Pancreatic Cancer-Associated Diabetes: Pathogenesis and Biomarkers

我们的长期计划目标是开发筛查策略来诊断无症状的胰腺 癌症(PAC)。高达80%的PAC有高血糖和糖尿病(DM)，这在几个月内就很明显 在癌症诊断之前，并在切除PAC后有所改善。相反，新发的老年受试者 糖尿病患者患PAC的风险是普通人群的8倍。认识到 新发糖尿病作为PAC的早期表现可导致无症状早期诊断 政治行动委员会。在这项建议中，我们将我们强有力和一致的临床和流行病学观察结果应用于 实验室了解PAC相关糖尿病(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 当B细胞不能补偿受损的胰岛素作用时，就会出现胰岛素抵抗。非常高的流行率 PAC中DM的出现提示B细胞失败率较高。我们已经在人类身上开发了一种技术，可以同时 使用3种放射性标记葡萄糖示踪剂评估B细胞功能、胰岛素敏感性和肝脏胰岛素提取。 我们已经使用这项技术研究了2型糖尿病、糖耐量受损和正常的受试者 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和 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是一种在正常人胰岛表达的52个氨基酸的多肽激素，它抑制 B细胞分泌胰岛素。它在PAC中显著过度表达，其血浆水平在 帕科姆。我们假设泰国AM是PAC中B细胞功能障碍的中介物。在初步研究中，我们 已经能够使用来自一名患有糖尿病的患者的PAC异种移植将DM从人类传播到SCID小鼠 PaCDM，而来自空腹血糖正常患者的PAC异种移植对血糖水平没有影响。 在使用胰岛素瘤细胞系INS-1的体外研究中，我们观察到PAC细胞系抑制糖基化 胰岛素释放。利用遗传和药理学方法调节基因的表达和 AM在这些体内和体外模型中的作用，我们将探讨AM在引起PaCDM中的作用。 具体目标3：建立新发糖尿病患者PAC的预测模型：PaCDM是 不仅与高血浆AM水平有关，还与年龄较大、肥胖和糖尿病家族史有关。 我们将测定血浆AM、胰岛素和血糖水平，以及最著名的肿瘤标志物CA19-9 PAC，在有和没有新发DM，新发2型DM， 以及健康和疾病控制。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来开发PAC预测模型 各种因素。翻译意义：如果PAC诱导的DM的生物标志物被识别出来，它将立即 临床影响，因为这将使我们能够开始对新发糖尿病患者进行无症状PAC的筛查。

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.