胰高糖素样肽-1及其类似物和二肽酰肽酶-Ⅳ抑制剂对胰岛功能的保护作用

胰岛β细胞功能受损是2型糖尿病发病的中心环节.随着病程的进展,多种机制参与导致β细胞功能进行性下降.胰高糖素样肽-1(GLP-1)是由肠道内分泌细胞L细胞分泌的肠促胰岛素,可以葡萄糖依赖性地增加胰岛素分泌、促进胰岛β细胞再生并抑制胰高糖素分泌.长效GLP-1类似物和二肽酰肽酶(DPP)-Ⅳ抑制剂能够减少内源性GLP-1在体内降解,从而更有效地保护胰岛β细胞功能,对于糖尿病的防治具有重要意义.     

胰高糖素样肽-1及其类似物和二肽酰肽酶-IV抑制剂对胰岛功能的保护作用

胰岛β细胞功能受损是2型糖尿病发病的中心环节。随着病程的进展,多种机制参与导致β细胞功能进行性下降。胰高糖素样肽-1(GLP-1)是由肠道内分泌细胞L细胞分泌的肠促胰岛素,可以葡萄糖依赖性地增加胰岛素分泌、促进胰岛β细胞再生并抑制胰高糖素分泌。长效GLP-1类似物和二肽酰肽酶(DPP)-IV抑制剂能够减少内源性GLP-1在体内降解,从而更有效地保护胰岛β细胞功能,对于糖尿病的防治具有重要意义。     

胰升糖素样肽-1的研究进展

胰升糖素样肽-1(GLP-1)是由肠道内分泌L细胞分泌的肠促胰岛素,具有促进胰岛素分泌、胰岛细胞生长、增殖和分化并抑制胰岛β细胞凋亡等多种作用,可用来预防和治疗糖尿病,辅助进行胰岛细胞移植,且不引起体重增加和低血糖。但GLP-1可很快被二肽基肽酶Ⅳ降解,限制了其临床应用。目前对长效的GLP-1类似物、二肽基肽酶Ⅳ抑制剂和GLP-1基因治疗的研究已成为热点。     

胰高血糖素样肽-1及其受体激动剂对胰岛β细胞功能和数量的影响

胰岛β细胞功能的逐渐衰退在2型糖尿病的发生发展中起着重要作用。胰高血糖素样肽-1（GLP-1）是目前发现与2型糖尿病发生发展相关的肠促胰岛素,是“Incretin效应”的主要成分,可以增加正常人体内胰岛β细胞胰岛素的分泌,帮助调节整体葡萄糖代谢的动态平衡,并能促进胰岛β细胞增殖分化并减少其凋亡,对胰岛β细胞功能有一定的保护作用。     

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.     

调控β细胞,直击糖尿病——GLP-1利拉鲁肽的基础与临床

β细胞功能障碍是2型糖尿病的主要发病机制之一,本文阐述了胰升糖素样肽1(GLP-1)促进胰岛β细胞胰岛素分泌,促进β细胞增殖、分化和抑制β细胞凋亡的分子信号转导机制.并对GLP-1的长效类似物利拉鲁肽的最近完成的一系列临床研究进行了介绍.     

GLP-1及受体激动剂联合间充质干细胞对1型糖尿病胰岛β细胞的保护作用

1型糖尿病(type1diabetes Mellitus,T1DM)由于自身免疫介导引起胰岛β细胞破坏、凋亡增加,同时α细胞功能失调,不恰当分泌胰高血糖素,进一步加重高血糖.因而,早期诱导免疫耐受,刺激β细胞再生,抑制α细胞分泌胰高血糖素,将是治疗T1DM关键.目前T1DM除药物治疗外,由于间充质干细胞(mesenchymalstemcells,MSCs)能分泌抗炎和免疫调节因子,诱导免疫耐受,抑制T细胞的增殖,趋化并修复受损伤组织;同时分泌多种营养因子,促进β细胞增殖分化,从而治疗糖尿病.但MSCs治疗后胰岛β细胞增生的同时,α细胞也出现了不同程度的增生.胰高血糖素样肽1(glucagon-likepeptide1,GLP-1)及受体激动剂能抑制α细胞分泌胰高血糖素,且有一定的促进胰岛β细胞增殖及再生,抑制β细胞凋亡,诱导干细胞向胰岛素分泌细胞分化的能力.两者联用,对胰岛β细胞保护方面具有协同作用.     

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...     

GLP-1受体激动剂的胰岛素增敏效应

2型糖尿病的发病机制主要涉及胰岛素抵抗张胰岛素分泌缺乏.研究表明,胰高血糖素样肽-1受体激动剂在有效改善胰岛β细胞功能,促进胰岛素分泌的同时,还能够作用于细胞信号转导,促进脂肪细胞分化和葡萄糖摄取,并通过减轻相关炎性反应因子表达,降低体重等,改善胰岛素抵抗,增加胰岛素敏感性.     

人胰升糖素样肽-1类似物利拉鲁肽临床作用探讨

2型糖尿病已成为全球范围内发病率增长最快的疾病之一,我国目前有9200万糖尿病患者和1．55亿糖尿病前期患者,胰岛功能的进行性衰退,包括β细胞胰岛素分泌缺陷和仅细胞升糖素不适当的分泌是2型糖尿病发生发展的重要原因。UKPDS显示,在2型糖尿病诊断时,患者胰岛β细胞功能已降至正常的50％,且随病程的延长,     

Rationale Use of GLP-1 Receptor Agonists in Patients with Type 1 Diabetes

Clinicians and patients are rapidly adapting GLP-1 receptor agonists as efficacious and safe therapeutic options for managing type 2 diabetes (T2DM). GLP-1 receptor agonists stimulate insulin production and secretion from the pancreatic β cells in a glucose-dependent manner, improve gastric emptying, favor weight reduction, and reduce postabsorptive glucagon secretion from pancreatic α cells. GLP-1 receptor activity is impaired in patients with T2DM. GLP-1 secretion and subsequent physiologic actions in patients with type 1 diabetes (T1DM) is ill-defined. Some researchers have suggested that the use of GLP-1 receptor agonists in T1DM may reduce excessive postprandial glucagon secretion allowing patients to reduce their total daily dose of exogenous insulin. Hypoglycemia risk may also be minimized in T1DM as glucagon counter-regulation can be preserved to some degree via the glucose-dependent action of the GLP-1 receptor agonists. This paper will consider the physiologic and pharmacologic benefits of adding GLP-1 receptor agonists to therapeutic regimens of patients with T1DM.     

The multifaceted potential of glucagon-like peptide-1 as a therapeutic agent

Glucagon-like peptide-1 (GLP-1), an intestinal gut hormone, is rapidly emerging as a new therapeutic agent for the treatment of diabetes mellitus. GLP-1, released from intestinal L-cells, is renowned for its potent stimulation of insulin biosynthesis and release from pancreatic b-cells. Exogenous administration of GLP-1 to subjects with type 2 diabetes results in the normalization of plasma glucose concentrations, in part, as a result of augmented glucose-stimulated insulin secretion. However, it is now recognized that GLP-1 has several other anti-diabetic actions that collectively improve the type 2 diabetic phenotype, and may also prove beneficial in the treatment of type 1 diabetes. These effects include the deceleration of gastric emptying and promotion of satiety, thereby reducing the availability of nutrients for absorption and reducing the requirement for insulin secretion. GLP-1 also reduces plasma glucose levels by suppressing glucagon secretion from pancreatic a-cells and potentially by improving insulin sensitivity in peripheral tissues. Further-more, GLP-1 upregulates expression of b-cell genes (GLUT2, glucokinase, insulin, and PDX-1) and promotes b-cell neogenesis and differentiation of ductal cells into insulin secreting cells. Although initial clinical trials indicate GLP-1 has excellent therapeutic potential, its relatively short-lived biological activity and delivery difficulties limit its appeal. Several approaches that are currently being explored to overcome these limitations include mobilizing endogenous GLP-1 release, preserving the biological activity of the native peptide, and developing GLP-1 analogues with extended durations of action.     

The incretin system and its role in type 2 diabetes mellitus

The incretin hormones are released during meals from gut endocrine cells. They potentiate glucose-induced insulin secretion and may be responsible for up to 70% of postprandial insulin secretion. The incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. However, in supraphysiological doses, GLP-1 administration may completely normalize beta as well as alpha cell sensitivity to glucose. The impaired action of GLP-1 and GIP in T2DM may be at least partly restored by improved glycaemic control, as shown in studies involving 4 weeks of intensive insulin therapy. The reduced incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM, and, in support of this, exogenous GLP-1 administration may restore blood glucose regulation to near normal levels. Thus, the pathogenesis of T2DM seems to involve a dysfunction of both incretins. Enhancement of incretin action may therefore represent a therapeutic solution. Clinical strategies therefore include the development of metabolically stable activators of the GLP-1 receptor; and inhibition of DPP-4, the enzyme that destroys native GLP-1 almost immediately. Orally active DPP-4 inhibitors and the metabolically stable activators, exenatide (Byetta), are now on the market, and numerous clinical studies have shown that both principles are associated with durable antidiabetic activity.     

GLP-1 receptor signaling: effects on pancreatic beta-cell proliferation and survival

Type 2 diabetes is a metabolic disorder characterized by insulin resistance as well as a progressive deterioration of pancreatic beta-cell mass and function. Glucagon-like peptide 1 (GLP-1), an incretin hormone secreted by intestinal L cells, is a promising therapeutic agent in the treatment of diabetes. GLP-1 analogs and enhancers constitute a novel class of anti-diabetes medications which address both the insulin secretion defect as well as the decline in beta-cell mass. GLP-1 improves glucose-stimulated insulin secretion, restores glucose competence in glucose-resistant beta-cells, and stimulates insulin gene expression and biosynthesis. Furthermore, GLP-1 acts as a growth factor by promoting beta-cell proliferation, survival and neogenesis. This review focuses on the molecular mechanisms by which GLP-1 signaling induces beta-cell mass expansion.     

Function of a long-term, GLP-1-treated, insulin-secreting cell line is improved by preventing DPP IV-mediated degradation of GLP-1

Glucagon-like peptide-1 (GLP-1) is an important insulinotropic hormone with potential in the treatment of type 2 diabetes. However, the short biological half-life of the peptide after cleavage by dipeptidylpeptidase IV (DPP IV) is a major limitation. Inhibition of DPP IV activity and the development of resistant GLP-1 analogues is the subject of ongoing research. In this study, we determined cell growth, insulin content, insulin accumulation and insulin secretory function of a insulin-secreting cell line cultured for 3 days with either GLP-1, GLP-1 plus the DPP IV inhibitor diprotin A (DPA) or stable N-acetyl-GLP-1. Native GLP-1 was rapidly degraded by DPP IV during culture with accumulation of the inactive metabolite GLP-1(9-36)amide. Inclusion of DPA or use of the DPP IV-resistant analogue, N-acetyl-GLP-1, improved cellular function compared to exposure to GLP-1 alone. Most notably, basal and accumulated insulin secretion was enhanced, and glucose responsiveness was improved. However, prolonged GLP-1 treatment resulted in GLP-1 receptor desensitization regardless of DPP IV status. The results indicate that prevention of DPP IV action is necessary for beneficial effects of GLP-1 on pancreatic beta cells and that prolonged exposure to GLP-1(9-36)amide may be detrimental to insulin secretory function. These observations also support the ongoing development of DPP-IV-resistant forms of GLP-1, such as N-acetyl-GLP-1.     

Beta-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic beta cells

Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted from enteroendocrine L cells and potentiates glucose-dependent insulin secretion in pancreatic beta cells. Recently the GLP-1 receptor (GLP-1 R) has been a focus for new anti-diabetic therapy with the introduction of GLP-1 analogues and DPP-IV inhibitors, and this has stimulated additional interest in the mechanisms of GLP-1 signaling. Here we identify a mechanism for GLP-1 action, showing that the scaffold protein beta-arrestin-1 mediates the effects of GLP-1 to stimulate cAMP production and insulin secretion in beta cells. Using a coimmunoprecipitation technique, we also found a physical association between the GLP-1 R and beta-arrestin-1 in cultured INS-1 pancreatic beta cells. beta-Arrestin-1 knockdown broadly attenuated GLP-1 signaling, causing decreased ERK and CREB activation and IRS-2 expression as well as reduced cAMP levels and impaired insulin secretion. However, beta-arrestin-1 knockdown did not affect GLP-1 R surface expression and ligand-induced GLP-1 R internalization/desensitization. Taken together, these studies indicate that beta-arrestin-1 plays a role in GLP-1 signaling leading to insulin secretion, defining a previously undescribed mechanism for GLP-1 action.     

初发2型糖尿病患者GLP-1水平变化对胰高血糖素及早相胰岛素分泌的影响

目的探讨初发2型糖尿病（T2DM）患者血胰高血糖素样肽-1（GLP-1）对胰高血糖素及早相胰岛素分泌的影响。方法以新发T2DM患者（T2DM组）、健康体检者（对照组）为研究对象,采用标准馒头餐试验,观察空腹、进餐后30 min、120 min静脉血浆GLP-1动态变化及对血浆葡萄糖、胰高血糖素、胰岛素分泌的影响。结果初发T2DM组患者馒头餐各时点GLP-1水平均分别较对照组显著降低,差异有统计学意义（P〈0.05）,馒头餐后30 min、120 min胰岛素水平显著降低（P〈0.05）,但空腹胰岛素无明显差异（P〉0.05）;而胰高血糖素则较对照组各时点显著升高,差异有统计学意义（P〈0.05）。初发T2DM组早相胰岛素分泌指数（ΔFINS30/ΔG30）显著低于对照组,差异有统计学意义（P〈0.05）。结论初发T2DM患者存在GLP-1分泌减少,GLP-1缺乏可能是T2DM患者胰岛β细胞分泌缺乏及胰高血糖素分泌过多的重要因素。     

Clinical utility of insulin and insulin analogs

Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes.