GLP—1—IR细胞在大鼠和成人肠道的分布

目的：研究比较GLP－1－IR细胞（L细胞）在大鼠和成人肠道的分布情况;方法：应用免疫组织化学SP法,评估细胞在Wistar大鼠和成人肠道中的分布。结果：肠道各段都可见L细胞,大鼠肠道中L细胞密度最大是回肠,成人肠道中密度最大是直肠,结论：不同种属间GLP－1－IR细胞密度不同,分布规律相同,即从小肠和大肠的近端向远端细胞密度逐渐增大。     

类胰升血糖素肽—1免疫细胞在大鼠和胎儿胃肠道的分布

为了研究类胰升血糖素肽－１免疫细胞在大鼠和胎儿胃肠道中的分布情况,应用免疫组织化学ＡＢＣ法,对大鼠和胎儿胃肠道中ＧＬＰ－１进行研究。结果表明,大鼠胃肠道中ＧＬＰ－１免疫细胞密度最大的是回肠,其次是结肠和直肠,月台 儿胃肠道中ＧＬＰ－１免疫细胞密度最大的是直肠,其次是结肠和回肠。     

类胰升血糖素肽—1在大鼠和胎儿胰腺中分布的研究

为了研究类胰升血糖素肽－１在大鼠和胎儿胰腺中的分布情况，应用免疫组织化学ＡＢＣ法，对大鼠和胎儿胰腺中ＧＬＰ－１进行研究。结果表明，ＧＬＰ－１免疫反应物存在大于大鼠和胎儿胰岛的周边部。     

人类胎盘组织中胰岛素样生长因子—I定位分析

了解各孕期胎盘组织中胰岛素生长因子－Ｉ（ＩＧＦ－Ｉ）的细胞定位，评估ＩＧＦ－１在胎儿，胎盘生长发育中的作用，采用免疫组化法对早，中，晚期妊娠胎盘组织中的ＩＧＦ－Ｉ阳性细胞定位，结果显示：三个时期胎盘组织中ＩＧＦ－Ｉ主要位于绒毛小叶的合体细胞滋养层及细胞滋养层胞浆中，此外，中，晚期妊娠的Ｈｏｆｆｂａｕｅｒ细胞及胎膜平滑绒毛亦存在，但当染色较以上两种细胞明显减弱，胎膜的羊膜细胞及蜕膜细胞偶尔可见阳性，     

磷脂酰肌醇3—激酶调控白介素—18诱导核因子—κB活化

目的：研究磷脂酰肌醇（PI）3－激酶在白介素18（IL－18）诱导核因子－κB（NF－κB）活化中的作用。方法：Lipofectin介导反义PI 3－激酶寡核苷酸转染HepG2细胞。用逆转录PCR法检测PI 3－激酶mRNA表达水平,以Sandwich ELISA法检测NF－κB的活化。结果：1）反义PI 3－激酶寡核苷酸抑制PI 3－激酶mRNA表达。（2）IL－18诱导NF－κB活化。（3）反义PI 3－激酶寡核苷酸呈时间（5－24h)和浓度（1－8mg/L)依赖性地抑制IL－18诱导的NF－κB活化。结论：PI 3－激酶调控白介素－18诱导的NF－κB活化。     

NovoNordisk的liraglutide控制血糖更好

Ⅲ期试验结果显示,NovoNordisk公司研发的每天使用一次的胰高血糖素样肽（GLP）－1类似物liraglutide（I）改善HbAk水平比Lilly和Amylin公司每日使用两次的GLP－1类似物Byetta（exenatide）（Ⅱ）效果更好。这项为期26周,464例患者参加的LEAD（1iraglutide效应对糖尿病的作用）6试验显示,用（I）治疗的患者的HbA1c平均降低1．1个百分点,而用（Ⅱ）治疗的患者平均降低0．8个百分点。     

胎儿超声诊断肠道强回声或肠管扩张与分娩结局相关性研究

目的：研究胎儿产前肠道超声异常情况与产后畸形之间的相关性。方法记录2008年至2011年胎儿超声检查的数据。把肠道超声异常结果68例分为肠道强回声组（HB 组,48例）和肠管扩张组（DB 组,20例）,分别跟踪随访超声诊断的确诊时间及分娩孕周,产后畸形情况及病情进展。结果两组68例中的56例胎儿数据有效。分娩的44例活产婴儿中,11例（25%）有腹部异常,33例（75%）出生时正常。与 DB 组的胎儿相比,HB 组患儿产前的死亡率更高（20.8%vs10%）,但出生时畸形的比例较低（10.3%vs53.3%）。9例出现持续性肠管强回声胎儿中的3例胎儿出生时患有胎粪性腹膜炎或胎粪性肠梗阻。在12例肠管扩张延续到产后的胎儿中,8例（66.7%）出生时有畸形,最常见的为先天性肠道闭锁。结论肠道强回声、肠管扩张与胎儿死亡率有联系。肠道强回声比肠管扩张更常见,肠管扩张与新生儿畸形的联系比肠道强回声更密切。     

肠促胰岛素相关药物的药代动力学／药效学模型研究进展

肠促胰岛素是一类在食物刺激下由肠道L细胞分泌并能促使胰岛素分泌的激素,其主要包括胰高血糖素样肽－1（ GLP－1）受体激动剂类似物和二肽基肽酶－4（DPP－4）抑制剂。药代动力学／药效学（PK／PD）结合模型可以为肠促胰岛素相关药物的治疗和临床研究提供有力的工具,同时,基于机制的模型可以更好地预测给药后的生理学特点和不同给药方案的治疗结果,有利于该类药物新药研发及给药方案的调整。本文主要针对 GLP －1受体激动剂类似物和DPP－4抑制剂代表药物基于其作用机制的PK／PD模型进行综述。     

尖锐湿疣患者血清ICAM—1的检测及其意义

目的：探讨细胞间粘附分子－1（ICAM－1）在尖锐湿疣患者血清中的水平及其临床意义，方法：用ELISA法测15例尖锐湿疣患者血清中细胞间粘附分子－1水平，结果15例尖锐湿疣患者血清中，ICAM－1水平明显高于对照组，复发者，病变范围大者，其增高更为显著，结论：尖锐湿\疣的发生，发展与ICAM－I增高有关，检测ICAM－1血清水平有助于尖锐湿疣预后的判断。     

丙型肝炎患者血清可溶性L-seletin、SICAM-1、IL-6、TNF水平和肝功能损伤的相关研究

目的 检测血清可溶性L－Selectin,SICAM-1(细胞粘附因子－1），IL－6（白细胞介素－6）和TNF-α（肿瘤坏死因子α），在丙型肝炎病毒感染造成肝功能损害过程中的作用。方法 分别利用酶联吸附法和放射免疫分析法对58例丙型肝炎患进行了血清L－选择素，SICAM－1，IL－6，TNF－α水平及肝功相关的生化指标进行检测并以35名正常健康人作对照。结果 丙型肝炎患血清L－选择素，SICAM－1，IL－6和TNF－α水平均非常显地高于正常人组（P＜0．01），且与ALT，TBIL呈明显正相关。结论 检测丙型肝炎患血清中L－选择素，SICAML－1，IL－6，TNF－α水平在一定程度上反映了机体的免疫功能状态肝损伤的程度，具有临床应用价值。     

Glucagon-like peptide-1 in the pathogenesis of obesity

The recently discovered gut peptide glucagon-like peptide-1 (GLP-1) is one of many peptides implicated in the short-term regulation of appetite. GLP-1 is a 30-amino-acid peptide that is produced in and secreted from the L cells of the intestinal mucosa after intake of a mixed meal. The amino acid sequence of GLP-1 is highly conserved and all mammals studied to date have identical GLP-1 sequences. GLP-1 receptors have been found in the lung and stomach, and binding of GLP-1 to skeletal muscle and fat cells has been demonstrated. At physiological plasma levels GLP-1 inhibits meal- and pentagastrin-induced gastric acid secretion. In addition, gastric emptying is delayed. Plasma GLP-1 is acutely elevated in normal-weight subjects after a meal, but obese subjects seem to have an attenuated GLP-1 release in response to meals. Consequently, GLP-1 may be a candidate for meal termination and intermeal satiety by either peripheral or central pathways. In terms of the importance of GLP-1 in the pathogenesis of obesity, research points in the direction of a vicious circle where overfeeding results in a down-regulation of postprandial GLP-1 release, which may result in the consumption of a larger amount of calories to elicit a "normal" GLP-1 satiety signal, thus perpetuating the obese state.     

Comparison of sandwich enzyme-linked immunoadsorbent assay and radioimmunoassay for determination of exogenous glucagon-like peptide-1(7–36)amide in plasma

A sensitive sandwich enzyme-linked immunoadsorbent assay (ELISA) for determination of exogenous glucagon-like peptide-1(7–36)amide (GLP-1(7–36)amide) in plasma samples from pharmacokinetic studies is described. The assay employs an N-terminally directed antibody and a C-terminally directed antibody. The ELISA has a working range from 10 to 500 pmol 1⁻¹, and can be applied to plasma samples from humans, dogs, pigs, minipigs, cats, rabbits, and rats. The assay was compared to a validated radioimmunoassay (RIA), employing an antibody directed against the mid-region of GLP-1. After s.c. administration of GLP-1(7–36)amide, the plasma immunoreactivity of GLP-1 (P-GLP-1-IR) measured by ELISA was markedly lower than P-GLP-1-IR measured by RIA. After HPLC fractionation of plasma samples with subsequent RIA and ELISA analyses of the fractions, this difference was shown to be due to cross reaction with biologically inactive fragments of GLP-1(7–36)amide in the RIA but not in the ELISA.     

Mitochondrial protein IF1 is a potential regulator of glucagon-like peptide (GLP-1) secretion function of the mouse intestine

IF1 (ATPIF1) is a nuclear DNA-encoded mitochondrial protein whose activity is inhibition of the F₁F_o-ATP synthase to control ATP production. IF1 activity remains unknown in the regulation of GLP-1 activity. In this study, IF1 was examined in the diet-induced obese mice using the gene knockout (If1-KO) mice. The mice gained more body weight on a high fat diet without a change in food intake. Insulin tolerance was impaired, but the oral glucose tolerance was improved through an increase in GLP-1 secretion. The KO mice exhibited an improved intestine structure, mitochondrial superstructure, enhanced mitophagy, reduced apoptosis and decreased adenine nucleotide translocase 2 (ANT2) protein in the intestinal epithelial cells together with preserved gut microbiota. The data suggest that GLP-1 secretion was enhanced in the obese If1-KO mice to preserve glucose tolerance through a signaling pathway of ANT2/mitochondria/L-cells/GLP-1/insulin. IF1 is a potential mitochondrial target for induction of GLP-1 secretion in L-cells.Key words: GLP-1, ATPIF1, ANT2, L-cells, Mitophagy, Microbiota, Glucose tolerance, Insulin resistance     

A new Alzheimer's disease interventive strategy: GLP-1

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemoarchitecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-beta peptide (Abeta) in mouse brain and to reduce levels of beta-amyloid precursor protein (betaAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimer's disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD.     

Glucagon-like peptide-1, a gastrointestinal hormone with a pharmaceutical potential.

Glucagon-like peptide-1 (GLP-1) is an insulinotropic hormone secreted from endocrine cells in the gut mucosa in response to meal ingestion. It is an important incretin hormone; mice with a null mutation in the GLP-1 receptor gene develop glucose intolerance. In addition, it inhibits gastrointestinal secretion and motility and is thought to be part of the "ileal brake" mechanism. Perhaps because of the latter actions it inhibits food intake, but intracerebral injection of GLP-1 also inhibits food intake. The insulinotropic effect is preserved in patients with type 2 diabetes mellitus, in whom also glucagon secretion is inhibited. Thus upon i.v. GLP-1 infusion blood glucose may be completely normalised. Because its actions are glucose-dependent hypoglycaemia does not develop. However, GLP-1 is metabolised extremely rapidly in vivo, initially by a mechanism that involves the enzyme dipeptidyl peptidase-IV. It is currently being investigated how GLP-1 or analogues thereof can be employed in practical diabetes therapy. Promising solutions include the development of stable analogues and inhibitors of the degrading enzyme.     

胰高血糖素样肽-1——阿尔采末病治疗新策略

胰高血糖素样肽-1(GLP-1)是一种由30个氨基酸组成的肠肽,结合于GLP-1R,并与cAMP第二信使途径相偶联。神经系统GLP-1 R的激活在神经可塑性及神经细胞的存活中起着重要作用。GLP-1可以诱导神经元轴突的生长,抵御体外培养神经细胞的兴奋性死亡和氧化损伤。GLP-1及其天然类似物exend in-4均可以降低小鼠脑中内源性Aβ的水平及神经元β前体蛋白(βAPP)的水平。因此,以GLP-1或其相关肽来实施治疗可以影响到AD相关的多个治疗靶点。该文对GLP-1治疗阿尔采末病(AD)的潜力进行探讨。     

A physiological role of glucagon-like peptide-1 receptors in the central nervous system of Suncus murinus (house musk shrew)

Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut as an incretin hormone to stimulate glucose-stimulated insulin secretion. GLP-1 is also produced in the central nervous system (CNS) as a neurotransmitter that regulates feeding behaviour. By using polyclonal antiserum against GLP-1 and GLP-1 receptors, we identified the distribution of GLP-1 immunoreactive fibres and GLP-1 receptor immunoreactivity in the ventromedial hypothalamus of Suncus murinus (house musk shrew). In functional studies, subcutaneous administration of exendin-4 (1 - 30 nmol/kg) reduced blood glucose levels dose-dependently by up to 49% during an intraperitoneal glucose tolerance test (P<0.001). The glucose-lowering effects were also observed after an intracerebroventricular (i.c.v.; 0.3 - 3 nmol) or intracerebral ventromedial hypothalamic microinfusion (iVMH; 0.3 - 3 pmol) of exendin-4. The area under the curve values for glucose after i.c.v. and iVMH administrations of exendin-4 were reduced by up to 53% (P<0.01) and 46% (P<0.01), respectively. Exendin-4 (i.c.v.; 3 nmol) also increased glucose-stimulated insulin secretion by 20% compared to controls (P<0.05). The GLP-1 receptor antagonist, exendin (9-39) (10 nmol, i.c.v.) did not modify blood glucose levels but it antagonized the glucose-lowering effect of exendin-4 (1 nmol, i.c.v.; P<0.05). The data suggests that the central GLP-1 system may regulate glucose homeostasis by increasing insulin secretion. Further, GLP-1 receptors in the ventromedial hypothalamus appear to play an important role in the regulation of glucose homeostasis in S. murinus.