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（由应用程序提供）：本申请旨在在Cedars-Sinai医疗中心建立临床中心（CC），以进行慢性胰腺炎（CP），糖尿病和胰腺癌（RFA-DK-14-027）进行研究。博士。斯蒂芬·潘多尔（Stephen Pandol）和马克·古德尔兹（Mark Goodarzi）（PDS）召集了一支胃肠病学家，内分泌学家，生理学家和流行病学家，他们渴望在转化胰腺研究中合作。除了临床投资和前瞻性随访研究的记录外，我们在洛杉矶县（> 900万居民）的所在地还提供了通过UCLA的临床伙伴和该地区其他大型医疗中心的临床伙伴，为潜水员人群提供了财团研究机会。我们还与来自奥克兰（新西兰）的生产性胰腺学同事合作。拟议的研究将阐明CP中葡萄糖摄入的基础机制。大多数CP患者都会发展胰腺生成糖尿病（即3C糖尿病，T3CDM）。胰腺炎和糖尿病患者患胰腺炎的风险增加了33倍。预防胰腺炎进展和糖尿病（因此胰腺癌）是财团的关键目标。一旦实施了财团，将提出下面的研究旨在向指导委员会提出的研究：目标1。检验假说，即患有糖尿病前期糖尿病的慢性胰腺炎患者具有胰岛素抵抗和胰岛素分泌受损。有或没有CP的患者，并且没有和没有糖尿病前（4组）将接受经常采样的静脉葡萄糖耐受性测试和混合饮食耐受性测试，以表征胰岛素抵抗，胰岛素分泌，胰岛素清除率；以及肠静脉素和胰岛激素反应。在关注糖尿病前期时，该目标将确定易于T3CDM的早期缺陷。 AIM 2。检验以下假设：慢性胰腺炎的胰腺酶不足会导致降量蛋白蛋白的反应增加，因此导致胰岛素分泌不足。具有CP和糖尿病前期的AIM 1的受试者将通过2周的胰酶补充（PES）进行治疗，然后进行重复的生理评估。预计PES会导致对餐食的增加增加，从而改善胰岛素分泌和葡萄糖水平的降低。目标3。检验二甲双胍治疗将防止急性复发性和慢性胰腺炎患者糖尿病的发展的假设。二甲双胍预防3C糖尿病的能力尚不清楚。在这些患者中，我们将对二甲双胍与安慰剂进行预防糖尿病研究。 CP和胰腺癌研究的研究需要潜水的领导力和多个临床部位。我们为CC组装了专家，并不总是针对拟议的目标，以表彰其优化财团潜力所需的广泛经验和专业知识的范围。我们致力于与NIDDK/NCI，其他CCS以及协调和数据管理中心互动。