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制定诊断无症状胰腺癌 (PaC) 的筛查策略。高达 80% 的 PaC 患有高血糖和糖尿病 (DM)，这种情况在癌症诊断前数月就很明显，并在 PaC 切除后得到改善。相反，患有新发糖尿病的老年受试者患 PaC 的风险比一般人群高约 8 倍。将新发 DM 识别为 PaC 的早期表现可能有助于诊断无症状的早期 PaC。在本提案中，我们将强有力且一致的临床和流行病学观察结果带入实验室，以了解 PaC 相关 DM (PaCDM) 的发病机制并确定其生物标志物。具体目标 1：确定 B 细胞功能障碍是否是糖尿病患者的早期关键缺陷PaCDM：当 B 细胞无法补偿受损的胰岛素作用时，就会在胰岛素抵抗状态下发生 DM。 PaC 中 DM 的患病率非常高，意味着 B 细胞衰竭率很高。我们开发了一种使用 3 种放射性标记的葡萄糖示踪剂同时评估人体 B 细胞功能、胰岛素敏感性和肝脏胰岛素提取的技术。我们使用该技术来研究 2 型糖尿病、糖耐量受损和糖耐量正常的受试者。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 2：确定肾上腺髓质素 (AM) 是否是 PaCDM 的介质：AM 是一种在正常人胰岛中表达的 52 个氨基酸肽激素，可抑制 B 细胞的胰岛素胞吐作用。它在 PaC 中显着过度表达，并且其血浆水平在 PaCDM 中增加。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