The Exocrine and Endocrine Pancreas in Type 2 Diabetes, Pancreatitis and Cancer

2 型糖尿病、胰腺炎和癌症中的外分泌和内分泌胰腺

• 批准号: 9352320
• 负责人: SURESH T. CHARI
• 金额: $ 42.93万
• 依托单位: MAYO CLINIC ROCHESTER
• 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/9352320
• 关键词: Address; Amyloid; Anatomy; Aspirin; Atrophic; Autopsy; Bicarbonates; Biological Markers; Blinded; Blood; C-Peptide; Cicatrix; Clinical; Clinical Research; Clinical Trials; Collaborations; Complex; Data; Diabetes Mellitus; Diagnosis; Diagnostic tests; Digestive System Disorders; Digital Libraries; Dinoprostone; Disease; Dyspepsia; Early Diagnosis; Early treatment; Endocrine; Endocrine System Diseases; Evaluation; Exocrine pancreas; Fasting; Fibrosis; Functional disorder; Gastroenterology; Histologic; Hormonal; Inflammation; Inflammatory; Institutional Review Boards; Insulin; Islets of Langerhans; KRAS2 gene; Knowledge; Lead; Lesion; Link; Lipase; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Methods; Morphology; Mutation; Nature; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; PTGS2 gene; Pancreas; Pancreatic Diseases; Pancreatic Intraepithelial Neoplasia; Pancreatic Polypeptide; Pancreatitis; Participant; Pathologist; Pathology; Patients; Performance; Persons; Pilot Projects; Placebos; Plasma; Protocols documentation; Publishing; Reader; Research; Resected; Resources; Risk Factors; Role; Secretin; Testing; Therapeutic; Validation; Work; accurate diagnosis; adrenomedullin; cancer risk; chronic pancreatitis; cyclooxygenase 2; diabetic; disorder control; feeding; high risk population; indexing; inflammatory marker; insight; inter-institutional; interest; islet; molecular pathology; neoplastic; novel; novel strategies; overexpression; pancreatic islet disorder; pancreatic juice; polypeptide C; prevent; public health relevance; ranpirnase; response

 DESCRIPTION (provided by applicant): In keeping with the objectives of the U01 RFA we propose 3 large clinical studies that are ideally suited for performance by a collaborative consortium and significantly advance our understanding of the interconnected pathologies of chronic pancreatitis (CP), pancreatic cancer (PC), and diabetes mellitus (DM). 1) Type 2 DM (T2DM) is considered purely a disorder of the endocrine pancreas. Our novel observation is that T2DM causes an exocrine pancreatopathy (EP), a new class of pancreatic affliction defined by marked, non-inflammatory pancreatic fibrosis associated with exocrine dysfunction. Diabetic EP (DEP) mimics CP and may predispose to PC. By studying autopsy and resected pancreata from diabetics and controls for both EP changes and preneoplastic lesions we expect to show that DEP and CP are distinct entities, and that DEP defines a high-risk group for PC among T2DM subjects. 2) Late-onset DM is a high-risk group for PC. The key to clinical use of this knowledge lies in distinguishing T2DM from PC-DM. In autopsy and resected pancreata we will study changes in islet morphology to establish that PC-DM is a unique form of pancreatogenic DM. We will also validate our preliminary observation that PC-DM has a blunted pancreatic polypeptide (PP) response to mixed meal compared to T2DM. In persons with T2DM and controls we will measure fasting and post-mixed meal plasma levels of insulin, c-peptide and PP to show that T2DM and pancreatogenic DM have unique hormonal signatures that distinguish T2DM from PC- DM. 3) Current diagnostic tests detect anatomic and functional changes of advanced CP. Our pilot data demonstrate that markers of inflammation in pancreatic juice (PJ) have the potential for early and accurate diagnosis of CP. Their suppression by aspirin (ASA) may indicate a role for ASA in the treatment of CP. We will measure secretin stimulated PGE2, lipase and bicarbonate levels in PJ and blood in CP, early or "minimal change" CP (MCCP), DEP and controls to validate the utility of PJ PGE2 for diagnosis of CP and MCCP. Furthermore, we will measure PJ PGE2 levels again after administration of ASA or placebo to participants with CP or MCCP. We expect to show that ASA decreases PJ PGE2 levels in these groups, providing rationale for clinical trials of COX-2 inhibition to prevent progression of MCCP/CP. Validation of our novel hypotheses will have significant impact on our understanding of pancreatic fibrosis, lead to clinical tests to distinguish T2DM from PC- DM, redefine our approach to early diagnosis of CP and provide insights into therapeutic approaches to slow progression of CP. Done in the U01 setting, these studies will lead to rapid acquisition and dissemination of new knowledge.

 描述（由适用提供）：与U01 RFA的目标保持一致，我们提出了3项大型临床研究，非常适合通过协作财团的表现，并显着提高了我们对慢性胰腺炎（CP），胰腺癌（PC）和Diabetes Mellitus Mellitus（DMellitus（DM）（DM）相互联系的病理的理解。 1）2型DM（T2DM）被认为纯粹是内分泌胰腺的疾病。我们的新发现是，T2DM会导致外分泌胰腺病（EP），这是一类新的胰腺痛苦，由与外分泌功能障碍相关的明显的，非炎性胰腺的定义。糖尿病EP（DEP）模仿CP，并且可能易于PC。通过研究尸检并从糖尿病患者和对照中切除的EP变化和前塑性病变的胰腺胰腺，我们希望表明DEP和CP是不同的实体，并且DEP在T2DM受试者中定义了PC的高风险组。 2）晚期DM是PC的高风险组。临床使用此知识的关键在于将T2DM与PC-DM区分开。在尸检和切除的胰腺中，我们将研究胰岛形态的变化，以确定PC-DM是胰腺生成DM的独特形式。我们还将验证我们的初步观察，即PC-DM与T2DM相比对混合餐的胰腺多肽（PP）反应钝化。在具有T2DM和对照的人中，我们将测量禁食和混合后的血浆胰岛素，C肽和PP水平，以表明T2DM和胰腺生成DM具有独特的激素特征，可将T2DM与PC-DM区分开。 3）当前诊断测试检测高级CP的解剖和功能变化。我们的试点数据表明，胰汁（PJ）的炎症标志物具有早期和准确诊断CP的潜力。它们被阿司匹林（ASA）抑制可能表明ASA在治疗CP中的作用。我们将在CP，早期或“最小变化” CP（MCCP），DEP和对照中测量PJ和血液中的分泌蛋白刺激的PGE2，脂肪酶和碳酸氢盐水平，以验证PJ PGE2在CP和MCCP的诊断中的效用。此外，我们将向患有CP或MCCP的参与者进行ASA或安慰剂后再次测量PJ PGE2水平。我们预计，ASA在这些组中降低了PJ PGE2水平，为COX-2抑制的临床试验提供了基本原理，以防止MCCP/CP的进展。对新假设的验证将对我们对胰腺纤维化的理解产生重大影响，从而导致临床测试将T2DM与PC-DM区分开，重新定义了我们对CP的早期诊断方法，并提供了对CP进展缓慢进展的治疗方法的见解。这些研究在U01环境中完成，将导致快速获取和传播新知识。