A PROOF-OF-CONCEPT CLINICAL TRIAL OF XENIN-25 IN THE TREATMENT OF TYPE 2 DIABETES

XENIN-25 治疗 2 型糖尿病的概念验证临床试验

基本信息

批准号：
7814484
负责人：
KENNETH S POLONSKY
金额：
$ 50万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-20 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7814484
关键词：
Accounting Acetylcholine Address Adverse effects American Area Attenuated Award Biological Preservation Cardiovascular system Caring Cell Survival Cells Clinical Clinical Research Clinical Trials Country Data Diabetes Mellitus Diagnosis Disease Economic Burden Economics Elements Endocrine Engineering Enteroendocrine Cell Epidemic Exhibits Expenditure Glucose Glucose Plasma Concentration Goals Grant Health Healthcare Systems Human Incidence Individual Infusion procedures Ingestion Insulin Intestines Islet Cell Islets of Langerhans Killer Cells L Cells Laboratories Life Mediating Metabolic Diseases Morbidity - disease rate Mus Muscarinic Acetylcholine Receptor Neurons Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Nutrient Oral Pancreas Peptides Performance Persons Physiological Physiology Plasma Play Prevalence Prevention approach Publishing Quality of life Reagent Recovery Regulation Regulatory Element Reporting Resistance Resources Role Small Intestines Stimulus Therapeutic Time Transgenic Mice United States Universities Vendor Washington base cost diabetic diphtheria toxin fragment A gastric inhibitory polypeptide receptor glucagon-like peptide 1 glucose metabolism glucose tolerance health care quality healthy volunteer human subject improved insulin secretion interest islet meetings mortality mouse model novel payment programs promoter public health relevance research study response volunteer

项目摘要

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area (04) Clinical Research and specific Challenge Topic, 04-DK-106: Preservation/Recovery of endogenous insulin secretion. Diabetes is a serious and common metabolic disorder that afflicts 18 million Americans with an annual estimated cost of approximately $170 billion per year. The prevalence and incidence are increasing worldwide and this disease threatens to overwhelm the health care systems in the United States and other countries. Type 2 diabetes mellitus (T2DM) is the commonest form of diabetes accounting for well over 80% of cases. Current therapies for T2DM have significant limitations. Efficacy is frequently short lived and potentially serious side effects particularly in the cardiovascular system have been reported. Only a small proportion of diabetics achieve treatment targets and as a result, complications of T2DM are a major cause of morbidity and mortality. It has been known for some time that peptides produced and secreted by endocrine cells in the intestine play a major role in glucose metabolism in part by enhancing the insulin secretory response to glucose. Modulating the action or plasma concentrations of Glucagon- Like Peptide-1 (GLP-1), an intestinal peptide produced by intestinal L cells, is the basis for the action of two novel treatments of T2DM that have recently been approved and are now in widespread clinical use. There is thus considerable interest in determining whether other intestinal peptides could play a similar role. Although Glucose-dependent Insulinotropic Polypeptide increases glucose-stimulated insulin release in healthy individuals, this peptide product of the intestinal K cells is inactive in persons with T2DM. In the course of studies in transgenic mice engineered to lack K cells, we have determined that xenin-25, a second peptide product of the K cell, regulates insulin secretion specifically by enhancing insulin secretory responses to Glucose-Dependent Insulinotropic Polypeptide (GIP). The mechanism of xenin-25 action is also novel because preliminary results indicate that xenin-25 does not act directly on the pancreatic -cell. Rather, xenin-25 stimulates acetylcholine release from parasympathetic neurons that innervate the islets and this neurotransmitter then activates muscarinic receptors on the pancreatic islet -cell. This unexpected finding is not only of interest and importance for understanding the physiology of insulin secretion, but suggests a role for xenin-25 in the treatment of T2DM by enhancing endogenous insulin secretion. Based on these preliminary data, the present application proposes to conduct a proof-of-concept clinical trial in humans with T2DM and matched controls with normal glucose tolerance to determine whether xenin-25 either alone or in combination with GIP increases endogenous insulin secretion in T2DM. In Specific Aim 1 we will determine whether xenin-25 enhances the insulin secretory response to exogenously infused GIP and in Specific Aim 2 we will determine whether xenin-25 enhances the insulin secretory response to endogenously secreted GIP. The specific deliverables that will result from the Challenge Award include: 1. Definition of the role of xenin-25 in regulation of insulin secretion in normal subjects; 2. Definition of the role of xenin-25 in regulating insulin secretion in persons with T2DM; 3. Determination of the potential for xenin-25 or compounds that mimic its mode of action to be used in the treatment of T2DM. PUBLIC HEALTH RELEVANCE: The American Diabetes Association [Diabetes Care, 31:1-2, (2008)] points out that in the United States alone, greater than 17.5 million persons have been diagnosed with type 2 diabetes mellitus (T2DM) with an associated yearly economic burden exceeding $174 billion. The incidence of the disease is increasing rapidly on a worldwide basis with staggering impact on cost of healthcare and quality of life. Thus, there is an urgent need to develop new and improved approaches to the prevention and treatment of T2DM. The proposed studies will determine whether an intestinal peptide called xenin-25 could be used to treat T2DM. If so, this would have a dramatic positive impact on human health.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (04) 临床研究和具体挑战主题 04-DK-106：内源性胰岛素分泌的保存/恢复。糖尿病是一种严重且常见的代谢性疾病，困扰着 1800 万美国人，每年造成的损失估计约为 1700 亿美元。全球范围内的患病率和发病率正在增加，这种疾病有可能使美国和其他国家的医疗保健系统不堪重负。 2 型糖尿病 (T2DM) 是最常见的糖尿病形式，占糖尿病病例的 80% 以上。目前 T2DM 的治疗方法有很大的局限性。据报道，疗效常常是短暂的，并且有潜在的严重副作用，特别是在心血管系统中。只有一小部分糖尿病患者达到治疗目标，因此，T2DM 并发症是发病和死亡的主要原因。一段时间以来，人们已经知道肠道内分泌细胞产生和分泌的肽在葡萄糖代谢中发挥着重要作用，部分原因是增强胰岛素对葡萄糖的分泌反应。调节胰高血糖素样肽-1 (GLP-1)（一种由肠道 L 细胞产生的肠肽）的作用或血浆浓度是最近获得批准并广泛应用的两种 T2DM 新疗法的作用基础临床使用。因此，人们对确定其他肠肽是否可以发挥类似的作用非常感兴趣。尽管葡萄糖依赖性促胰岛素多肽可增加健康个体中葡萄糖刺激的胰岛素释放，但肠道 K 细胞的这种肽产物在 T2DM 患者中没有活性。在对缺乏 K 细胞的转基因小鼠进行研究过程中，我们确定 K 细胞的第二种肽产物 xenin-25 通过增强对葡萄糖依赖性促胰岛素多肽 (GIP) 的胰岛素分泌反应来特异性调节胰岛素分泌。 xenin-25 的作用机制也很新颖，因为初步结果表明 xenin-25 不直接作用于胰腺细胞。相反，xenin-25 刺激支配胰岛的副交感神经元释放乙酰胆碱，然后这种神经递质激活胰岛细胞上的毒蕈碱受体。这一意外发现不仅对于了解胰岛素分泌的生理学具有重要意义，而且表明 xenin-25 通过增强内源性胰岛素分泌在治疗 T2DM 中发挥作用。基于这些初步数据，本申请提出在患有T2DM的人和具有正常糖耐量的对照对照中进行概念验证临床试验，以确定xenin-25单独或与GIP组合是否增加T2DM中的内源性胰岛素分泌。在具体目标 1 中，我们将确定 xenin-25 是否增强对外源输注 GIP 的胰岛素分泌反应，在具体目标 2 中，我们将确定 xenin-25 是否增强对外源分泌 GIP 的胰岛素分泌反应。挑战奖的具体成果包括： 1. xenin-25 在正常受试者胰岛素分泌调节中的作用的定义； 2. xenin-25在调节T2DM患者胰岛素分泌中的作用的定义； 3.确定xenin-25或模拟其作用方式的化合物用于治疗T2DM的潜力。公共健康相关性：美国糖尿病协会 [Diabetes Care, 31:1-2, (2008)] 指出，仅在美国，就有超过 1750 万人被诊断患有 2 型糖尿病 (T2DM)，并伴有相关疾病。每年的经济负担超过1740亿美元。该疾病的发病率在全球范围内迅速增加，对医疗保健成本和生活质量产生了惊人的影响。因此，迫切需要开发新的和改进的方法来预防和治疗 T2DM。拟议的研究将确定一种名为 xenin-25 的肠肽是否可用于治疗 T2DM。如果是这样，这将对人类健康产生巨大的积极影响。