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.