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

描述（由申请人提供）：该申请涉及广泛的挑战领域（04）临床研究和特定的挑战主题，04- dk -106：内源性胰岛素分泌的保存/恢复。糖尿病是一种严重而常见的代谢紊乱疾病，每年约有1800万美国人患有糖尿病，据估计每年的成本约为1700亿美元。在世界范围内，这种疾病的患病率和发病率都在上升，这种疾病有可能使美国和其他国家的卫生保健系统不堪重负。2型糖尿病（T2DM）是最常见的糖尿病，占所有病例的80%以上。目前治疗T2DM的方法有明显的局限性。疗效通常是短暂的，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了治疗目标，因此，2型糖尿病的并发症是发病和死亡的主要原因。一段时间以来，人们已经知道肠内内分泌细胞产生和分泌的肽在葡萄糖代谢中起主要作用，部分原因是通过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）的作用或血浆浓度，胰高血糖素样肽-1是肠道L细胞产生的一种肠道肽，是最近批准并广泛应用于临床的两种新型T2DM治疗方法的基础。因此，确定其他肠道肽是否能发挥类似的作用是相当有兴趣的。虽然葡萄糖依赖性胰岛素依赖性多肽在健康个体中增加葡萄糖刺激的胰岛素释放，但这种肠K细胞的肽产物在T2DM患者中不活跃。在对缺乏K细胞的转基因小鼠的研究过程中，我们确定了K细胞的第二种肽产物xenin-25，通过增强胰岛素分泌对葡萄糖依赖性胰岛素性多肽（GIP）的反应来特异性调节胰岛素分泌。xenin-25的作用机制也是新颖的，因为初步结果表明xenin-25不直接作用于胰腺细胞。相反，xenin-25刺激控制胰岛的副交感神经释放乙酰胆碱，然后这种神经递质激活胰岛细胞上的毒蕈碱受体。这一意想不到的发现不仅对理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T2DM治疗中的作用。基于这些初步数据，本申请建议在T2DM患者和糖耐量正常的对照人群中进行概念验证临床试验，以确定xenin-25单独使用或与GIP联合使用是否会增加T2DM患者的内源性胰岛素分泌。在Specific Aim 1中，我们将确定xenin-25是否会增强外源性输注GIP对胰岛素分泌的反应；在Specific Aim 2中，我们将确定xenin-25是否会增强内源性分泌的GIP对胰岛素分泌的反应。挑战奖将产生的具体可交付成果包括：xenin-25在正常人胰岛素分泌调节中的作用2. xenin-25在T2DM患者胰岛素分泌调节中的作用3. 确定xenin-25或类似其作用模式的化合物用于治疗2型糖尿病的可能性。

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.