Pancreatic Cancer-Associated Diabetes: Pathogenesis and Biomarkers

我们的长期规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患者患有高血糖和糖尿病（DM），这在癌症诊断前几个月就很明显，并在PaC切除术后得到改善。相反，与一般人群相比，新发DM的老年受试者患PaC的风险高8倍。认识到新发糖尿病是PaC的早期表现可以导致无症状早期PaC的诊断。在这项建议中，我们将我们强有力的和一致的临床和流行病学观察结果带入实验室，以了解pac相关性DM （PaCDM）的发病机制并确定其生物标志物。特异性目的1：确定b细胞功能障碍是否是PaCDM的早期和关键缺陷：当b细胞无法补偿受损的胰岛素作用时，DM发生在胰岛素抵抗状态。糖尿病在PaC中的高发病率意味着高的b细胞衰竭率。我们开发了一种利用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。我们已经使用这项技术来研究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。特异性目的2：确定肾上腺髓质素（AM）是否是PaCDM的介质：AM是一种在正常人类胰岛中表达的52个氨基酸肽激素，可抑制b细胞的胰岛素分泌。它在PaC中明显过表达，在pacdm中其血浆水平升高。我们假设AM是PaC中b细胞功能障碍的中介。在初步研究中，我们已经能够

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