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（由申请人提供）：为了与 U01 RFA 的目标保持一致，我们提出了 3 项大型临床研究，这些研究非常适合由合作联盟执行，并显着增进我们对慢性胰腺炎 (CP)、胰腺癌相互关联的病理学的理解(PC) 和糖尿病 (DM) 1) 2 型糖尿病 (T2DM) 被认为是纯粹的内分泌胰腺疾病。 T2DM 会导致外分泌性胰腺病 (EP)，这是一种新的胰腺疾病，其定义为与外分泌功能障碍相关的显着非炎症性胰腺纤维化，与 CP 类似，通过研究糖尿病患者的尸检和切除的胰腺，可能会导致 PC。以及对 EP 变化和肿瘤前病变的控制，我们希望表明 DEP 和 CP 是不同的实体，并且 DEP 定义了高风险2) 晚发型糖尿病是 PC 的高危人群，临床应用这一知识的关键在于区分 T2DM 和 PC-DM，我们将研究胰岛的变化。我们还将验证我们的初步观察结果，即与 T2DM 相比，PC-DM 对混合膳食的胰多肽 (PP) 反应减弱。对于 T2DM 患者和对照组，我们将测量空腹和混合餐后血浆胰岛素、C 肽和 PP 水平，以表明 T2DM 和胰源性 DM 具有区分 T2DM 和 PC-DM 的独特激素特征 3) 目前的诊断测试可检测解剖学。我们的试验数据表明，胰液 (PJ) 中的炎症标志物具有早期准确诊断 CP 的潜力，而阿司匹林 (ASA) 对其的抑制可能表明这一点。我们将测量 CP、早期或“微小变化”CP (MCCP)、DEP 和对照中 PJ 和血液中促胰液素刺激的 PGE2、脂肪酶和碳酸氢盐水平，以验证 PJ PGE2 的效用。此外，我们将在对患有 CP 或 MCCP 的参与者施用 ASA 或安慰剂后再次测量 PJ PGE2 水平，我们希望表明 ASA 会降低 PJ。这些组中的 PGE2 水平为抑制 COX-2 以预防 MCCP/CP 进展的临床试验提供了理论基础，验证我们的新假设将对我们对胰腺纤维化的理解产生重大影响，并导致临床试验来区分 T2DM 和 PC-。 DM，重新定义了我们的 CP 早期诊断方法，并提供了对减缓 CP 进展的治疗方法的见解。这些研究在 U01 环境中完成，将导致新知识的快速获取和传播。