胰高血糖素样肽-1与骨质疏松

糖尿病性骨质疏松发病率高、易致骨折,严重威胁老年人的健康.胰高血糖素样肽-1是由肠道L细胞分泌的一种重要的肠促胰岛素,近年来研究发现,其不仅具有降糖作用,而且表现出独立于胰岛素和甲状旁腺激素的促进骨形成作用,并通过降钙素间接抑制骨吸收,同时抑制骨髓间充质干细胞在早期向脂肪细胞分化,在糖尿病骨质疏松的发生、发展中发挥重要作用.     

胰高血糖素样肽-1与糖尿病心肌病变

胰高血糖素样肽-1(GLP-1)的生物学作用主要是促进胰岛素的分泌和合成、抑制胰高血糖素的分泌、增加胰岛β细胞的数量并抑制其凋亡等.研究显示,GLP-1有独特的心肌保护效应,如:抗心肌细胞凋亡、减轻微小血管病变、改善心肌能量代谢紊乱等.因此,进一步对GLP-1及其心肌保护作用机制做深入研究,可为治疗2型糖尿病及其心肌病...     

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.     

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。     

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.     

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.     

中枢神经系统中胰高血糖素样肽-1与应激的关系

<正>胰高血糖素样肽(GLP)-1长期以来被认为是一种有效的胰岛素分泌刺激剂,由胰高血糖素前体蛋白水解裂解产生,而胰高血糖素前体是一种在肠道L细胞、胰腺α细胞及脑干孤束核中表达的蛋白质。GLP-1 能够通过促进胰岛素分泌并且抑制胰高血糖素分泌来防止高血糖症^[1],除了葡萄糖依赖性刺激胰岛素分泌外,GLP-1还可以减少胃排空、抑制食物摄入、增加尿钠排泄和利尿及调节啮齿动物β细胞增殖,还具有心脏和神经保护作用,减少炎症和细胞凋亡,     

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及其类似物的降糖机制

Glucagon-like peptide-1 (GLP-1) is an insulin secretagogue that secreted by intestinal L-cells. After binding with its receptor, GLP-1 stimulates glucose-dependent insulin secretion, β-cell prolifera-tion and differentiation as well as inhibits its apeptosis, decelerates gastric emptying, improves insulin sensi-tivity of periphery tissue. The long-acting GLP-1 analogues decrease hyperglycemia safely without weight gain and hypoglycemia and protect the function of pancreatic islet beta-cell. Using GLP-1 analogues at early stages of the disease,impaired beta-cell function and possibly beta-cell mass appear to be reversible. These agents axe, therefore, considered new therapeutic agents for the treatment of patients with type 2 diabetes.     

胰高血糖素样肽-1及其类似物的降糖机制

Glucagon-like peptide-1 (GLP-1) is an insulin secretagogue that secreted by intestinal L-cells. After binding with its receptor, GLP-1 stimulates glucose-dependent insulin secretion, β-cell prolifera-tion and differentiation as well as inhibits its apeptosis, decelerates gastric emptying, improves insulin sensi-tivity of periphery tissue. The long-acting GLP-1 analogues decrease hyperglycemia safely without weight gain and hypoglycemia and protect the function of pancreatic islet beta-cell. Using GLP-1 analogues at early stages of the disease,impaired beta-cell function and possibly beta-cell mass appear to be reversible. These agents axe, therefore, considered new therapeutic agents for the treatment of patients with type 2 diabetes.     

中枢食欲调节研究进展

食欲调节网络的协调性摄食活动是维持人类生命的基本生理活动,食欲调节具有复杂而精细的调节机制,而下丘脑正是接受、整合与发放食欲调节信号、维持体重稳定的重要中枢.中枢神经系统或外周组织产生的具有促/抑食欲作用的神经内分泌因子在下丘脑形成复杂的食欲调节网络和相互投射的神经环路,对食欲进行精确的调控.不断完善下丘脑食欲调节区域,不断发现新的调控因子及其作用机制,对深入了解肥胖及糖尿病的病理生理机制及设计开发各种有效控制体重和血糖的药物有重大意义.     

Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets

Summary Glucagon-like peptide-1 and glucagon-like peptide-2 are encoded by the m-RNA of pancreatic preproglucagon. They show high conservation in different species and substantial sequence homology to glucagon. Because no definite biological activity of these peptides has been reported, we investigated the effect of synthetic C-terminally amidated glucagon-like peptide-1 [1–36] and synthetic human glucagon-like peptide-2 [1–34] with a free C-terminus on insulin release from isolated precultured rat pancreatic islets in the presence of glucose. Glucagon-like peptide-1 stimulates insulin release at 10 and 16.7 mmol/l glucose in a dose-dependent manner. Significant stimulation starts at 2.5 nmol/l in the presence of 10 mmol/l glucose and near maximal release is observed at 250 nmol/l, with approximately 100% increase over basal at both glucose concentrations. The peptide reaches 63% of the maximal stimulatory effect of glucagon. No stimulation occurs in the presence of 2.8 mmol/l glucose. Glucagon-like peptide-2 has no effect on insulin secretion at any glucose concentration tested. It is concluded that glucagon-like peptide-1, in contrast to glucagon-like peptide-2, exhibits a glucose-dependent insulinotropic action on isolated rat pancreatic islets similar to that of glucagon and gastric inhibitory polypeptide.     

Glucagon-like peptide-1, a new hormone of the entero-insular axis

Summary The post-translational processing of proglucagon in the small intestine gives rise to glucagon-like peptide-1 (PG 78–107 amide) which has profound effects on the endocrine pancreas, and in many species also on the stomach. Glucagon-like peptide-1 (PG 78–107 amide) is secreted in man in response to physiological stimuli e.g. a mixed meal. Glucagon-like peptide-1, in concentrations corresponding to those observed in response to meals, strongly stimulates insulin secretion, in all mammals studied, even more potently than the gastric inhibitory peptide. Thus, glucagon-like peptide-1 fulfills the classic criteria for being a hormone and is likely to be a new incretin. The glucagon inhibitory effect of glucagon-like peptide-1 (PG 78–107 amide) probably further potentiates the effect of glucagon-like peptide-1 on glucose metabolism and distinguished this peptide from other intestinal peptides which have been proposed as incretins. Glucagon-like peptide-1 also inhibits gastric acid secretion and gastric emptying in man. The latter delays nutrient entry to the intestine and thereby diminishes meal-induced glucose excursions. Elevated plasma concentrations of immunoreactive glucagon-like peptide-1 have been reported in Type 2 (noninsulin-dependent) diabetic patients, however, the consequences of the elevation are not yet known. However, elevated levels of glucagon-like peptide-1 in patients with increased gastric emptying rate (post-gastrectomy syndromes) may be responsible for the exaggerated insulin secretion seen in these patients.     

胰升糖素样肽1受体激动剂与糖尿病、肥胖和银屑病

肠促胰素治疗具有越来越多的胰外作用,最近有病例报道胰升糖素样肽1( GLP-1)受体激动剂治疗能缓解银屑病的临床症状.银屑病是以慢性炎症为特征的常见皮肤病变,流行病学研究发现银屑病患者的心血管疾病、肥胖和糖尿病的发生率增加,这可能与增加的局部和(或)全身的炎症有关.GLP-1受体激动剂可以通过直接或间接的机制影响免疫功能产生抗炎作用,从而改善银屑病症状,这为进一步研究肠促胰素的非经典的抗炎机制提供了新的切入点,同时对拓展GLP-1的临床应用也提供了一个新的研究方向.     

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

AIM: To investigate whether a glucagon-like peptide-1(GLP-1) analogue inhibits nonalcoholic steatohepatitis(NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet(MCD) along with exendin-4(20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice(non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride(TG) and free fatty acid(FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry.RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fattyacid transport protein 4(FATP4), a hepatic FFA influxrelated gene; macrophage recruitment; and the level of malondialdehyde(MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c(SREBP-1c) m RNA(lipogenesis-related gene) and acyl-coenzyme A oxidase 1(ACOX1) m RNA(β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein m RNA(a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 m RNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model.     

Glucagon-like peptide-1: a potent regulator of food intake in humans

Background/Aims—Studiesin animals suggest a physiological role for glucagon-likepeptide-1-(7-36)-amide (GLP-1) in regulating satiety. The role ofGLP-1 in regulating food intake in man has, however, not been investigated.
Subjects—Sixteen healthy male subjects were examined in adouble blind placebo controlled fashion.
Methods—The effect ofgraded intravenous doses (0,0.375, 0.75, and 1.5 pmol/kg/min) ofsynthetic human GLP-1 on food intake and feelings of hunger and satietywas tested in healthy volunteers.
Results—Graded GLP-1infusions resulted in a dose dependent reduction in food intake(maximal inhibition 35%, p<0.001 vcontrol) and a similar reduction in calorie intake (32%; p<0.001). Fluid ingestion was also reduced by GLP-1 (18% reduction, p<0.01). Noovert side effects were produced by GLP-1, but subjects experienced less hunger and early fullness in the period before a meal during GLP-1infusion at the highest dose (p<0.05).
Conclusions—Intravenousinfusions of GLP-1 decrease spontaneous food intake even atphysiological plasma concentrations, implying an important role forGLP-1 in the regulation of the early satiety response in humans.

Keywords:glucagon-like peptide-1; satiety; food intake; hunger and fullness score

     

Glucagon-like peptide-1 does not have a role in hepatic carbohydrate metabolism

Summary Glucagon-like peptide-1 does not have specific, high-affinity receptors on rat liver membranes, does not displace glucagon from glucagon receptors on these membranes and does not stimulate the production of cyclic AMP by isolated rat hepatocytes. In the presence of glucagon, high concentrations of glucagon-like peptide-1 do not significantly alter the production of cyclic AMP. Thus, glucagon-like peptide-1 appears unlikely to have a direct action on hepatic carbohydrate metabolism.     

Glucagon-like peptide-1 receptor agonists and pancreatitis: A meta-analysis of randomized clinical trials

Aims

Several randomized trials with metabolic outcomes have reported that glucagon like peptide-1 receptor agonists (GLP-1 RA) could be associated with an increased risk of pancreatitis. The present meta-analysis aimed to examine this hypothesis.

Methods

An extensive Medline, Embase, and Cochrane Database search for “exenatide”, “liraglutide”, “albiglutide”, “taspoglutide”, “dulaglutide”, “lixisenatide”, and “semaglutide” was performed up to March 31st, 2013. Inclusion criteria: (i) randomized trials, (ii) duration ≥12 weeks; (iii) on type 2 diabetes; and (iv) comparison of GLP-1RA with placebo or active drugs. Mantel–Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for pancreatitis.

Results

80 eligible trials were identified. Of these, 39 had not disclosed their findings or did not report any information on pancreatitis. The remaining 41 trials enrolled 14,972 patients, with a total exposure of 14,333 patient × years (8353 and 5980 patient × years for GLP-1 receptor agonists and comparators, respectively). The overall risk of pancreatitis was not different between GLP-1RA and comparators (MH-OR: 1.01[0.37; 2.76]; p = 0.99).

Conclusions

The present meta-analysis does not suggest any increase in the risk of pancreatitis with the use of GLP-1RA. However, it should be recognized that the number of observed cases of incident pancreatitis is very small and the confidence intervals of risk estimates are wide.