Release of glucagon-like peptide-1 (GLP-1) by carbohydrates in the perfused rat ileum

The effect of various carbohydrates on glucagon-like peptide-1 (GLP-1) release was studied in the in vivo perfused rat ileum. GLP-1 concentrations in the mesenteric venous effluent increased significantly after luminal perfusion with substrates of a sodium/glucose cotransporter (d-glucose, d-galactose, methyl-α d-glucoside, and 3-O-methyl-d-glucose). d-Fructose induced a sodium-independent release of GLP-1. Carbohydrates like 2-deoxy-d-glucose and N-acetyl-d-glucosamine, which are not substrates of a luminal sodium/glucose or fructose transporter, did not affect GLP-1 release. Since methyl-α d-glucoside is not a substrate of the basolateral glucose transport mechanism and 3-O-methyl-d-glucose is not metabolized within intestinal cells, it is concluded that intracellular metabolism of carbohydrates and intracellular removal are not essential to induce GLP-1 secretion in rats. Received: 15 November 1996 / Accepted in revised form: 20 December 1996     

Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity

Summary Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or α-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t_1/2 of 159 min (Gly⁸ analogue) to undetectable degradation after 6 h (Aib⁸ analogue; t_1/2 for GLP-1 (7–36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50 % of each analogue remained undegraded compared to 22.7 % for GLP-1 (7–36) amide. In vivo, analogues had longer N-terminal t_1/2 (intact peptides: means, 3.3–3.9 min) than GLP-1 (7–36) amide (0.9 min; p < 0.01), but these did not exceed the C-terminal t_1/2 (intact plus metabolite: analogues, 3.5–4.4 min; GLP-1 (7–36) amide, 4.1 min). Analogues were assessed for receptor binding using a cell line expressing the cloned receptor, and for ability to stimulate insulin or inhibit glucagon secretion from the isolated perfused porcine pancreas. All bound to the receptor, but only the Aib⁸ and Gly⁸ analogues had similar affinities to GLP-1 (7–36) amide (IC₅₀; Aib⁸ = 0.45 nmol/l; Gly⁸ = 2.8 nmol/l; GLP-1 (7–36) amide = 0.78 nmol/l). All analogues were active in the isolated pancreas, with the potency order reflecting receptor affinities (Aib⁸ > Gly⁸ > Ser⁸ > Thr⁸). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically active and have prolonged metabolic stability in vivo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy. [Diabetologia (1998) 41: 271–278] Received: 9 September 1997 and in revised form: 20 October 1997     

Truncated and full-length glucagon-like peptide-1 (GLP-1) differentially stimulate intestinal somatostatin release

Glucagon-like peptide-1^7–36NH2 (GLP-1^7–36NH2) is a potent stimulator of insulin secretion, as well as of somatostatin-14 (SS-14) release from the pancreatic and gastric D-cells. To investigate the possible effects of this peptide on release of intestinal somatostatin (SS-28 and SS-14), rat intestinal cultures were treated with 10⁻¹²–10⁻⁶ M GLP-1^7–36NH2, as well as with the structurally related peptides, GLP-1^1–36NH2 and GLP-2. Both forms of GLP-1 stimulated dose-dependent increases in intestinal somatostatin; secretion reached 643±126% of controls (p<0.001) after treatment with 10⁻⁶ M GLP-1^7–36NH2, and 398±76% of controls (p<0.001) after 10⁻⁶ M GLP-1^1–36NH2. Thus, GLP-1^7–36NH2 was more effective than GLP-1^1–36NH2 in stimulating secretion of intestinal somatostatin-like immunoreactivity (SLI) (p<0.05). GLP-2 did not affect intestinal somatostatin release. Gel permeation analysis demonstrated that 10⁻⁶ M GLP-1^7–36NH2 stimulated SS-28 by 2.9±0.4-fold and SS-14 by 9.1±3.7-fold, whereas GLP-1^1–36NH2 exerted equivalent effects (2.8±0.9-fold) on both forms of somatostatin. These findings define a novel biological role for GLP-1^7–36NH2 in the regulation of intestinal somatostatin secretion, and demonstrate that GLP-1^1–36NH2 exerts unique biological activities in this system.     

GLP-1 does not acutely affect insulin sensitivity in healthy man

Summary Previous studies have suggested that glucagon-like peptide-1 (GLP-1) (7–36 amide) may have the direct effect of increasing insulin sensitivity in healthy man. To evaluate this hypothesis we infused GLP-1 in seven lean healthy men during a hyperinsulinaemic (0.8 mU · kg⁻¹ · min⁻¹), euglycaemic (5 mmol/l) clamp. Somatostatin (450 μg/h) was infused to suppress endogenous insulin secretion, and growth hormone (3 ng · kg⁻¹ · min⁻¹) and glucagon (0.8 ng · kg⁻¹ · min⁻¹) were infused to maintain basal levels. GLP-1 (50 pmol · kg⁻¹ · h⁻¹) or 154 mmol/l NaCl (placebo) was infused after 3 h of equilibration, i.e. from 180-360 min. GLP-1 infusion resulted in GLP-1 levels of approximately 40 pmol/l. Plasma glucose, insulin, growth hormone, and glucagon levels were similar throughout the clamps. The rate of glucose infusion required to maintain euglycaemia was similar with or without GLP-1 infusion (7.69±1.17 vs 7.76±0.95 mg · kg⁻¹ · min⁻¹ at 150–180 min and 8.56±1.13 vs 8.55±0.68 mg · kg⁻¹ · min⁻¹ at 330–360 min) and there was no difference in isotopically determined hepatic glucose production rates (− 0.30±0.23 vs −0.16±0.22 mg · kg⁻¹ · min⁻¹ at 330–360 min). Furthermore, arteriovenous glucose differences across the forearm were similar with or without GLP-1 infusion (1.43±0.23 vs 1.8±0.29 mmol/l), (ANOVA;p>0.60, in all instances). In conclusion, GLP-1 (7–36 amide) administered for 3 h, leading to circulating levels within the physiological range, does not affect insulin sensitivity in healthy man.     

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.     

胰高血糖素样肽-1及其类似物的降糖机制

破骨细胞生成抑制因子 (OCIF) /骨保护素 (osteoprotegerin ,OPG)是一种新发现的以可溶性蛋白质形式存在的破骨细胞负性调节因子 ,属于肿瘤坏死因子受体超家族成员 ,其配基ODF/OPGL被证明是破骨细胞分化因子 ,OCIF/OPG可与其配基结合阻断其配基的信号下传而抑制破骨细胞生成、活化 ,其它骨吸收调节因子可能部分或全部通过调节OCIF/OPG生成而发挥作用。该因子的发现 ,为探讨骨质疏松的发病机制及其预防和治疗提出了新方向。     

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.     

Effect of glucagon-like peptide-1 (GLP-1) analogues on epicardial adipose tissue: A meta-analysis

Background and aimsGlucagon-like peptide-1 (GLP-1) analogues reduce body fat and cardiovascular events in patients with type 2 diabetes. Accumulation of epicardial adipose tissue (EAT) is associated with increased cardio-metabolic risks and coronary events in type 2 diabetes.MethodsA systematic review and meta-analysis were performed from Glucagon-like peptide-1 analogues therapy on type 2 diabetes patients, reporting data from changes in EAT, after searching the PubMed/MEDLINE, Embase, Science Direct, Scopus, Google Scholar, and Cochrane databases.ResultsIt has been found a limited number of studies, a total of 4 studies (n = 160 patients with GLP-1 analogues therapy) were included in the final analysis. Pooled analysis revealed that GLP-1 analogues reduce EAT (MD: 1.83 mm [-2.50; ?1.10]; P < 0.01). Compared with the patients before the treatment, the patients after the treatment had a smaller HbA1c (MD -1.10%[-1.80; ?0.30]; p = 0.0143) and body mass index was reduced (MD -2.20 kg/m²[-3.70; ?0.60]; p = 0.0058), GLP-1 therapy reduced low-density lipoprotein levels (MD-13.53 mg/dL [-21.74; ?5.31]; p = 0.001) and reduced triglycerides levels significantly (MD -18.32 -28.20 mg/dL; ?8.50); p = 0.0003).ConclusionsThis meta-analysis suggests that the amount of EAT is significantly reduced in T2D patients with Glucagon-like peptide-1 analogues.     

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.     

Fasting proinsulin and 2-h post-load glucose levels predict the conversion to NIDDM in subjects with impaired glucose tolerance: The Hoorn Study

Summary The aims of the present study were to observe the natural history of impaired glucose tolerance and to identify predictors for development of non-insulin-dependent diabetes mellitus (NIDDM). A survey of glucose tolerance was conducted in subjects aged 50–74 years, randomly selected from the registry of the middle-sized town of Hoorn in the Netherlands. Based on the mean values of two oral glucose tolerance tests subjects were classified in categories of glucose tolerance according to the World Health Organization criteria. All subjects with impaired glucose tolerance (n=224) were invited to participate in the present study, in which 70% (n=158) were subsequently enrolled. During follow-up subjects underwent a repeated paired oral glucose tolerance test. The mean follow-up time was 24 months (range 12–36 months). The cumulative incidence of NIDDM was 28.5% (95% confidence interval 15–42%). Age, sex, and anthropometric and metabolic characteristics at baseline were analysed simultaneously as potential predictors of conversion to NIDDM using multiple logistic regression. The initial 2-h post-load plasma glucose levels and the fasting proinsulin levels were significantly (p<0.05) related to the incidence of NIDDM. Anthropometric characteristics, the 2-h post-load specific insulin levels and the fasting proinsulin/fasting insulin ratio were not related to the incidence of NIDDM. These results suggest that beta-cell dysfunction rather than insulin resistance plays the most important role in the future development of diabetes in a high-risk Caucasian population.Abbreviations IGT Impaired glucose tolerance - NIDDM non-insulin-dependent diabetes mellitus - OGTT oral glucose tolerance test - CI confidence interval - W/H ratio waist/hip ratio - BMI body mass index - OR odds ratio     

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。     

胰高血糖素样肽-1诱导干细胞定向分化

最近研究显示,胰高血糖素样肽(GLP)-1与 干细胞的定向分化功能有重要关系.其可明显提高干细胞向胰岛素分泌细胞的阳性诱导率,并增加诱导细胞对高糖刺激的反应性.推测这是由于GLP-1促进与胰腺功能和发育成熟相关的多种转录因子的高表达,增强G蛋白耦联受体(GPCRs)信号转导通路,激活G蛋白信号调节子(Rgs) 16、Rgs8重新表达有关.体外利用GLP-1使干细胞定向分化为可分泌胰岛素的功能细胞,然后再进行自体移植,成为干细胞治疗糖尿病的一种新途径.     

胰升糖素样肽-1对胰岛β细胞凋亡的影响

凋亡在胰腺正常的生理活动和糖尿病发生的病理过程中均起重要的作用。细胞因子毒性、脂毒性和糖毒性均可引起β细胞凋亡。胰升糖素样肽-1由小肠内分泌细胞分泌,在糖尿病鼠类、培养细胞系、新鲜离体的人胰岛细胞及胰岛移植模型中均有抵抗凋亡的作用,可通过cAMP依赖途径激活cAMP反应元件结合蛋白、磷脂酰肌醇3激酶、蛋白激酶B,上调抗凋亡蛋白,下调caspase-3,减少β细胞凋亡。     

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.     

重组人胰高血糖素样肽1(7-36)促进INS-1细胞胰岛素释放与合成

在INS 1细胞中分别加入不同浓度的葡萄糖和重组人胰高血糖素样肽 1〔rhGLP 1(7 3 6〕溶液 ,孵育 4h ,用放免法测定上清液中胰岛素含量 ,并利用RT PCR技术对INS 1细胞的胰岛素mRNA水平作半定量分析。结果提示rhGLP 1(7 3 6)不仅能促进INS细胞的胰岛素释放 ,而且能促进胰岛素基因表达。     

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.     

胰升血糖素样肽-1治疗的胰腺外作用研究进展

随着研究的不断深入,人们发现胰升血糖素样肽-1 （GLP-1）不仅可以刺激胰岛β细胞分泌胰岛素调节血糖,还可保护肝脏、肾脏功能,调节脂类代谢,降低心血管危险因素,影响及保护中枢神经系统等.本文就GLP-1胰腺外作用的最新研究进展进行系统综述.     

胰高血糖素样肽1影响动脉粥样硬化的研究进展

胰高血糖素样肽1(GLP-1)是一种新型治疗2型糖尿病肠促胰液素,它可以在进食后血糖升高而刺激肠道分泌进而控制血糖。越来越多的研究表明,GLP-1可直接作用于心血管系统,例如可以影响内皮功能、炎症反应、血压、血脂代谢等。本文将对GLP-1类药物包括GLP-1类似物和二肽激肽酶4抑制剂影响动脉粥样硬化以及其潜在的机制进行综述。