ABSTRACT
Purpose: Pancreatic cyst neoplasm (PCN) is a precursor of pancreatic cancer. Previous studies reported PCN was often concurrent with diabetes. We aim to examine the association between diabetes with PCN malignancy and to detect the potential role of diabetes in PCN management and treatment. Patients and Methods: A total of 224 patients who were diagnosed with the three major types of PCN (IPMN, MCN, and SCN) and underwent surgical resection were selected. Patients were divided into three groups (normal group, new-onset diabetes group (NODM) (<4years), and long-standing diabetes group (LSDM) (>4years)) according to diabetic history and diagnostic time interval. Diabetes, fast blood glucose level, HbA1c, and insulin resistance level were measured. Malignant PCN (mPCN) radiological features (worrisome features and high-risk stigmata) were analyzed. Pathological features (PCN type, dysplasia grade, tumor stage, and tumor volume) and immunohistology of Ki67 and SMAD4 were performed. Diagnostic efficacy of each variable was determined by the ROC curve. mPCN diagnosis was the main outcome in diagnostic prediction and overall survival as the glucose controlling outcome variables. Results: Diabetes groups (NODM and LSDM) showed difference with the normal group in age, weight loss, malignancy, CA19-9 value, CEA value, Ki-67 value, tumor volume, pathological grade, and a lowered pancreatic fistula risk. NODM was related to insulin resistance, weight loss, and SMAD4 mutation. NODM (87.3%) and high insulin resistance rate (93.6%) significantly increased the sensitivity of radiological evidence-based mPCN diagnosis. Moreover, long-standing diabetes and elevated HbA1c led to reduced survival in mPCN patients than the normal PCN group. Anti-diabetic drugs showed limited influence on PCN malignancy and tumor volume. Conclusion: NODM in PCN patients was associated with malignancy, insulin resistance, weight loss, and SMAD4 mutation. Prediabetic status and NODM diagnosis enhanced the diagnostic accuracy of radiological standards (worrisome features and high-risk stigmata). Stable glucose surveillance is necessary for mPCN patients' survival.
ABSTRACT
Increased insulin level (or "hyperinsulinemia") is a common phenomenon in pancreatic ductal adenocarcinoma (PDA) patients and signals poor clinical outcomes. Insulin is safe in low PDA risk population, while insulin significantly promotes PDA risk in high PDA risk population. The correlation between insulin and PDA is a reciprocal self-reinforcing relationship. On the one hand, pancreatic cancer cells synthesize multiple molecules to cause elevated peripheral insulin resistance, thus enhancing hyperinsulinemia. On the other hand, insulin promotes pancreatic cancer initiation and sustains PDA development by eliciting tumorigenic inflammation, regulating lipid and glucose metabolic reprogram, overcoming apoptosis through the crosstalk with IGF-1, stimulating cancer metastasis, and activating tumor microenvironment formation (inflammation, fibrosis, and angiogenesis). Currently, taking glucose sensitizing agents, including metformin, SGLT-2 inhibitor, and GLP-1 agonist, is an effective way of lowering insulin levels and controlling PDA development at the same time. In the future, new drugs targeting insulin-related signal pathways may pave a novel way for suppressing PDA initiation and progression.
