetic rats, TQ increased plasma GLP-1 levels, which were inhibited by BU-224 treatment. Functionally, TQ-attenuated hyperglycemia is also evidenced through GLP-1 using pharmacological manipulations.ConclusionsThis report demonstrates that TQ may promote GLP-1 secretion through I-R activation to reduce hyperglycemia in type-1 diabetic rats.