Scientists Confirm Elevated Insulin as Key Trigger for Pancreatic Cancer

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Scientists Confirm Elevated Insulin as Key Trigger for Pancreatic Cancer

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Scientists Confirm Elevated Insulin as Key Trigger for Pancreatic Cancer

Whenever we come across the words “died of pancreatic cancer,” it’s a moment of profound sadness.

Facing the “king of cancers,” patients often seem to have an insurmountable battle ahead, and the situation is filled with a sense of tragedy.

Moreover, from an epidemiological perspective, the incidence of pancreatic cancer continues to rise, making it urgent to uncover the underlying causes.

In recent years, several studies have linked pancreatic cancer to elevated insulin levels. It is believed that under the influence of factors such as obesity and type 2 diabetes, high insulin levels can drive the development of pancreatic cancer. As obesity and diabetes become increasingly prevalent, the incidence of pancreatic cancer is also on the rise.

A recent study published in the journal Cell Metabolism has revealed the key mechanism by which elevated insulin levels induce pancreatic cancer. Researchers from McGill University in Canada and the University of British Columbia confirmed that high insulin levels can directly induce the transformation of some acinar cells in the pancreas that express insulin receptors and carry KRAS mutations into pancreatic intraepithelial neoplasia (PanIN), a crucial precursor lesion of pancreatic cancer.

These acinar cells play a minor role in regulating blood glucose in the human body. However, when acted upon by insulin, they induce local inflammation, increase the translation of pancreatic digestive enzyme proteins, and promote the development of PanIN and acinar-to-ductal metaplasia (ADM). Therefore, the carcinogenic effect controlled by insulin/insulin receptors should not be underestimated.

To validate the role of the insulin/insulin receptor pathway in the development of pancreatic cancer, researchers first created a mouse model by feeding them a high-fat diet (HFD) and treating them with tamoxifen (inducing KRASG12D mutation). They confirmed that knocking out the expression of insulin receptors in pancreatic acinar cells did not disrupt blood glucose homeostasis. Moreover, pancreatic tissue loss caused by KRASG12D mutation could be partially reversed after knocking out insulin receptors.

Further analysis showed that knocking down or knocking out insulin receptors indeed reduced the number of PanIN lesions and subsequent carcinomas, i.e., pancreatic ductal adenocarcinomas (PDAC). This inhibitory effect primarily manifested in the early stages of PanIN development in mice (at 12 weeks of age). By thwarting pancreatic cancer at its inception, the insulin receptor-activated downstream signaling pathways PI3K/AKT/mTOR and MAPK/ERK also exhibited reduced activity.

However, researchers believe that the role of insulin receptors extends beyond the activation of the known signaling pathways mentioned above. Therefore, they conducted proteomic and phosphoproteomic analyses and found that after knocking out insulin receptors, various proteins associated with PanIN formation were significantly enriched in acinar cells. This was consistent with previous experimental results.

The unexpected part of the conclusion from the proteomic analysis was that after knocking out insulin receptors, the levels of various digestive enzymes routinely packaged into zymogen granules and secreted in acinar cells were significantly reduced. This regulation occurred post-transcriptionally, affecting digestive enzyme synthesis.

With elevated insulin levels and the presence of insulin receptors, the increased digestive enzymes appear to be associated with mechanisms involved in PanIN formation and inflammation. High insulin levels lead to self-catalysis of pancreatic proteases, promoting digestive enzyme secretion, causing a more extensive promotion of carcinogenic inflammation and PanIN formation. Phosphoproteomic analysis also indicates that elevated insulin levels may promote carcinogenesis through the regulation of specific transcription factors and RNA splicing.

So, to what extent can inhibiting the insulin/insulin receptor pathway reduce the risk of cancer? Staining experiments showed that in the absence of insulin receptors, with only the KRASG12D mutation remaining, the fibrosis and inflammation induced by KRAS mutations in the pancreas were significantly reduced, and the numbers of PanIN and ADM were also decreased.

In conclusion, this study has revealed the significant role of the insulin/insulin receptor pathway in the transformation of pancreatic acinar cells and the early development of pancreatic cancer. The potential beneficiaries of this discovery may extend beyond pancreatic cancer treatment; it could also revolutionize early screening for pancreatic cancer. It appears that measuring insulin levels, rather than blood glucose levels, may be the key.

Scientists Confirm Elevated Insulin as Key Trigger for Pancreatic Cancer

References:

[1] Zhang A M Y, Magrill J, de Winter T J J, et al. Endogenous hyperinsulinemia contributes to pancreatic cancer development. Cell Metabolism, 2019, 30(3): 403-404.

[2] Zhang A M Y, Xia Y H, Lin J S H, et al. Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation. Cell Metabolism, 2023.

(source:internet, reference only)

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