Pancreatic Cancer-Associated Diabetes: Pathogenesis and Biomarkers

胰腺癌相关糖尿病：发病机制和生物标志物

• 批准号: 8719561
• 负责人: SURESH T. CHARI
• 金额: $ 12.8万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719561
• 关键词: Amino Acids; B-Lymphocytes; Biological Markers; Cell physiology; Clinic; Clinical; Defect; Diabetes Mellitus; Diagnosis; Epidemiology; Excision; Exocytosis; Failure; Functional disorder; General Population; Glucose; Goals; Hepatic; Human; Hyperglycemia; Insulin; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator of activation protein; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Pathogenesis; Plasma; Population; Radiolabeled; Research; Resistance; Role; Series; Staging; Study Subject; Symptoms; Techniques; Tracer; Unresectable; adrenomedullin; cancer diagnosis; glucose metabolism; high risk; impaired glucose tolerance; improved; insulin sensitivity; islet; overexpression; peptide hormone; programs; radiotracer; screening

Our long-term programmatic goal is to develop screening strategies to diagnose asymptomatic pancreaticcancer (PaC). Up to 80% of PaCs have hyperglycemia and diabetes (DM), which is evident many monthsprior to the cancer diagnosis and improves following resection of PaC. Conversely, older subjects with newonsetDM have a ~8 fold higher risk of having PaC compared to the general population. Recognition ofnew-onset DM as an early manifestation of PaC could lead to diagnosis of asymptomatic early stagePaC. In this proposal we take our strong and consistent clinical and epidemiological observations to thelaboratory to understand the pathogenesis of PaC-associated DM (PaCDM) and identify its biomarkers.Specific Aim 1: To determine if B-cell dysfunction is an early and key defect in PaCDM: DM occurs ininsulin resistant states when B-cells fail to compensate for impaired insulin action. The very high prevalenceof DM in PaC implies high rate of B-cell failure. We have developed a technique in humans to simultaneouslyassess B-cell function, insulin sensitivity, and hepatic insulin extraction using 3 radiolabeled glucose tracers.We have used this technique to study subjects with type 2 DM, impaired glucose tolerance and normalglucose tolerance. We will perform similar studies in PaC to determine if B-cell dysfunction is an early andkey defect in glucose metabolism in PaCDM. Specific Aim 2: To determine if adrenomedullin (AM) is themediator of PaCDM: AM is a 52 amino acid peptide hormone expressed in normal human islets that inhibitsinsulin exocytosis from B-cells. It is markedly overexpressed in PaC and its plasma levels are increased inPaCDM. We hypothesize thai AM is the mediator of B-cell dysfunction in PaC. In preliminary studies wehave been able to

我们的长期计划目标是开发诊断无症状胰腺癌（PaC）的筛查策略。高达80%的PaC具有高血糖症和糖尿病（DM），这在癌症诊断前多个月就很明显，并且在PaC切除后得到改善。相反，新发DM的老年受试者患PaC的风险比一般人群高8倍。将新发DM识别为PaC的早期表现可能导致无症状早期PaC的诊断。在这个建议中，我们采取我们强有力的和一致的临床和流行病学观察thelaboratory了解PaC相关DM（PaCDM）的发病机制，并确定其生物标志物。具体目标1：以确定是否B细胞功能障碍是一个早期和关键的缺陷PaCDM：DM发生在胰岛素抵抗状态时，B细胞不能弥补受损的胰岛素作用。PaC中DM的高发病率意味着B细胞衰竭的高发生率。我们开发了一种技术，利用3种放射性标记的葡萄糖示踪剂对人体B细胞功能、胰岛素敏感性和肝脏胰岛素提取进行了准确的评估，并将该技术用于2型糖尿病、糖耐量受损和正常糖耐量的研究。我们将在PaC中进行类似的研究，以确定B细胞功能障碍是否是PaCDM中葡萄糖代谢的早期和关键缺陷。具体目标二：为了确定肾上腺髓质素（AM）是否是PaCDM的介导剂：AM是正常人胰岛中表达的52个氨基酸的肽类激素，其抑制B细胞的胰岛素分泌。它在PaC中显著过表达，并且其血浆水平在PaCDM中升高。我们假设AM是PaC中B细胞功能障碍的介导者。在初步研究中我们已经能够