State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
Int J Mol Sci. 2023 Apr 22;24(9):7701. doi: 10.3390/ijms24097701.
Diabetes poses a significant threat to human health. Exocrine pancreatic dysfunction is related to diabetes, but the exact mechanism is not fully understood. This study aimed to describe the pathological phenotype and pathological mechanisms of the pancreas of transgenic pigs (PIGinH11) that was constructed in our laboratory and to compare it with humans. We established diabetes-susceptible transgenic pigs and subjected them to high-fat and high-sucrose dietary interventions. The damage to the pancreatic endocrine and exocrine was evaluated using histopathology and the involved molecular mechanisms were analyzed using single-nucleus RNA-sequencing (SnRNA-seq). Compared to wild-type (WT) pigs, PIGinH11 pigs showed similar pathological manifestations to type 2 diabetes patients, such as insulin deficiency, fatty deposition, inflammatory infiltration, fibrosis tissue necrosis, double positive cells, endoplasmic reticulum (ER) and mitochondria damage. SnRNA-seq analysis revealed 16 clusters and cell-type-specific gene expression characterization in the pig pancreas. Notably, clusters of Ainar-M and Endocrine-U were observed at the intermediate state between the exocrine and endocrine pancreas. Beta cells of the PIGinH11 group demonstrated the dysfunction with insulin produced and secret decreased and ER stress. Moreover, like clinic patients, acinar cells expressed fewer digestive enzymes and showed organelle damage. We hypothesize that TXNIP that is upregulated by high glucose might play an important role in the dysfunction of endocrine to exocrine cells in PIGinH11 pigs.
糖尿病对人类健康构成重大威胁。外分泌胰腺功能障碍与糖尿病有关，但确切的机制尚未完全阐明。本研究旨在描述我们实验室构建的转基因猪（PIGinH11）的胰腺病理表型和病理机制，并将其与人类进行比较。我们建立了易感糖尿病的转基因猪，并对其进行高脂肪和高蔗糖饮食干预。使用组织病理学评估胰腺内分泌和外分泌的损伤，并使用单核 RNA 测序（SnRNA-seq）分析涉及的分子机制。与野生型（WT）猪相比，PIGinH11 猪表现出类似于 2 型糖尿病患者的病理表现，如胰岛素缺乏、脂肪沉积、炎症浸润、纤维化组织坏死、双阳性细胞、内质网（ER）和线粒体损伤。SnRNA-seq 分析显示猪胰腺中有 16 个簇和细胞类型特异性基因表达特征。值得注意的是，在胰腺的外分泌和内分泌之间的中间状态观察到 Ainar-M 和 Endocrine-U 簇。PIGinH11 组的β细胞表现出胰岛素产生和分泌减少以及 ER 应激的功能障碍。此外，与临床患者一样，胰岛细胞表达的消化酶较少，细胞器受损。我们假设高葡萄糖上调的 TXNIP 可能在 PIGinH11 猪的内分泌到外分泌细胞功能障碍中发挥重要作用。
