The Intricate Crosstalk Between Insulin and Pancreatic Ductal Adenocarcinoma: A Review From Clinical to Molecular

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.

Quantitative Metabolomics and Lipoprotein Analysis of PDAC Patients Suggests Serum Marker Categories for Pancreatic Function, Pancreatectomy, Cancer Metabolism, and Systemic Disturbances

“…60 Moreover, the enzyme plays a role for insulin secretion, 61 and hyperinsulinemia is frequently observed in PDAC patients. 62 We observed decreased proline and asparagine in P1 compared to healthy controls, which is consistent with results from Fukutake et al 63 and Zhao et al 64 Our results may then reflect metabolic rewiring in PDAC. PDACs highly express proline oxidase to acquire proline-derived glutamate from collagen-derived proline 65 and asparagine synthase to evade apoptosis.…”

The Role of Diabetes Mellitus in the Malignant Pancreatic Cyst Neoplasm Diagnosis and Prognosis

“… 24 Interestingly, the frequency of the newly occurred hyperglycemia in PDA patients was about 50%. 25 In pancreatic cancer, SMAD4 protein works as a vital negative regulator of the TGF-β signal pathway. 26 The transforming growth factor -β (TGF-β) signaling pathway is an important factor for malignant transformation, cancer invasion and metastasis in PDA.…”

Obesity and endocrine-related cancer: The important role of IGF-1

“…Du et al indicated that high IGF-1R expression was associated with shorter overall survival and relapse in patients (60). In PDAC, both insulin and IGF-1 are considered to play a role in cancer development and progression, with the PI3K and MAPK signaling pathways as its central pathways, and these signals are enhanced in obesity (61,62). Tian et al inhibited the PI3K/Akt signaling pathway by knocking down the IGF-1R gene, thereby inhibiting the proliferation of pancreatic cancer cells and increasing the sensitivity of anticancer drugs, which to some extent proves the role of IGF-1 in pancreatic cancer (63).…”

“…indicated that high IGF-1R expression was associated with shorter overall survival and relapse in patients ( 60 ). In PDAC, both insulin and IGF-1 are considered to play a role in cancer development and progression, with the PI3K and MAPK signaling pathways as its central pathways, and these signals are enhanced in obesity ( 61 , 62 ). Tian et al.…”