03-DK-0245 (Effect of AC2993 (synthetic exendin-4) on pancreatic islet function)

03-DK-0245（AC2993（合成exendin-4）对胰岛功能的影响）

• 批准号: 7734207
• 负责人: David Harlan
• 金额: $ 28.41万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734207
• 关键词: Antibodies; Antidiabetic Drugs; Arginine; Automobile Driving; Beta Cell; Binding; Biological Assay; Blood Glucose; C-Peptide; Cell Line; Cells; Chronic; Clinical; Crossover Design; Cyclic AMP; Daclizumab; Data; Data Collection; Diabetic Ketoacidosis; Employee Strikes; GLP-I receptor; Gastroenteritis; Gene Expression; Genes; Glucose; Glutamate Decarboxylase; Goals; Homeodomain Proteins; Human; Immune; Immune response; Immune system; Immunosuppression; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Lead; Life; Lizards; Manuscripts; Measurable; Mediating; Metabolic; Monitor; Muscle Cells; Names; Natural regeneration; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Onset of illness; Organ Transplantation; Pancreas; Participant; Patient Recruitments; Patients; Peptides; Phase; Process; Production; Proliferating; Protocols documentation; Publications; Purpose; Questionnaires; Race; Randomized; Rate; Recovery; Reporting; Research Personnel; Residual state; Rodent; Running; Serious Adverse Event; Serological; Speed; Stem cells; Structure of beta Cell of islet; Testing; Therapeutic immunosuppression; Thinking; Tissues; Treatment Protocols; United States National Institutes of Health; Update; Venoms; cell growth; exenatide; experience; glucagon like peptide; glucagon-like peptide; human study; insulin secretion; islet; novel; pancreatic islet function; pre-clinical; proglucagon

Type 1 diabetes mellitus (T1DM) typically results from immune mediated destruction of pancreatic beta cells. Previous studies indicate that some patients retain the capacity for limited endogenous insulin production. AC2993 (synthetic exendin-4) has been shown in preclinical and in preliminary human studies to have several potentially beneficial antidiabetic actions, including recovery and neogenesis of pancreatic islets. Purpose of this protocol: We investigated whether pancreatic insulin production can be enhanced in patients with long-standing T1DM (more than 5 years) by administering synthetic exendin-4, with or without concomitant immunosuppression (daclizumab). To be eligible, patients had evidence of some residual pancreatic insulin production as reflected by measurable circulating C-peptide (between 0.3 ng/ml and < 1.2 ng/ml). All patients received synthetic exendin-4 in a crossover design; half received immunosuppression with daclizumab. We assessed endogenous islet function with repeated arginine-stimulated C-peptide tests. The protocol also monitored glycemia control, insulin requirements, and assays to quantitate anti-islet immune responses. Background information: Considerable evidence, albeit indirect, supports the proposed chronic "race" between the immune system mediated islet destruction and a counter beta cell regenerative process. For instance, it is now well accepted that the anti-islet immune response exists for months and even years prior to T1DM onset. This observation is most intriguing since the immune system typically destroys targets with great efficiency and speed (e.g., the immune response leading to organ allograft rejection). While the gradual beta cell destruction could be due to immune regulatory processes bridling the destructive immune response, the fact that serologic evidence, e.g., anti-glutamic acid decarboxylase (GAD) antibodies persist in many patients with T1DM years after disease onset, suggests some persistence of the target cells driving the immune response. Further, ample data in rodents document that islet cell turnover persists at a low but steady rate throughout life, so islet regeneration can and does occur. Indeed, while controversial, a number of recent studies have demonstrated that a variety of tissues thought to have lost regenerative capacity (e.g., myocytes and neurons) can, under certain circumstances, be induced to proliferate. In 1992, Eng et al reported the isolation and characterization of exendin-4, a novel peptide from lizard venom that displays 52% identity to mammalian glucagon-like peptide (GLP 1). Exendin-4 was subsequently shown to bind the GLP 1 receptor, stimulate glucose-dependent insulin secretion, and increase both cAMP accumulation and insulin gene expression in cultured islet cell lines in vitro. More recently it has been found that GLP 1 induced activation of the GLP 1 receptor resulted in beta cell growth and differentiation by inducing the expression of the homeodomain protein IDX 1 (also known as PDX-1 or IPF-1) and that GLP 1 may lead to differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Though there is a striking homology between lizard exendin-4 and mammalian GLP 1 (a product of posttranslational processing of the proglucagon gene), it was determined that both are distinct peptides encoded by different genes and that there is no human equivalent of exendin-4. So far, all metabolic effects of exendin-4 appear to be mediated via the GLP 1 receptor. Synthetic exendin-4 (exenatide or Byetta (trade name)) has recently been approved for treatment in patients with type 2 diabetes and require insulin. Protocol update: Using the NIH patient recruitment center, more than 800 patients contacted the NIH patient recruitment center and were sent a questionnaire of which 150 were returned. Seventy-two patients were invited, we screened 43 patients, 23 patients were rejected for clinical reasons, and 20 patients were randomized. Fourteen patients completed the entire trial. Another 6 patients terminated their participation early. First, patients completed the run-in protocol phase during which their baseline C-peptide producing capacity was assessed over 4 months with three arginine stimulation tests while the patients' blood glucose was maintained as closely to normal as possible. Thereafter, the patients entered study period A, then study period B (each 6-month duration) during which they received AC2993 (for 6 months) with or without daclizumab. Then followed a 3-month extension during which the patients remained on the treatment regimen administered in period B. One of our patients has experienced a serious adverse event (diabetic ketoacidosis in association with gastroenteritis). All participants recently completed active protocol participation. Data collection has been completed and final statistical analyses are underway. Study investigators anticipate submitting several manuscripts for publication within the next fiscal year.

1型糖尿病(T1 DM)通常是由免疫介导的胰岛β细胞破坏引起的。以前的研究表明，一些患者保留了有限的内源性胰岛素产生能力。AC2993(人工合成的exendin-4)已经在临床前和初步的人类研究中被证明具有几种潜在的有益的抗糖尿病作用，包括胰岛的恢复和新生。 该方案的目的：我们研究了长期存在的T1 DM患者(超过5年)是否可以通过给予合成的exendin-4，在伴随或不伴随免疫抑制(Daclizumab)的情况下促进胰腺胰岛素的产生。符合条件的患者有证据表明，可测量的循环C-肽(在0.3 ng/ml和1.2 ng/ml之间)反映了一些残余的胰腺胰岛素产生。所有患者都接受了交叉设计的合成exendin-4；一半患者接受了Daclizumab的免疫抑制。我们用重复的精氨酸刺激的C-肽试验评估内源性胰岛功能。该方案还监测了血糖控制、胰岛素需求和量化抗胰岛免疫反应的方法。 背景信息：大量的证据，尽管是间接的，支持免疫系统介导的胰岛破坏和反β细胞再生过程之间的慢性“竞赛”。例如，现在公认的是，在T1 DM发病前几个月甚至几年内，抗胰岛免疫反应就已经存在了。这一观察结果最耐人寻味，因为免疫系统通常以极高的效率和速度摧毁目标(例如，导致器官移植排斥反应的免疫反应)。虽然β细胞的逐渐破坏可能是由于免疫调节过程抑制了破坏性的免疫反应，但事实上，许多T1 DM患者在发病数年后仍存在抗谷氨酸脱羧酶(GAD)抗体的事实表明，驱动免疫反应的靶细胞具有一定的持久性。此外，啮齿动物的大量数据表明，胰岛细胞在一生中以低但稳定的速度持续更新，因此胰岛再生可以而且确实发生。事实上，尽管存在争议，但最近的一些研究表明，在某些情况下，各种被认为已经失去再生能力的组织(如肌细胞和神经元)可以被诱导增殖。 1992年，Eng等人报道了从蜥蜴毒中分离出的一种新的多肽exendin-4，它与哺乳动物胰高血糖素样肽(GLP-1)有52%的同源性。在体外培养的胰岛细胞系中，Exendin-4被证明能结合GLP-1受体，刺激葡萄糖依赖的胰岛素分泌，并增加cAMP积聚和胰岛素基因表达。最近发现，GLP-1通过诱导同源结构域蛋白IDX-1(也称为PDX-1或IPF-1)的表达而激活GLP-1受体，从而导致β细胞的生长和分化，并且GLP-1可能导致人胰岛来源的祖细胞分化为胰岛素产生细胞。虽然蜥蜴的exendin-4与哺乳动物的GLP-1(原胰高血糖素基因的翻译后处理产物)有惊人的同源性，但已确定两者是由不同基因编码的不同的多肽，并且人类没有等同的exendin-4。到目前为止，exendin-4的所有代谢效应似乎都是通过GLP 1受体介导的。合成exendin-4(exenatide或Byetta(商标))最近已被批准用于治疗需要胰岛素的2型糖尿病患者。 方案更新：通过NIH患者招募中心，800多名患者联系了NIH患者招募中心，并收到了一份问卷，其中150份被收回。我们邀请了72名患者，我们筛选了43名患者，23名患者因临床原因被拒绝，20名患者被随机分组。14名患者完成了整个试验。另有6例患者提前终止参与。首先，患者完成磨合程序阶段，在此期间，通过三次精氨酸刺激试验在4个月内评估他们的基线C肽产生能力，同时患者的血糖尽可能保持在正常水平。此后，患者进入研究期A，然后进入研究期B(每个为期6个月)，在此期间，他们接受AC2993(为期6个月)加或不加达利珠单抗。然后延长3个月，在此期间，患者继续接受B期给药方案，其中一名患者经历了严重的不良事件(糖尿病酮症酸中毒合并胃肠炎)。 所有参与者最近都完成了积极的礼仪参与。数据收集工作已经完成，最后的统计分析正在进行中。研究调查人员预计将在下一财年提交几份手稿供出版。