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

描述（由申请人提供）：本申请涉及广泛挑战领域（04）临床研究和特定挑战主题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紊乱，其折磨1800万美国人，每年估计花费约1700亿美元。世界范围内的患病率和发病率正在增加，这种疾病威胁到美国和其他国家的卫生保健系统。2型糖尿病（T2 DM）是最常见的糖尿病形式，占病例的80%以上。目前的T2 DM治疗具有显著的局限性。疗效通常是短暂的，并且已经报告了潜在的严重副作用，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，T2 DM并发症是发病率和死亡率的主要原因。一段时间以来，已知肠内分泌细胞产生和分泌的肽部分通过增强胰岛素对葡萄糖的分泌反应而在葡萄糖代谢中起主要作用。调节胰高血糖素样肽-1（GLP-1）（一种由肠L细胞产生的肠肽）的作用或血浆浓度是最近批准的两种新型T2 DM治疗方法的作用基础，目前已广泛用于临床。因此，有相当大的兴趣，以确定是否其他肠肽可以发挥类似的作用。虽然葡萄糖依赖性促胰岛素多肽增加了健康个体中葡萄糖刺激的胰岛素释放，但这种肠K细胞的肽产物在T2 DM患者中无活性。在缺乏K细胞的转基因小鼠的研究过程中，我们已经确定，xenin-25，K细胞的第二肽产物，通过增强胰岛素分泌反应葡萄糖依赖性促胰岛素多肽（GIP）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刺激从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。这一出乎意料的发现不仅对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T2 DM中的作用。基于这些初步数据，本申请提出在患有T2 DM的人和具有正常葡萄糖耐量的匹配对照中进行概念验证临床试验，以确定单独的或与GIP组合的氙-25是否增加T2 DM中的内源性胰岛素分泌。在具体目标1中，我们将确定异种蛋白-25是否增强对外源性输注的GIP的胰岛素分泌应答，在具体目标2中，我们将确定异种蛋白-25是否增强对内源性分泌的GIP的胰岛素分泌应答。挑战奖将产生的具体成果包括：1。明确xenin-25在正常人胰岛素分泌调节中的作用; 2.明确xenin-25在2型糖尿病患者胰岛素分泌调节中的作用; 3.测定氙-25或模拟其作用模式的化合物用于治疗T2 DM的潜力。 公共卫生相关性：美国糖尿病协会[Diabetes Care，31：1-2，（2008）]指出，仅在美国，超过1750万人已被诊断患有2型糖尿病（T2 DM），相关的年经济负担超过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T2 DM。拟议的研究将确定一种名为xenin-25的肠肽是否可用于治疗T2 DM。如果是这样，这将对人类健康产生巨大的积极影响。

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.