High insulin levels linked to pancreatic cancer


By Geir O'Rourke

13 Nov 2023

Researchers say they have identified a link between high insulin levels and pancreatic cancer, potentially paving the way to new prevention and therapeutic approaches to the cancer.

Conducted in a mouse model, their study showed excessive insulin levels overstimulated pancreatic acinar cells, which produce digestive juices. This overstimulation leads to inflammation that converts these cells into precancerous cells, according to the Canadian team.

The study focused on pancreatic ductal adenocarcinoma (PDAC), for which obesity and T2DM had previously been established as risk factors.

However, the mechanism behind this link had previously been unknown, and in particular it was unclear whether hyperinsulinaemia affected pancreatic intraepithelial neoplasia (PanIN) precursor cells directly or indirectly, noted the researchers in Cell Metabolism (link here).

Mouse models were generated in which in which KrasG12D expression and loss of insulin receptors were both induced in pancreatic acinar cells.

The mice were then fed a high-fat diet, known to lead to sustained hyperinsulinaemia and accelerate PanIN/PDAC development, according to the researchers.

Analysis after the mice were harvested “clearly support a model in which insulin receptors in acinar cells play a causal role in supporting cancer initiation in the context of diet-induced obesity and mutant Kras,” reported the team, from the University of British Columbia (UBC) in Vancouver.

The contribution of direct insulin action on acinar cells during initiation from normal cells explained a large portion of the cancer-accelerating effects of obesity, although the results did not formally preclude minor roles for insulin receptors in other local or distant cell types, the researchers said.

“Our data, combined with our previous studies, effectively rule out an essential role for hyperglycaemia in PanIN and PDAC formation, but do not preclude roles for hyperglycaemia in the later stages of disease,” they added.

Co-senior author Dr Janel Kopp, assistant professor in the department of cellular and physiological sciences at UBC, said that while the study had important limitations, its results could be the first step towards a significant public health breakthrough.

“We hope this work will change clinical practice and help advance lifestyle interventions that can lower the risk of pancreatic cancer in the general population,” she said.

“This research could also pave the way for targeted therapies that modulate insulin receptors to prevent or slow the progression of pancreatic cancer.”

She noted that, in collaboration with researchers at BC Cancer and the Pancreas Centre BC, the team had since initiated a clinical trial to help patients diagnosed with PDAC control their blood sugar and circulating insulin levels with the help of an endocrinologist.

Beyond that, the findings may have implications for other cancers associated with obesity and type 2 diabetes, where elevated insulin levels may also play a contributing role in disease initiation, said the study’s other co-senior author, Dr James Johnson, also of UBC.

“Colleagues in Toronto have shown similar connections between insulin and breast cancer,” he said.

“In the future, we hope to determine whether and how excess insulin might contribute to other types of obesity- and diabetes-driven cancers.”

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