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: 7593679
• 负责人: David Harlan
• 金额: $ 32.47万
• 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/7593679
• 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; 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; Laboratories; 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 receive 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. Clinical and laboratory data are now being collated and analyzed. Study investigators anticipate submitting several manuscripts for publication within the next fiscal year.

1型糖尿病（T1 DM）通常由免疫介导的胰腺β细胞破坏引起。 先前的研究表明，一些患者保留了有限的内源性胰岛素产生的能力。 AC 2993（合成毒蜥外泌肽-4）已在临床前和初步人体研究中显示具有几种潜在的有益抗糖尿病作用，包括胰岛的恢复和新生。 本方案的目的：我们研究了在长期T1 DM（超过5年）患者中，通过给予合成exendin-4，伴随或不伴随免疫抑制（daclizumab），是否可以增强胰腺胰岛素的产生。 为了合格，患者具有一些残余胰腺胰岛素产生的证据，如通过可测量的循环C肽（在0.3ng/ml和<1.2ng/ml之间）所反映的。 所有患者在交叉设计中接受合成exendin-4;一半接受daclizumab的免疫抑制。 我们用重复的精氨酸刺激C肽试验评估内源性胰岛功能。 该方案还监测了胰岛素控制、胰岛素需求和定量抗胰岛免疫应答的测定。 背景资料：相当多的证据，尽管是间接的，支持所提出的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，抗胰岛免疫应答在T1 DM发作前存在数月甚至数年。 这一观察结果是最有趣的，因为免疫系统通常以极大的效率和速度破坏靶标（例如，导致器官同种异体移植排斥的免疫反应）。 虽然β细胞的逐渐破坏可能是由于抑制破坏性免疫反应的免疫调节过程，但血清学证据，例如，抗谷氨酸脱羧酶（GAD）抗体在许多T1 DM患者发病数年后持续存在，表明驱动免疫应答的靶细胞具有一定的持续性。 此外，啮齿动物的大量数据证明，胰岛细胞的更新在整个生命过程中持续以低但稳定的速率进行，因此胰岛再生可以并且确实发生。 事实上，尽管存在争议，但最近的一些研究表明，许多被认为失去再生能力的组织（例如，肌细胞和神经元）在某些情况下可以被诱导增殖。 1992年，Eng等报道了毒蜥外泌肽-4的分离和表征，毒蜥外泌肽-4是一种来自蜥蜴毒液的新肽，与哺乳动物胰高血糖素样肽（GLP 1）具有52%的同一性。 Exendin-4随后显示结合GLP 1受体，刺激葡萄糖依赖性胰岛素分泌，并在体外培养的胰岛细胞系中增加cAMP积累和胰岛素基因表达。最近，已经发现GLP 1诱导的GLP 1受体的活化通过诱导同源结构域蛋白IDX 1（也称为PDX-1或IPF-1）的表达而导致β细胞生长和分化，并且GLP 1可以导致人胰岛衍生的祖细胞分化为胰岛素产生细胞。尽管蜥蜴毒蜥外泌肽-4和哺乳动物GLP 1（胰高血糖素原基因翻译后加工的产物）之间存在惊人的同源性，但已确定两者都是由不同基因编码的不同肽，并且没有毒蜥外泌肽-4的人类等同物。到目前为止，毒蜥外泌肽-4的所有代谢作用似乎都是通过GLP 1受体介导的。合成的exendin-4（exendin或Byetta（商品名））最近已被批准用于治疗2型糖尿病患者，并需要胰岛素。 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份被退回。72名患者被邀请，我们筛选了43名患者，23名患者因临床原因被拒绝，20名患者被随机分配。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，患者完成导入方案阶段，在此期间，在4个月内用三次精氨酸刺激试验评估其基线C肽产生能力，同时患者的血糖尽可能接近正常。 此后，患者进入研究阶段A，然后进入研究阶段B（每6个月持续时间），在此期间他们接受AC 2993（持续6个月）联合或不联合达克珠单抗。然后进行3个月的扩展，在此期间患者继续接受阶段B的治疗方案。我们的一名患者发生了严重不良事件（糖尿病酮症酸中毒与胃肠炎相关）。 所有参与者最近都完成了主动方案参与。 目前正在整理和分析临床和实验室数据。 研究者预计在下一个财政年度内提交几份手稿供出版。