2型糖尿病患者早期使用胰高血糖素样受体激动剂

糖尿病目前已成为继心血管疾病和肿瘤之后的第三位主要非传染性疾病,其中90%为2型糖尿病患者。胰高血糖素样肽-1类似物(GLP-I类似物)作为一种新型的降糖药物,具有降低体重、降低收缩压、改善胰岛细胞功能,已成为2型糖尿病治疗的新热点。艾塞那肽和利拉鲁肽作为肠促胰素激素,与人体内天然GLP-1保持了高度同源性(97%)。近几年来受到人们广泛关注。本综述针对2型糖尿病患者早期使用胰岛素样受体激动剂艾塞那肽和利拉鲁肽的安全性和有效性进行评估。     

sGLP-1对GK糖尿病大鼠治疗效果的研究

目的研究人工合成胰高血糖素样截短肽（sGLP-1）对II型糖尿病大鼠的治疗效果。方法GKⅡ型糖尿病大鼠随机分为三组,以合成的GLP-1为阳性对照,观察sGLP-1对GKⅡ型糖尿病大鼠血糖水平、胰岛素分泌以及糖耐量的影响。结果与GLP-1相比sGLP-1能够长效控制的血糖水平,明显改善糖尿病大鼠的糖耐量（P〈0.01）。结论sGLP-1控制血糖的长效能力优于GLP-1,可能从刺激胰岛素分泌方面对Ⅱ型糖尿病具有治疗作用。     

利拉鲁肽治疗2型糖尿病的研究进展

利拉鲁肽是一种胰高糖素样肽-1(GLP-1)类似物,作为一种新型的2型糖尿病治疗药物,具有降低体质量、改善胰岛β细胞功能、降低收缩压,减少低血糖发生率的作用。本文通过对近期国内外文献中关于利拉鲁肽研究进展的归纳和分析,从其药理作用研究、动物实验研究、临床研究、安全性和耐受性等方面进行阐述,为今后的研究提供参考和依据。     

sGLP-1对Ⅱ型糖尿病大鼠治疗效果的研究

目的 研究人工合成胰高血糖素样截短肽(sGLP-1)对Ⅱ型糖尿病大鼠的治疗效果.方法 Ⅱ型糖尿病GK大鼠随机分为三组,以合成的GLP-1为阳性对照,观察sGLP-1对Ⅱ型糖尿病GK大鼠血糖水平、胰岛素分泌以及糖耐量的影响,通过MTT法测定sGLP-1对胰岛β细胞系β-TC3增殖作用.结果 与GLP-1相比sGLP-1能够长效控制的血糖水平,明显改善糖尿病大鼠的糖耐量(P<0.01).同时sGLP-1能促进胰岛素分泌和胰岛β-TC3细胞的增殖,使得胰岛体积增大,数量增多.结论 sGLP-1控制血糖的长效能力优于GLP-1,可能从刺激胰岛素分泌和促进胰岛β细胞增殖两个方面对Ⅱ型糖尿病具有治疗作用.     

胰高血糖素样肽1对胰腺β细胞的作用及其机制

胰高血糖素样肽1(GLP-1)是一种主要由肠道L细胞分泌的肠促胰素。GLP-1能通过葡萄糖依赖模式刺激胰岛素的分泌,同时有延缓胃排空、抑制胰高血糖素分泌、降低体重的作用,有利于维持体内血糖稳态。目前,基于GLP-1的药物作为新的糖尿病治疗手段已越来越受到重视。我们简要综述GLP-1对胰腺β细胞的作用及机制研究进展。     

一种GLP-1过表达肠类器官构建的方法

胰高血糖素样肽1 (glucagon-like peptide 1, GLP-1)作为一种肠促胰岛素,主要由肠道L细胞分泌,由于其能够有效促进胰岛素的释放从而降低血糖,因此GLP-1及其类似物在2型糖尿病的治疗上具有良好的应用前景。本研究优化了慢病毒感染类器官的方法,利用该方法成功构建了GLP-1过表达的小鼠小肠类器官(organoids)。结果显示该类器官分泌的GLP-1能够有效地提高野生型及糖尿病小鼠的葡萄糖耐受能力。因此,本研究构建的GLP-1过表达类器官可以为2型糖尿病的治疗提供一种新的策略。     

胰高血糖素样肽1与心血管疾病的研究进展

胰高血糖素样肽1(glucagon like peptide-1,GLP-1)是一种肠促胰岛素多肽,在调节葡萄糖稳态中发挥重要作用,能够通过多种途径降低血糖,且不易引起低血糖反应,被认为是治疗2型糖尿病的理想药物。在人类的心肌细胞、冠状动脉、血管内皮及血管平滑肌(vascular smooth muscle,VSM)均有GLP-1受体(GLP-1R)分布。因此,GLP-1除降低血糖外,尚有诸多胰腺外作用。近年来对GLP-1的研究发现其对心血管系统具有保护作用,如调节心率、血压、改善血管内皮功能、改善心肌缺血等。     

GLP-1类似物蛋白结构及功能研究进展

基于胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)结构改变得到的GLP-1类似物,能迅速、高效、持久地降低血糖及糖化血红蛋白,具有改善胰岛β细胞功能、调节收缩压、保护心血管、降低血脂、减轻体重、延迟胃排空、增加饱腹感等作用,成为近年来2型糖尿病治疗领域研究的热点。本文对GLP-1及其类似物的结构、功能、不良反应、蛋白质结构研究的方法作一综述。     

贝那鲁肽与利拉鲁肽对2型糖尿病患者长期结局影响的对比研究

摘要 目的：对比分析贝那鲁肽与利拉鲁肽对2型糖尿病患者长期结局的影响，为二甲双胍和磺脲类药物治疗后血糖不能达标的患者应用胰高糖素样肽-1（GLP-1） 受体激动剂提供临床依据。方法：选取2018年3月～2019年3月在我院就诊的使用二甲双胍或者二甲双胍联合磺脲类药物血糖未达标的2型糖尿病患者150例作为研究对象，随机分为观察组和对照组，每组各75例。观察组使用贝那鲁肽注射液治疗，对照组使用利拉鲁肽注射液治疗，所有患者均连续治疗24周。比较两组患者治疗前后空腹血糖（FPG）、餐后2 h血糖（2hPG）、糖化血红蛋白（HbA1c）、收缩期血管峰值血流( PSV)、血管内膜中层厚度(IMT) 、肌酐（Scr）和尿素氮（BUN）水平，两年内的不良事件发生率、心血管相关死亡率和全因死亡率。结果：两组患者之间治疗前、后FPG、2hPG、HbA1c、PSV、IMT、Scr和BUN水平无统计学差异（P>0.05）, 观察组的不良事件总发生率（8.00%）较对照组（20.00%）明显降低（P<0.05），两组患者心血管相关死亡率和全因死亡率相比，差异无统计学意义（P>0.05）。结论：在使用二甲双胍或者二甲双胍联合磺脲类药物血糖未达标的2型糖尿病患者中，与利拉鲁肽相比，贝那鲁肽在降低血糖、改善下肢血管功能、肾功能和死亡率方面无明显差异，但不良事件发生率更低。     

胰高血糖素样肽-1与受体相互作用研究进展

胰高血糖素样肽-1(GLP-1)具有促胰岛素分泌、抑制胰高血糖素分泌、刺激胰岛β细胞的增殖和分化、抑制β细胞凋亡、抑制胃排空等作用,近年来成为治疗糖尿病药物研究中的热点。GLP-1与受体的相互作用一直备受关注,我们从4个方面对GLP-1与受体相互作用的研究进行了综述:GLP-1的二级结构、GLP-1单个残基改变及残基间的相互作用、GLP-1不同残基片段对GLP-1结合并激活受体的影响和GLP-1受体的相互作用模式。     

A novel GLP-1 analog,a dimer of GLP-1 via covalent linkage by a lysine,prolongs the action of GLP-1 in the treatment of type 2 diabetes

GLP-1 is an incretin hormone that can effectively lower blood glucose, however, the short time of biological activity and the side effect limit its therapeutic application. Many methods have been tried to optimize GLP-1 to extend its in vivo half-time, reduce its side effect and enhance its activity. Here we have chosen the idea to dimerize GLP-1 with a C-terminal lysine to form a new GLP-1 analog, DLG3312. We have explored the structure and the biological property of DLG3312, and the results indicated that DLG3312 not only remained the ability to activate the GLP-1R, but also strongly stimulated Min6 cell to secrete insulin. The in vivo bioactivities have been tested on two kinds of animal models, the STZ induced T2DM mice and the db/db mice, respectively. DLG3312 showed potent anti-diabetic ability in glucose tolerance assay and single-dose administration of DLG3312 could lower blood glucose for at least 10 hours. Long-term treatment with DLG3312 can reduce fasted blood glucose, decrease water consumption and food intake and significantly reduce the HbA1c level by 1.80% and 2.37% on STZ induced T2DM mice and the db/db mice, respectively. We also compared DLG3312 with liraglutide to investigate its integrated control of the type 2 diabetes. The results indicated that DLG3312 almost has the same effect as liraglutide but with a much simpler preparation process. In conclusion, we, by using C-terminal lysine as a linker, have synthesized a novel GLP-1 analog, DLG3312. With simplified preparation and improved physiological characterizations, DLG3312 could be considered as a promising candidate for the type 2 diabetes therapy.     

Early intervention with liraglutide improves glucose tolerance without affecting islet microcirculation in young Goto-Kakizaki rats

Liraglutide, an analog of glucagon-like peptide-1 (GLP-1), is an effective anti-diabetic agent with few side effects. Since native GLP-1 exerts vascular effects, we investigated changes in pancreatic islet blood flow using a non-radioactive microsphere technique, as well as insulin concentration and glucose tolerance after 17 day treatment with liraglutide in 6-week-old Goto-Kakizaki (GK) rats. Compared to saline-treated control GK rats, liraglutide limited body weight gain, decreased glycemia, improved glucose tolerance and lowered serum insulin concentration. Neither pancreatic or islet blood flow, nor pancreatic insulin content, was affected by liraglutide treatment. We conclude that early intervention with liraglutide decreases glycemia and improves glucose tolerance, thus halting the natural progression towards diabetes, without affecting islet microcirculation or pancreatic insulin content in young female GK rats.     

Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis

Background

Glucagon-like peptide (GLP-1) analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs.

Methods

MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events.

Results

Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily. Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg) than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists have some effect on beta-cell function, but this is not sustained after the drug is stopped.

Conclusions

GLP-1 agonists are effective in improving glycaemic control and promoting weight loss.     

Adenoviral vector-mediated glucagon-like peptide 1 gene therapy improves glucose homeostasis in Zucker diabetic fatty rats

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that plays an important role in glucose homeostasis. Its functions include glucose-stimulated insulin secretion, suppression of glucagon secretion, deceleration of gastric emptying, and reduction in appetite and food intake. Despite the numerous antidiabetic properties of GLP-1, its therapeutic potential is limited by its short biological half-life due to rapid enzymatic degradation by dipeptidyl peptidase IV. The present study aimed to demonstrate the therapeutic effects of constitutively expressed GLP-1 in an overt type 2 diabetic animal model using an adenoviral vector system. METHODS: A novel plasmid (pAAV-ILGLP-1) and recombinant adenoviral vector (Ad-ILGLP-1) were constructed with the cytomegalovirus promoter and insulin leader sequence followed by GLP-1(7-37) cDNA. RESULTS: The results of an enzyme-linked immunosorbent assay showed significantly elevated levels of GLP-1(7-37) secreted by human embryonic kidney cells transfected with the construct containing the leader sequence. A single intravenous administration of Ad-ILGLP-1 into 12-week-old Zucker diabetic fatty (ZDF) rats, which have overt type 2 diabetes mellitus (T2DM), achieved near normoglycemia for 3 weeks and improved utilization of blood glucose in glucose tolerance tests. Circulating plasma levels of GLP-1 increased in GLP-1-treated ZDF rats, but diminished 21 days after treatment. When compared with controls, Ad-ILGLP-1-treated ZDF rats had a lower homeostasis model assessment for insulin resistance score indicating amelioration in insulin resistance. Immunohistochemical staining showed that cells expressing GLP-1 were found in the livers of GLP-1-treated ZDF rats. CONCLUSIONS: These data suggest that GLP-1 gene therapy can improve glucose homeostasis in fully developed diabetic animal models and may be a promising treatment modality for T2DM in humans.     

GLP-1 C-terminal structures affect its blood glucose lowering-function.

Glucagon-like peptide-1 (GLP-1), which is an endogenous insulinotropic peptide that can stimulate islet cells to secret insulin, is a promising new drug candidate for the treatment of type 2 diabetes. However, due to the very short half-life of this peptide, the clinical value of GLP-1 is restricted. A GLP-1 peptide analog that had been altered by deletion of five amino acids from the C-terminus (sGLP-1) was selected and investigated in vivo for the therapeutic effect on GK rats with type II DM (T2DM). The results revealed that sGLP-1 exhibited decreased blood glucose-lowering ability compared to GLP-1 in the first week, as measured after once-daily administration. However, after drug administration for 2 weeks, the blood glucose-lowering effect of sGLP-1 became superior to that of GLP-1. sGLP-1 reduced apoptosis of the old islets, enhanced insulin production, and promoted new islets replication. sGLP-1 is a shorter but more efficient GLP-1 analog for type 2 diabetes management. Because sGLP-1 prolonged the proliferation and recovery of islet cells, the ability to maintain blood glucose (BG) within a normal range was still present 2 weeks after drug withdrawal. These results confirmed the importance of the C-terminus of GLP-1 molecule, and further demonstrated that GLP-1 (7-37) can be truncated till the 32nd amino acid to have a better long-term BG lowing function. This result may imply for the presence of glucagon family clearance receptors in vivo and demonstrates that the C-terminus participates in GLP-1 clearance.     

Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes

Glucagon-like peptide 1 (GLP-1) is a product of proglucagon that is secreted by specialized intestinal endocrine cells after meals. GLP-1 is insulinotropic and plays a role in the incretin effect, the augmented insulin response observed when glucose is absorbed through the gut. GLP-1 also appears to regulate a number of processes that reduce fluctuations in blood glucose, such as gastric emptying, glucagon secretion, food intake, and possibly glucose production and glucose uptake. These effects, in addition to the stimulation of insulin secretion, suggest a broad role for GLP-1 as a mediator of postprandial glucose homeostasis. Consistent with this role, the most prominent effect of experimental blockade of GLP-1 signaling is an increase in blood glucose. Recent data also suggest that GLP-1 is involved in the regulation of beta-cell mass. Whereas other insulinotropic gastrointestinal hormones are relatively ineffective in stimulating insulin secretion in persons with type 2 diabetes, GLP-1 retains this action and is very effective in lowering blood glucose levels in these patients. There are currently a number of products in development that utilize the GLP-1-signaling system as a mechanism for the treatment of diabetes. These compounds, GLP-1 receptor agonists and agents that retard the metabolism of native GLP-1, have shown promising results in clinical trials. The application of GLP-1 to clinical use fulfills a long-standing interest in adapting endogenous insulinotropic hormones to the treatment of diabetes.     

Glucagon-like peptide 1 improved glycemic control in type 1 diabetes

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. METHODS: Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis. RESULTS: In 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 PlusMinus; 0.9, mean PlusMinus; se, vs 5.4 PlusMinus; 0.8 mmol/l, p <.05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 PlusMinus; 3.1 vs 37 PlusMinus; 9.6 pmol/l, p <.05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 PlusMinus; 2.5 vs 3.1 PlusMinus; 1.9 ng/l, p <.04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 PlusMinus; 0.33 vs 0.34 PlusMinus; 0.26 mmol/l, p <.05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1. CONCLUSION: We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs.     

Crosstalk between diabetes and brain: Glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration

According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a “type 3 diabetes” or “brain insulin resistant state”. Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.     

Regulation of adipocyte formation by GLP-1/GLP-1R signaling

Increased nutrient intake leads to excessive adipose tissue accumulation, obesity, and the development of associated metabolic disorders. How the intestine signals to adipose tissue to adapt to increased nutrient intake, however, is still not completely understood. We show here, that the gut peptide GLP-1 or its long-lasting analog liraglutide, function as intestinally derived signals to induce adipocyte formation, both in vitro and in vivo. GLP-1 and liraglutide activate the GLP-1R, thereby promoting pre-adipocyte proliferation and inhibition of apoptosis. This is achieved at least partly through activation of ERK, PKC, and AKT signaling pathways. In contrast, loss of GLP-1R expression causes reduction in adipogenesis, through induction of apoptosis in pre-adipocytes, by inhibition of the above mentioned pathways. Because GLP-1 and liraglutide are used for the treatment of type 2 diabetes, these findings implicate GLP-1 as a regulator of adipogenesis, which could be an alternate pathway leading to improved lipid homeostasis and controlled downstream insulin signaling.