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Endogenous insulin contributes to pancreatic cancer development

Anni M.Y. Zhang, Jamie Magrill, Twan J.J. de Winter, Xiaoke Hu, Søs Skovsø, David F. Schaeffer, Janel L. Kopp, James D. Johnson
doi: https://doi.org/10.1101/530097
Anni M.Y. Zhang
1Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.
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Jamie Magrill
1Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.
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Twan J.J. de Winter
1Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.
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Xiaoke Hu
1Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.
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Søs Skovsø
1Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.
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David F. Schaeffer
2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
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Janel L. Kopp
1Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.
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  • For correspondence: James.D.Johnson@ubc.ca Janel.Kopp@ubc.ca
James D. Johnson
1Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.
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  • For correspondence: James.D.Johnson@ubc.ca Janel.Kopp@ubc.ca
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Abstract

Obesity and early-stage type 2 diabetes (T2D) increase the risk for many cancers, including pancreatic ductal adenocarcinoma (PDAC). The mechanisms linking obesity and T2D to cancer have not been established, preventing targeted interventions. Arguments have been made that hyperinsulinemia, hyperglycemia, or inflammation could drive cancer initiation and/or progression1. Hyperinsulinemia is a cardinal feature of obesity and T2D, and is independently associated with PDAC incidence and mortality2–4, even in non-obese people5. Despite ample human epidemiological evidence linking hyperinsulinemia to PDAC, there is no direct in vivo evidence of a causal role for endogenous insulin in cancer in any system. Using mice with reduced insulin gene dosage6, 7, we show here that a modest reduction in endogenous insulin production leads to a ~50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in high fat diet-fed mice expressing the KrasG12D oncogene8. The significant reduction in PanIN lesions occurred in the absence of changes in fasting glucose. Reduced insulin also led to a ~50% reduction in pancreatic fibrosis, suggesting that endogenous insulin drives PanIN development, in part, via its pro-fibrotic effects on the stroma surrounding acinar cells and PanIN. Collectively, our data indicate that endogenous insulin hypersecretion contributes causally to pancreatic cancer development. This suggests a modest reduction in fasting insulin via lifestyle interventions or therapeutics may be useful in cancer prevention.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 24, 2019.
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Endogenous insulin contributes to pancreatic cancer development
Anni M.Y. Zhang, Jamie Magrill, Twan J.J. de Winter, Xiaoke Hu, Søs Skovsø, David F. Schaeffer, Janel L. Kopp, James D. Johnson
bioRxiv 530097; doi: https://doi.org/10.1101/530097
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Endogenous insulin contributes to pancreatic cancer development
Anni M.Y. Zhang, Jamie Magrill, Twan J.J. de Winter, Xiaoke Hu, Søs Skovsø, David F. Schaeffer, Janel L. Kopp, James D. Johnson
bioRxiv 530097; doi: https://doi.org/10.1101/530097

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