Pathophysiology, Epidemiology, and Prevention of Pancreatogenic Diabetes

 描述(申请人提供)：此申请旨在建立一个临床中心(CC)在锡达斯-西奈医学中心，以进行研究慢性胰腺炎(CP)，糖尿病和胰腺癌(RFA-DK-14-027)。Stephen Pandol博士和Mark Goodarzi博士(PDS)已经组建了一个由胃肠病专家、内分泌学家、生理学家和流行病学家组成的团队，他们渴望在转换胰腺研究联盟中进行合作。除了作为拟议CC基础的临床研究和前瞻性跟踪研究方面的记录外，我们位于洛杉矶县(&gt；900万居民)的位置为财团提供了通过我们在加州大学洛杉矶分校和该地区其他大型医疗中心的临床合作伙伴在不同人群中进行研究的机会。我们还与来自奥克兰(新西兰)的多产胰腺科同事进行了合作。这项拟议的研究将阐明慢性胰腺炎患者糖耐量异常的机制。胰源性糖尿病(即3c型糖尿病，T3cDM)在大多数CP患者中发生。同时患有胰腺炎和糖尿病的患者患胰腺癌的风险增加了33倍。预防胰腺炎进展和糖尿病(从而预防胰腺癌)是该联盟的关键目标。以下概述了一旦该联盟实施后将向指导委员会提出的研究目标：目的1.检验慢性胰腺炎合并糖尿病前期患者存在胰岛素抵抗和胰岛素分泌受损的假设。患有和不患有CP的患者以及有和不有糖尿病前期(4组)的患者将接受频繁采样的静脉葡萄糖耐量试验和混合膳食耐量试验，以表征胰岛素抵抗、胰岛素分泌、胰岛素清除以及胰岛素和胰岛激素反应。在专注于糖尿病前期的过程中，这一目标将确定易患T3cDM的早期缺陷。目的2.验证慢性胰腺炎患者胰酶功能不全导致胰岛素反应减弱，从而导致胰岛素分泌不足的假说。来自AIM 1的患有CP和前驱糖尿病的受试者将接受为期2周的胰酶补充(PES)治疗，随后进行重复的生理评估。预计PES将导致对进餐的胰岛素反应增强，从而改善胰岛素分泌和降低血糖水平。目的3.验证二甲双胍治疗将预防急性复发性和慢性胰腺炎患者发生糖尿病的假设。二甲双胍预防3c型糖尿病的能力尚不清楚。我们将在这些患者中进行二甲双胍与安慰剂的糖尿病预防研究。CP和胰腺癌的研究需要不同的领导和多个临床地点。我们已经为我们的CC召集了专家，他们的技能并不总是满足拟议的目标，因为我们认识到优化财团潜力所需的广泛经验和专业知识。我们致力于与NIDDK/NCI、其他CCS以及协调和数据管理中心进行互动。

 DESCRIPTION (provided by applicant): This application seeks to establish a Clinical Center (CC) at Cedars-Sinai Medical Center to conduct studies on chronic pancreatitis (CP), diabetes, and pancreatic cancer (RFA-DK-14-027). Drs. Stephen Pandol and Mark Goodarzi (PDs) have assembled a team of gastroenterologists, endocrinologists, physiologists, and epidemiologists who are eager to collaborate in the Consortium in translational pancreatic research. Aside from a track record in clinical investigation and prospective follow-up studies that are the foundation for the proposed CC, our location in Los Angeles County (>9 million inhabitants) affords the Consortium research opportunities in diverse populations through our clinical partners at UCLA and other large medical centers in the region. We have also partnered with productive pancreatology colleagues from Auckland (New Zealand). The proposed studies will elucidate the mechanisms underlying glucose intolerance in CP. Pancreatogenic diabetes (i.e., Type 3c diabetes, T3cDM) develops in most individuals with CP. The risk for pancreatic cancer in patients with both pancreatitis and diabetes is increased 33-fold. Prevention of pancreatitis progression and diabetes (and thus pancreatic cancer) is a critical goal of the Consortium. The following outlines study aims that will be proposed to the Steering Committee once the Consortium is implemented: Aim 1. Test the hypothesis that chronic pancreatitis patients with prediabetes have insulin resistance as well as impaired insulin secretion. Patients with and without CP and with and without prediabetes (4 groups) will undergo the frequently-sampled intravenous glucose tolerance test and mixed meal tolerance tests to characterize insulin resistance, insulin secretion, insulin clearance; and incretin and islet hormonal responses. In focusing on prediabetes, this Aim will identify early defects that predispose to T3cDM. Aim 2. Test the hypothesis that pancreatic enzyme insufficiency in chronic pancreatitis leads to attenuated incretin responses and consequent deficient insulin secretion. The subjects from Aim 1 who have CP and prediabetes will be treated with 2 weeks of pancreatic enzyme supplementation (PES), followed by a repeat physiologic evaluation. It is anticipated that PES will result in augmented incretin responses to a meal, resulting in improved insulin secretion and reduction in glucose levels. Aim 3. Test the hypothesis that metformin treatment will prevent development of diabetes in patients with acute recurrent and chronic pancreatitis. The ability of metformin to prevent Type 3c diabetes is unknown. We will conduct a diabetes prevention study of metformin versus placebo in these patients. Research in CP and pancreatic cancer research requires diverse leadership and multiple clinical sites. We have assembled experts for our CC with skills not always addressing the proposed Aims in recognition of the broad scope of experience and expertise needed to optimize the Consortium's potential. We are committed to interaction with the NIDDK/NCI, the other CCs, and the Coordination and Data Management Center.