Pathophysiology, Epidemiology, and Prevention of Pancreatogenic Diabetes

 描述（由申请人提供）：本申请旨在在Cedars-Sinai Medical Center建立临床中心（CC），以开展慢性胰腺炎（CP）、糖尿病和胰腺癌研究（RFA-DK-14-027）。Stephen Pandol博士和Mark Goodarzi博士（PD）组建了一个由胃肠病学家，内分泌学家，生理学家和流行病学家组成的团队，他们渴望在转化胰腺研究的联盟中合作。除了临床研究和前瞻性随访研究的跟踪记录是拟议CC的基础之外，我们在洛杉矶县（> 900万居民）的位置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为联盟在不同人群中提供研究机会。我们还与来自奥克兰（新西兰）的富有成效的胰腺病学同事合作。这些研究将有助于阐明CP葡萄糖耐受不良的机制。胰源性糖尿病（即，3c型糖尿病（T3 cDM）在大多数CP患者中发展。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（以及胰腺癌）是该联盟的关键目标。以下概述了一旦联盟实施将向指导委员会提出的研究目标：目标1。检验慢性胰腺炎伴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的患者以及患有和不患有前驱糖尿病的患者（4组）将接受频繁采样的静脉内葡萄糖耐量试验和混合餐耐量试验，以表征胰岛素抵抗、胰岛素分泌、胰岛素清除以及肠促胰岛素和胰岛激素反应。在关注前驱糖尿病时，该目标将确定易患T3 cDM的早期缺陷。目标2.检验慢性胰腺炎中胰酶不足导致肠促胰岛素反应减弱和胰岛素分泌不足的假设。目标1中患有CP和前驱糖尿病的受试者将接受2周的胰酶补充（PES）治疗，然后重复进行生理学评价。预计PES将导致对膳食的肠促胰岛素反应增强，从而改善胰岛素分泌并降低葡萄糖水平。目标3.验证二甲双胍治疗可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和胰腺癌研究需要多样化的领导和多个临床研究中心。我们已经为我们的CC召集了专家，他们的技能并不总是解决拟议的目标，这是因为我们认识到优化联盟潜力所需的广泛经验和专业知识。我们致力于与NIDDK/NCI、其他CC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.