Pathophysiology, Epidemiology, and Prevention of Pancreatogenic Diabetes

胰源性糖尿病的病理生理学、流行病学和预防

• 批准号: 9150584
• 负责人: Mark Goodarzi
• 金额: $ 45.93万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-28 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150584
• 关键词: Acute; Address; Alcohols; Attenuated; Beta Cell; Blood Glucose; California; Cancer Etiology; Cell physiology; Cells; Cessation of life; Clinical; Conflict (Psychology); County; Defect; Desmoplastic; Development; Diabetes Mellitus; Diabetes prevention; Disease; Endocrinologist; Endocrinology; Environment; Epidemic; Epidemiologist; Epidemiology; Evaluation; Exocrine pancreas; Exocrine pancreatic insufficiency; Fatality rate; Foundations; Functional disorder; Gastroenterologist; Gastroenterology; Glucose; Glucose Intolerance; Glucose Metabolism Disorders; Goals; Health; High Fat Diet; Hormonal; Incidence; Individual; Inflammatory; Injury; Insulin; Insulin Resistance; Intervention; Intervention Studies; Investigation; Islets of Langerhans; Knowledge; Lead; Leadership; Location; Los Angeles; Malignant neoplasm of pancreas; Medical center; Metformin; Modality; National Institute of Diabetes and Digestive and Kidney Diseases; New Zealand; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pancreatic Polypeptide; Pancreatic enzyme; Pancreatitis; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Physiological; Physiology; Placebos; Play; Population Heterogeneity; Prediabetes syndrome; Prevention; Preventive therapy; Process; Public Health; Publishing; Recurrence; Research; Research Design; Research Personnel; Risk; Risk Factors; Role; Sampling; Smoking; Supplementation; Testing; Time; United States; Vulnerable Populations; acute pancreatitis; anticancer research; arm; blood glucose regulation; chronic pancreatitis; clinical investigation; clinical research site; data management; design; ethnic diversity; experience; follow-up; gastric inhibitory polypeptide receptor; glucagon-like peptide; hepatic gluconeogenesis; improved; innovation; insulin secretion; intravenous glucose tolerance test; islet; patient subsets; prevent; prospective; response; skills

 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.

 描述（由申请人提供）：本申请旨在在 Cedars-Sinai 医疗中心建立一个临床中心 (CC)，以开展慢性胰腺炎 (CP)、糖尿病和胰腺癌 (RFA-DK-14-027) 的研究。博士。 Stephen Pandol 和 Mark Goodarzi (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方面与联盟合作。除了作为拟议 CC 基础的临床调查和前瞻性后续研究记录外，我们位于洛杉矶县（超过 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提供了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）的富有成效的胰腺学同事合作。拟议的研究将阐明 CP 中葡萄糖不耐受的潜在机制。大多数 CP 患者都会发生胰源性糖尿病（即 3c 型糖尿病，T3cDM）。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）是该联盟的一个重要目标。以下概述了联盟实施后将向指导委员会提出的研究目标： 目标 1. 检验患有糖尿病前期的慢性胰腺炎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以及患有和不患有糖尿病前期的患者（4组）将进行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；以及肠促胰岛素和胰岛激素反应。该目标重点关注糖尿病前期，将识别易患 T3cDM 的早期缺陷。目标 2. 检验以下假设：慢性胰腺炎中胰酶不足会导致肠促胰素反应减弱，进而导致胰岛素分泌不足。目标 1 中患有 CP 和糖尿病前期的受试者将接受为期 2 周的胰酶补充剂 (PES) 治疗，然后重复进行生理评估。预计 PES 将增强肠促胰岛素对膳食的反应，从而改善胰岛素分泌并降低血糖水平。目标 3. 检验二甲双胍治疗可预防急性复发性和慢性胰腺炎患者发展为糖尿病的假设。二甲双胍预防 3c 型糖尿病的能力尚不清楚。我们将对这些患者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元化的领导和多个临床中心。我们为我们的 CC 召集了专家，他们的技能并不总能解决拟议的目标，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。