Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida.
Gastroenterology. 2019 May;156(6):1742-1752. doi: 10.1053/j.gastro.2019.01.039. Epub 2019 Jan 22.
BACKGROUND & AIMS: Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC.
We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age- and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRASG12D P53 mice with PDACs, C57/BL6 (control) mice, and 5 patients and analyzed by histology and immunohistochemistry.
There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls.
We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early-stage PDAC, but further studies are needed.
识别在胰腺导管腺癌（PDAC）诊断之前发生的代谢异常可能会增加早期检测的机会。我们收集了 219 名 PDAC 患者（患者）和 657 名健康个体（对照）在 2000 年至 2015 年期间的数据，用于研究代谢参数（葡萄糖、血清脂质、甘油三酯；总胆固醇、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇；以及总体重）和软组织（腹部皮下脂肪[SAT]、脂肪组织、内脏脂肪组织[VAT]和肌肉）的变化。我们将患者的代谢谱与年龄和性别匹配的对照进行比较，构建空腹血糖、血清脂质（包括甘油三酯）、胆固醇谱和体重及体温的时间谱，时间为 PDAC 诊断前 60 个月（索引日期）。为了构建软组织变化的时间谱，我们从 68 名患者中收集了计算机断层扫描（CT），比较了 L2/L3 椎骨处 SAT、VAT 和肌肉的基线（>18 个月前诊断）区域与后来的扫描区域，直到诊断时间。从 PDAC 细胞系中分离的外泌体暴露于从 KRASG12D P53 小鼠 PDAC、C57/BL6（对照）小鼠和 5 名患者中分离的 SAT 和 VAT，并通过 RNA 测序进行分析。对 SAT 进行了组织学和免疫组织化学分析。
在 PDAC 诊断前 30 个月之前，患者与对照组之间的代谢或软组织特征没有明显差异。在 PDAC 诊断前 30 至 18 个月（第 1 阶段，高血糖）期间，与对照组相比，相当一部分患者出现了高血糖，而没有软组织变化。在 PDAC 诊断前 18 至 6 个月（第 2 阶段，恶病质前期）期间，患者的高血糖和血清脂质、体重和 SAT 显著增加，而 VAT 和肌肉保持不变。在 PDAC 诊断前 6 至 0 个月（第 3 阶段，恶病质）期间，与对照组相比，相当一部分患者出现了高血糖，所有血清脂质、SAT、VAT 和肌肉均显著减少。我们认为患者在 PDAC 诊断前 18 个月开始出现体温升高，这表明 SAT 发生了褐变。我们观察到暴露于 PDAC 外泌体的 SAT、PDAC 小鼠的 SAT 和所有 5 名患者的 SAT 中 UCP1 的表达，但只有 4 名对照中的 1 名。
我们确定了在 PDAC 诊断之前存在 3 个代谢和软组织变化阶段。SAT 的丢失始于 PDAC 识别前 18 个月，可能是由于褐变。SAT 中 UCP1 的过度表达可能是早期 PDAC 的生物标志物，但需要进一步研究。
