胰高血糖素样多肽-1拮抗2型糖尿病胰岛细胞凋亡损伤（英文）

胰高血糖素样多肽-1(glucogen-like peptide-1,GLP-1)在胰岛素分泌过程中扮演重要角色,并在改善β细胞功能方面有着令人瞩目的效应,但有关其作用机制尚需更深入研究。本研究探讨GLP-1对2型糖尿病(type 2 diabetes mellitus,T2DM)大鼠模型胰岛细胞损伤的影响,观察GLP-1在T2DM大鼠胰岛细胞凋亡损伤机制中所发挥的作用。HE染色结果发现,糖尿病大鼠胰岛损伤。ELISA结果表明,糖尿病患者和糖尿病大鼠血清中GLP-1表达水平上调。放射免疫结果表明,GLP-1和谷氧还蛋白1(Grx1)促进HIT-T 15细胞分泌胰岛素,Cd抑制胰岛素的分泌。免疫组化结果表明,糖尿病大鼠GLP-1加药处理后,各组与糖尿病组相比,药物提高了Grx1和胰岛素表达水平,降低了胰高血糖素表达水平,同时降低了活性胱天蛋白酶3(caspase-3)的表达。本研究结果提示,GLP-1在肥胖T2DM大鼠胰岛细胞凋亡中起保护作用,同时可调节胰岛素和胰高血糖素水平,其机制可能与Grx1相关。     

GLP-1(7-36)NH2的促胰岛素分泌作用和胞内cAMP浓度改变与胰岛素mRNA表达

目的:观察GLP-1(7-36)NH2的促胰岛素分泌作用,并进一步探讨GLP-1(7-36)NH2促进胰岛素分泌的机制.方法:放射免疫分析和细胞原位杂交的方法.结果:随着GLP-1(7-36)NH2浓度的增加,胰岛素分泌逐渐增加;8-Br-cAMP增加了胰岛素分泌,GLP-1(7-36)NH2则增加了胞内第二信使cAMP的浓度;GLP-1(7-36)NH2可增加胰岛素mRNA的表达.结论:GLP-1(7-36)NH2可促进胰岛素分泌,在一定范围内呈剂量依赖性,其机制与GLP-1(7-36)NH2增加胞内第二信使cAMP和促进胰岛素基因表达有关.     

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.     

胰高血糖素样多肽-1拮抗2型糖尿病胰岛细胞凋亡损伤

胰高血糖素样多肽-1（glucogen like peptide 1, GLP-1）在胰岛素分泌过程中扮演重要角色,并在改善β细胞功能方面有着令人瞩目的效应,但有关其作用机制尚需更深入研究。本研究探讨GLP-1对2型糖尿病（type 2 diabetes mellitus, T2DM）大鼠模型胰岛细胞损伤的影响,观察GLP-1在T2DM大鼠胰岛细胞凋亡损伤机制中所发挥的作用。HE染色结果发现,糖尿病大鼠胰岛损伤。ELISA结果表明,糖尿病患者和糖尿病大鼠血清中GLP-1表达水平上调。放射免疫结果表明,GLP-1和谷氧还蛋白1（Grx1）促进HIT-T 15细胞分泌胰岛素,Cd抑制胰岛素的分泌。免疫组化结果表明,糖尿病大鼠GLP-1加药处理后,各组与糖尿病组相比,药物提高了Grx1和胰岛素表达水平,降低了胰高血糖素表达水平,同时降低了活性胱天蛋白酶3（caspase-3）的表达。本研究结果提示,GLP-1在肥胖T2DM大鼠胰岛细胞凋亡中起保护作用,同时可调节胰岛素和胰高血糖素水平,其机制可能与Grx1相关     

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。     

长效GLP-1受体激动剂的研发进展

胰高血糖素样肽-1(glucagon-like Peptide-1,GLP-1)是机体在葡萄糖等刺激下释放的一类肠促胰岛素。GLP-1具有促进葡萄糖依赖性胰岛素分泌,促进胰岛β细胞增殖并抑制其凋亡、抑制摄食、减慢胃排空和减轻体重等作用。GLP-1在体内极不稳定,易被二肽基肽酶-IV(dipeptidyl peptidase-IV,DPP-IV)降解,半衰期短。从墨西哥巨蜥蜴唾液中分离得到GLP-1的天然类似物Exendin-4与其有着相似的作用,且不易被DPP-IV降解。以GLP-1及Exendin-4为基础,研发长效GLP-1受体激动剂,已成为研发新型糖尿病治疗药物的热点之一。本文就长效GLP-1受体激动剂的研发现状予以综述。     

胰高血糖素样肽-1在胰腺中作用机制的研究进展

胰高血糖素样肽-1（GLP-1）是胰高血糖素原基因编码的一种激素,主要由肠道L细胞产生并分泌进入血液。GLP-1能激活胰腺、肾脏、肺、胃、心脏和脑等组织中存在的特异性G蛋白偶联受体（GPCR）。通过GLP-1受体（GLP-1R）的激活,活化腺苷酸环化酶,产生3＇,5＇-环腺苷酸,随后通过cAMP依赖性第二信使途径激活蛋白激酶A和鸟苷酸交换因子。大量围绕胰岛素产生细胞——β细胞开展的研究证明,GLP-1短期作用能够加强葡萄糖依赖性的胰岛素分泌作用,持续的GLP-1R激活也能增加胰岛素的合成,促进β细胞的增殖和新生,抑制β细胞凋亡。GLP-1在胰岛素和胰高血糖素分泌方面的独特作用引发了大量针对GLP-1受体激动剂的研究。我们对胰腺中GLP-1R激活所产生作用的机制进行简要综述。     

阿必鲁肽：一种超长效Ⅱ型糖尿病治疗新药

阿必鲁肽(Albiglutide)为新型GLP-1受体激动剂,可通过与胰岛β细胞表面的GLP-1受体结合,激活由细胞膜偶联G蛋白调控的胞内信号传导系统,修复及促进胰岛β细胞功能,增加胰岛素的分泌,从而降低血糖浓度及糖化血红蛋白(Hb A1c)水平,是治疗Ⅱ型糖尿病的理想药物。目前开发的各种长效GLP-1受体激动剂成为近二十年糖尿病药物的研究热点。本文对一种极具市场潜力的新型GLP-1受体激动剂阿必鲁肽(Albiglutide)的分子结构、作用机制、剂量研究、药代动力学、药效学以及副作用等临床试验研究进展进行综述。     

胰高血糖素样肽1或其类似物体外生物活性检测方法的建立

目的:通过对不同活性检测方法的综合比较,筛选最适的胰高血糖素样肽1(GLP-1)或其类似物的体外活性检测方法,为GLP-1类似物的体外生物活性检测奠定基础。方法:以GLP-1作为阳性药物,用MTT方法检测其对RIN-m-5F、MIN6细胞增殖的影响;用ELISA方法检测其对INS-1、MIN6细胞胰岛素分泌量的影响;用ELISA方法检测其对BHK-GLP-1R细胞cAMP分泌水平的影响。通过对上述方法的综合比较,筛选出最适的活性检测方法。结果:GLP-1对细胞增殖的影响实验结果并不显著,对胰岛素分泌量影响的实验效果明显,对cAMP分泌水平的实验无明显效果。结论:ELISA检测GLP-1或其类似物对MIN6细胞胰岛素分泌量实验可用于GLP-1或其类似物的体外活性检测。     

2型糖尿病候选基因TCF7L2的研究进展

自发现转录因子7类似物2(TCF7L2)基因多态性与成人2型糖尿病(T2D)相关以来,该结论在不同人种中得到广泛证实.研究认为它可能通过影响肠胰岛素轴Wnt信号传导通路的胰高血糖素样肽-1(GLP-1)的表达或通过在胰岛β细胞的表达,或参与胰岛素的合成、加工、分泌,影响胰岛素敏感性等方式导致糖尿病发生.本文对该基因目前的研究成果及趋势进行相关论述.     

Snapin mediates incretin action and augments glucose-dependent insulin secretion

Impaired insulin secretion contributes to the pathogenesis of type 2 diabetes mellitus (T2DM). Treatment with the incretin hormone glucagon-like peptide-1 (GLP-1) potentiates insulin secretion and improves metabolic control in humans with T2DM. GLP-1 receptor-mediated signaling leading to insulin secretion occurs via cyclic AMP stimulated protein kinase A (PKA)- as well as guanine nucleotide exchange factor-mediated pathways. However, how these two pathways integrate and coordinate insulin secretion remains poorly understood. Here we show that these incretin-stimulated pathways converge at the level of snapin, and that PKA-dependent phosphorylation of snapin increases interaction among insulin secretory vesicle-associated proteins, thereby potentiating glucose-stimulated insulin secretion (GSIS). In diabetic islets with impaired GSIS, snapin phosphorylation is reduced, and expression of a snapin mutant, which mimics site-specific phosphorylation, restores GSIS. Thus, snapin is a critical node in GSIS regulation and provides a potential therapeutic target to improve β cell function in T2DM.     

Cellular glucose availability and glucagon-like peptide-1

Glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP, glucose-dependent insulinotropic polypeptide) are produced in enteroendocrine L-cells and K-cells, respectively. They are known as incretins because they potentiate postprandial insulin secretion. Although unresponsiveness of type 2 diabetes (T2D) patients to GIP has now been reconsidered, GLP-1 mimetics and inhibitors of the GLP-1 degradation enzyme dipeptidyl peptidase (DPP)-4 have now been launched as drugs against T2D. The major roles of GLP-1 in T2D are reduction of appetite, gastric motility, glucagon secretion, enhancement of insulin secretion and β-cell survival. For insulin secretion and peripheral insulin function, GLP-1 and its mimetics sensitise β-cells to glucose; accelerate blood glucose withdrawal, in-cell glucose utilisation and glycogen synthesis in insulin-sensitive tissues; and assist in the function and survival of neurons mainly using glucose as an energy source. Taken together, GLP-1 acts to potentiate glucose availability of various cells or tissues to assist with their essential functions and/or survival. Herein, we review the signalling pathways and clinical relevance of GLP-1 in enhancing cellular glucose availability. On the basis of our recent research results, we also describe a mechanism that regulates GLP-1 for glucokinase activity. Because diabetic tissues including β-cells resist glucose, GLP-1 may be useful for treating T2D.     

Emerging roles for β-arrestin-1 in the control of the pancreatic β-cell function and mass: New therapeutic strategies and consequences for drug screening

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in β-cell mass, decreased β-cell survival and impaired glucose-dependent insulin release. Pancreatic β-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. β-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that β-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for β-arrestin-1 in the regulation of insulin secretion and β-cell survival by GPCRs.     

Incretin hormones in the treatment of type 2 diabetes. Part II. Incretins - new possibilities for pharmacotherapy of type 2 diabetes

In the pathogenesis of diabetes type 2, increasing insulin resistance is accompanied by dysfunction of pancreatic islet b cells. It is hypothesized that at the basis of this pathology lies an incretin defect of insulinotropic gut-derived hormones, relying on decreased secretion of GLP-1 (glucagon-like peptide 1), with preserved insulinotropic effect, whereas GIP (glucose-dependent insulinotropic polypeptide) secretion remains within physiological limits, but its action is mostly impaired due to total loss of possibility for stimulation of the second phase insulin secretion. Possibilities for pharmacological correction of incretin defect create an opportunity of causative treatment of diabetes and provide basis for development of research on a new group of drugs which promote hypoglycemia. In the presence of these findings there are many ongoing clinical studies with the use of GLP-1 analogues or GLP-1 receptors activators (GLP-1 agonists), as well as the inhibitors of dipeptidyl peptidase IV (DPP-IV), the enzyme responsible for incretin proteolysis, in the treatment of type 2 diabetes. Multidirectional, glucoregulative mechanism of action of these drugs, aiming at the pathogenesis of the disease, restores the proper function of the intestinal-pancreatic axis in subjects with type 2 diabetes and ensures good metabolic control and improvement in quality of life in this group of patients.     

Gastric inhibitory polypeptide: the neglected incretin revisited

After the ingestion of fat- and glucose-rich meals, gut hormones are secreted into the circulation in order to stimulate insulin secretion. This so-called "incretin effect" is primarily conferred by Glucagon-like peptide 1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP). In contrast to GLP-1, GIP has lost most of its insulinotropic effect in type 2 diabetic patients. In addition to its main physiological role in the regulation of endocrine pancreatic secretion, GIP exerts various peripheral effects on adipose tissue and lipid metabolism, thereby leading to increased lipid deposition in the postprandial state. In some animal models, an influence on gastrointestinal functions has been described. However, such effects do not seem to play an important role in humans. During the last years, the major line of research has focussed on GLP-1, due to its promising potential for the treatment of type 2 diabetes mellitus. However, the physiological importance of GIP in the regulation of insulin secretion has been shown to even exceed that of GLP-1. Furthermore, work from various groups has provided evidence that GIP contributes to the pathogenesis of type 2 diabetes to a considerable degree. Recent data with modified GIP analogues further suggested a possibility of therapeutic use in the treatment of type 2 diabetes. Thus, it seems worthwhile to refocus on this important and-sometimes-neglected incretin hormone. The present work aims to review the physiological functions of GIP, to characterize its role in the pathogenesis of type 2 diabetes, and to discuss possible clinical applications and future perspectives in the light of new findings.     

胰升血糖素样肽-1及其受体与 2 型糖尿病的治疗

胰岛素对治疗 2 型糖尿病有一定效果,但长期使用会引起低血糖反应;双胍类药物降糖疗效显著,但会引起消化道不良反应 . 因此,寻找一种安全有效的药物是 2 型糖尿病治疗的当务之急 . 胰升血糖素样肽-1 作为一种胰岛素分泌促进剂和胰岛素增敏剂越来越受人们的关注,将它用于治疗糖尿病不会产生低血糖,对 1 型和 2 型糖尿病都有疗效 . 讨论胰升血糖素样肽-1及其受体的最新研究状况 .     

Prkar1a in the regulation of insulin secretion

The incidence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide with significant consequences on individual quality of life as well as economic burden on states' healthcare costs. While origins of the pathogenesis of T2DM are poorly understood, an early defect in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is considered a hallmark of T2DM 1.Upon a glucose stimulus, insulin is secreted in a biphasic manner with an early first-phase burst of insulin, which is followed by a second, more sustained phase of insulin output 2. First phase insulin secretion is diminished early in T2DM as well is in subjects who are at risk of developing T2DM 3 4 5 6.An effective treatment of T2DM with incretin hormone glucagon-like peptide-1 (GLP-1) or its long acting peptide analogue exendin-4 (E4), restores first-phase and augments second-phase glucose stimulated insulin secretion. This effect of incretin action occurs within minutes of GLP-1/E4 infusion in T2DM humans. An additional important consideration is that incretin hormones augment GSIS only above a certain glucose threshold, which is slightly above the normal glucose range. This ensures that incretin hormones stimulate GSIS only when glucose levels are high, while they are ineffective when insulin levels are below a certain threshold 7 8.Activation of the GLP-1 receptor, which is highly expressed on pancreatic β-cells, stimulates 2 -distinct intracellular signaling pathways: a) the cAMP-protein kinase A branch and b) the cAMP-EPAC2 (EPAC=exchange protein activated by cAMP) branch. While the EPAC2 branch is considered to mediate GLP-1 effects on first-phase GSIS, the PKA branch is necessary for the former branch to be active 9 10. However, how these 2 branches interplay and converge and how their effects on insulin secretion and insulin vesicle exocytosis are coordinated is poorly understood.Thus, at the outset of our studies we have a poorly understood intracellular interplay of cAMP-dependent signaling pathways, which - when stimulated - restore glucose-dependent first phase and augment second phase insulin secretion in the ailing β-cells of T2DM.