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Background Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that genetically reduced insulin production resulted in ~ 50% suppression of pancreatic intraepithelial neoplasia (PanIN) precancerous lesions in mice. However, only female mice remained normoglycemic, and only the gene dosage of the rodent-specific  Ins1  alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. Methods We studied how reduced  Ins2  gene dosage affects PanIN lesion development in both male and female  Ptf1a   Cre ER ; Kras  LSL-G12D  mice lacking the rodent-specific  Ins1  gene ( Ins1  -/- ). We generated control mice having two alleles of the wild-type  Ins2  gene ( Ptf1a   Cre ER ; Kras  LSL-G12D ; Ins1  -/- ; Ins2  +/+ ) and experimental mice having one allele of  Ins2  gene ( Ptf1a   Cre ER ; Kras  LSL-G12D ; Ins1  -/- ; Ins2  +/- ). We then performed thorough histopathological analyses and single-cell transcriptomics for both genotypes and sexes. Results High-fat diet–induced hyperinsulinemia was transiently or modestly reduced in female and male mice, respectively, with only one allele of  Ins2 . This occurred without dramatically affecting glucose tolerance. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell types that were highly represented in our sampled cell population. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. Conclusions These data suggest a potential role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types.

Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics