Pancreatic cancer, with its five-year survival rate of less than 10%, is associated with various risk factors including family history, smoking, obesity, and type 2 diabetes. Notably, hyperinsulinemia — a hallmark of obesity and type 2 diabetes — has been linked to an increased risk of pancreatic cancer and poorer prognoses. Yet a knowledge gap exists in understanding the precise mechanisms by which hyperinsulinemia can lead to pancreatic cancer.
A new study conducted by researchers at the University of British Columbia sheds light on the intricate relationship between hyperinsulinemia, obesity, and the initiation of pancreatic cancer. Published in Cell Metabolism, and led by Dr. James Johnson and Dr. Janel Kopp, the study provides valuable insights into the molecular mechanisms that lead to pancreatic tumours.
The research focuses on acinar cells, which are a subset of pancreas cells responsible for synthesizing, storing, and secreting digestive enzymes. The study reveals that pancreatic ductal adenocarcinoma, or PDAC — the most common type of pancreatic cancer — is initiated through direct insulin receptor signalling in acinar cells.
Generally speaking, signalling refers to the ways that cells communicate with each other and their environment. And while insulin signalling is crucial for various cellular functions, the role of insulin receptor signalling in pancreatic acinar cells has to date remained understudied.
However, researchers do know that insulin signalling can activate signalling pathways — that is, specific types of communication between cells — that are frequently mutated in cancer. In particular, it can activate pathways involving a gene known as KRAS, that is frequently mutated in pancreatic cancer. Activation of these mutated pathways can cause normal cells to become cancerous.
In the present study, the researchers found a link between hyperinsulinemia — that is, having a higher amount of insulin than normal — and increased production of digestive enzymes in pancreatic acinar cells. While this heightened enzyme production can help breakdown lipid-rich food, it also elevates the risk of enzyme-induced injuries, triggering inflammation and cell transformations. In the presence of KRAS mutations, this inflammation can lead to irreversible transformations in the body’s acinar cells.
The research also highlights the complex interplay between insulin signalling, cellular metabolism, and pancreatic cancer initiation. The researchers found that the loss of insulin receptors in acinar cells can affect cellular metabolism, providing us with a deeper understanding of the intricate molecular mechanisms at play.
This study highlights the pivotal role of insulin receptor signalling in acinar cells in the development of pancreatic cancer. The findings suggest that by targeting insulin receptor signalling pathways, or by addressing hyperinsulinemia itself, we could offer potential avenues for treating and preventing pancreatic cancer.
With insulin being a clinically actionable and easily measured hormone — which can be modified through diet, exercise, and FDA-approved drugs — the study opens up novel possibilities for developing pancreatic cancer prevention strategies in humans.
