P-2: Pancreatic Cancer-Associated Diabetes: Pathogenesis and Biomarkers

P-2：胰腺癌相关糖尿病：发病机制和生物标志物

• 批准号: 7510778
• 负责人: SURESH T. CHARI
• 金额: $ 20.36万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7510778
• 关键词: Age; Amino Acids; Angiogenesis Inhibition; B-Lymphocytes; Biological Markers; Blood Glucose; Cancer Etiology; Cancer cell line; Case-Control Studies; Cell Line; Cell physiology; Cells; Characteristics; Clinical; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Endocrine; Endocrinologist; Excision; Exocytosis; Failure; Family history of; Fasting; Functional disorder; Gastroenterologist; General Population; Genetic; Glucose; Glucose Intolerance; Goals; Hepatic; High Prevalence; Hormones; Human; Hyperglycemia; Impaired fasting glycaemia; In Vitro; Insulin; Insulin Resistance; Integration Host Factors; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Mediator of activation protein; Methods; Numbers; Obesity; Operative Surgical Procedures; P-2; Pancreas; Pathogenesis; Patients; Performance; Peripheral; Physiological; Plasma; Population; Predictive Factor; Prevalence; Protein Overexpression; Radiolabeled; Rate; Reporting; Research; Resectable; Retrospective Studies; Risk; Role; SCID Mice; Scientist; Screening procedure; Series; Staging; Structure of beta Cell of islet; Study Subject; Symptoms; Techniques; Testing; Tracer; Tumor Markers; Unresectable; Weight; Xenograft procedure; adrenomedullin; autocrine; base; cancer diagnosis; clinical Diagnosis; cohort; diabetic; disorder control; experience; glucose metabolism; glucose tolerance; impaired glucose tolerance; improved; in vitro Model; in vivo; insulin sensitivity; insulinoma; islet; loss of function; novel; paracrine; peptide hormone; predictive modeling; programs; radiotracer

Our long-term programmatic goal is to develop screening strategies to diagnose asymptomatic pancreatic cancer (PaC). Up to 80% of PaCs have hyperglycemia and diabetes (DM), which is evident many months prior to the cancer diagnosis and improves following resection of PaC. Conversely, older subjects with newonset DM have a ~8 fold higher risk of having PaC compared to the general population. Recognition of new-onset DM as an early manifestation of PaC could lead to diagnosis of asymptomatic early stage PaC. In this proposal we take our strong and consistent clinical and epidemiological observations to the laboratory 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 in insulin resistant states when B-cells fail to compensate for impaired insulin action. The very high prevalence of DM in PaC implies high rate of B-cell failure. We have developed a technique in humans to simultaneously assess 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 normal glucose tolerance. We will perform similar studies in PaC to determine if B-cell dysfunction is an early and key defect in glucose metabolism in PaCDM. Specific Aim 2: To determine if adrenomedullin (AM) is the mediator of PaCDM: AM is a 52 amino acid peptide hormone expressed in normal human islets that inhibits insulin exocytosis from B-cells. It is markedly overexpressed in PaC and its plasma levels are increased in PaCDM. We hypothesize thai AM is the mediator of B-cell dysfunction in PaC. In preliminary studies we have been able to "transmit" DM from a human to SCID mice using a xenograft of PaC from a patient with PaCDM, while a xenograft of PaC from a patient with normal fasting glucose had no effect on glucose levels. In in vitro studies using INS-1, an insulinoma cell line, we have observed that PaC cell lines inhibit glucosemediated insulin release. Using genetic and pharmacological methods to modulate the expression and action of AM in these in vivo and in vitro models, we will investigate the role of AM in causing PaCDM. Specific Aim 3: To develop a predictive model for PaC among new-onset diabetics: PaCDM is associated not only with high plasma AM levels, but also with older age, obesity and family history of DM. We will measure plasma AM, insulin and glucose levels as well as CA 19-9, the best known tumor marker of PaC, in a large cohort (n=420) of subjects with PaC with and without new-onset DM, new-onset type 2 DM, and healthy and disease controls. We will determine the performance characteristics of AM as a biomarker of PaCDM and develop a predictive model for PaC using laboratory, clinical and demographic predictive factors. Translational Significance: If a biomarker of PaC-induced DM is identified it will have immediate clinical impact as it will allow us to start screening for asymptomatic PaC in the subjects with new-onset DM.

我们的长期计划目标是制定筛查策略，以诊断无症状胰腺炎。 癌症（PaC）。高达80%的PAC患有高血糖症和糖尿病（DM），这在许多个月内是明显的。 在癌症诊断之前，并且在切除PaC之后改善。相反，新发的老年受试者 与一般人群相比，糖尿病患者患PaC的风险高约8倍。承认 新发DM作为PaC的早期表现可导致无症状早期诊断 PAC。在本提案中，我们将我们强有力和一致的临床和流行病学观察结果用于 实验室了解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PaCDM的早期和关键缺陷：DM发生在 胰岛素抵抗状态是指B细胞不能补偿受损的胰岛素作用。非常高的患病率 DM在PaC中的高表达意味着B细胞衰竭率高。我们在人类身上开发了一种技术， 使用3种放射性标记的葡萄糖示踪剂评估B细胞功能、胰岛素敏感性和肝脏胰岛素提取。 我们已经使用这种技术研究了2型糖尿病患者，糖耐量受损和正常人。 葡萄糖耐量我们将在PaC中进行类似的研究，以确定B细胞功能障碍是否是早期的， PaCDM中葡萄糖代谢的关键缺陷。具体目标2：确定肾上腺髓质素（AM）是否是 PaCDM的介体：AM是在正常人胰岛中表达的52个氨基酸的肽激素，其抑制 B细胞分泌胰岛素。它在PaC中显著过表达，并且其血浆水平在PaC中升高。 PaCDM。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， 已经能够使用来自患有糖尿病的患者的PaC异种移植物将DM从人“传播”到SCID小鼠。 PaCDM，而来自空腹血糖正常患者的PaC异种移植物对血糖水平没有影响。 在使用INS-1（一种胰岛素瘤细胞系）的体外研究中，我们观察到PaC细胞系抑制葡萄糖介导的 胰岛素释放使用遗传和药理学方法调节表达， 在这些体内和体外模型中，我们将研究AM在导致PaCDM中的作用。 具体目标3：开发新发糖尿病患者PaC的预测模型：PaCDM是 不仅与高血浆AM水平有关，而且与年龄较大、肥胖和DM家族史有关。 我们将测量血浆AM、胰岛素和葡萄糖水平以及CA 19-9，CA 19-9是最知名的肿瘤标志物。 PaC，在伴有和不伴有新发DM的PaC受试者的大型队列（n=420）中，新发2型DM， 健康和疾病控制。我们将确定AM作为生物标志物的性能特征 并使用实验室、临床和人口统计学预测数据开发PaC预测模型 因素翻译意义：如果确定了PaC诱导的DM的生物标志物， 临床影响，因为它将允许我们开始筛查新发DM受试者中的无症状PaC。