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. We studied how reduced Ins2 gene dosage affects PanIN lesion development in both male and female Ptf1aCreER;KrasLSL-G12D mice lacking the rodent-specific Ins1 gene (Ins1-/-). We generated control mice having two alleles of the wild-type Ins2 gene (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/+) and experimental mice having one allele of Ins2 gene (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/-). We then performed thorough histopathological analyses and single-cell transcriptomics for both genotypes and sexes. 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. 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.

中文翻译：

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单细胞转录组学揭示高胰岛素血症对胰腺癌发展和免疫微环境的影响

高胰岛素血症与胰腺癌风险和死亡率增加独立相关。我们最近报道，基因减少的胰岛素产生导致小鼠胰腺上皮内瘤变 (PanIN) 癌前病变的抑制率约为 50%。然而，只有雌性小鼠血糖保持正常，并且在我们之前的模型中只测试了啮齿动物特异性 Ins1 等位基因的基因剂量。此外，我们没有深入研究与调节高胰岛素血症相关的分子和细胞机制。我们研究了减少 Ins2 基因剂量如何影响雄性和雌性 Ptf1aCreER 的 PanIN 病变发展；缺乏啮齿动物特异性 Ins1 基因 (Ins1-/-) 的 KrasLSL-G12D 小鼠。我们生成了具有两个等位基因的野生型 Ins2 基因的对照小鼠 (Ptf1aCreER;KrasLSL-G12D;Ins1-/-; Ins2+/+) 和具有 Ins2 基因的一个等位基因的实验小鼠 (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/-)。然后，我们对基因型和性别进行了彻底的组织病理学分析和单细胞转录组学。高脂饮食诱导的高胰岛素血症分别在雌性和雄性小鼠中短暂或适度减少，只有一个 Ins2 等位基因。这在没有显着影响葡萄糖耐量的情况下发生。胰岛素产生的遗传减少导致小鼠具有较少的 PanIN 和腺泡-导管化生 (ADM) 病变的倾向。使用单细胞转录组学，我们发现高胰岛素血症影响胰腺中的多种细胞类型，对在我们的采样细胞群中高度代表的局部免疫细胞类型具有最显着的统计学影响。具体来说，高胰岛素血症调节与蛋白质翻译、MAPK-ERK 信号传导和 PI3K-AKT 信号传导相关的通路，这些通路在上皮细胞和免疫细胞亚群中发生了变化。这些数据表明免疫微环境在高胰岛素血症驱动的 PanIN 发展中的潜在作用。连同我们之前的工作，我们提出通过作用于多种细胞类型，轻度抑制胰岛素水平可能有助于预防胰腺癌。