The damage to the endocrine pancreas among patients with diseases of the exocrine pancreas (DP) leads to reduced glycemic deterioration, ultimately resulting in diabetes of the exocrine pancreas (DEP). The present research aims to investigate the mechanism responsible for glycemic deterioration in DP patients, and to identify useful biomarkers, with the ultimate goal of enhancing clinical practice awareness. Gene expression profiles of patients with DP in this study were acquired from the Gene Expression Omnibus database. The original study defines DP patients to belong in one of three categories: non-diabetic (ND), impaired glucose tolerance (IGT) and DEP, which correspond to normoglycemia, early and late glycemic deterioration, respectively. After ensuring quality control, the discovery cohort included 8 ND, 20 IGT, and 12 DEP, while the validation cohort included 27 ND, 15 IGT, and 20 DEP. Gene set enrichment analysis (GSEA) employed differentially expressed genes (DEGs), while immunocyte infiltration was determined using single sample gene set enrichment analysis (ssGSEA). Additionally, correlation analysis was conducted to establish the link between clinical characteristics and immunocyte infiltration. The least absolute shrinkage and selection operator regression and random forest combined to identify biomarkers indicating glycemic deterioration in DP patients. These biomarkers were further validated through independent cohorts and animal experiments. With glycemic deterioration, biological processes in the pancreatic islets such as nutrient metabolism and complex immune responses are disrupted in DP patients. The expression of ACOT4, B2M, and ACKR2 was upregulated, whereas the expression of CACNA1F was downregulated. Immunocyte infiltration in the islet microenvironment showed a significant positive correlation with the age, body mass index (BMI), HbA1c and glycemia at the 2-h of patients. It was a crucial factor in glycemic deterioration. Additionally, B2M demonstrated a significant positive correlation with immunocyte infiltration and clinical features. Quantitative real-time PCR (qRT-PCR) and western blotting confirmed the upregulation in B2M. Immunofluorescent staining suggested the alteration of B2M was mainly in the alpha cells and beta cells. Overall, the study showed that gradually increased immunocyte infiltration was a significant contributor to glycemic deterioration in patients with DP, and it also highlighted B2M as a biomarker.

患有外分泌胰腺（DP）疾病的患者中，内分泌胰腺受到损害，导致血糖恶化程度降低，最终导致外分泌胰腺糖尿病（DEP）。本研究旨在调查 DP 患者血糖恶化的机制，并确定有用的生物标志物，最终目标是提高临床实践意识。本研究中 DP 患者的基因表达谱是从 Gene Expression Omnibus 数据库中获取的。最初的研究将 DP 患者定义为三类之一：非糖尿病 (ND)、糖耐量受损 (IGT) 和 DEP，分别对应于血糖正常、早期和晚期血糖恶化。在确保质量控制后，发现队列包括 8 个 ND、20 个 IGT 和 12 个 DEP，而验证队列包括 27 个 ND、15 个 IGT 和 20 个 DEP。基因集富集分析（GSEA）采用差异表达基因（DEG），而免疫细胞浸润则使用单样本基因集富集分析（ssGSEA）来确定。此外，还进行了相关性分析，以确定临床特征和免疫细胞浸润之间的联系。最小绝对收缩和选择算子回归以及随机森林相结合来识别表明 DP 患者血糖恶化的生物标志物。这些生物标志物通过独立队列和动物实验得到进一步验证。随着血糖恶化，DP 患者的胰岛生物过程（例如营养代谢和复杂的免疫反应）受到破坏。 ACOT4、B2M和ACKR2的表达上调，而CACNA1F的表达下调。 胰岛微环境中的免疫细胞浸润与患者年龄、体重指数（BMI）、HbA1c和2小时血糖呈显着正相关。这是血糖恶化的关键因素。此外，B2M 与免疫细胞浸润和临床特征呈显着正相关。实时定量 PCR (qRT-PCR) 和蛋白质印迹证实了 B2M 中的上调。免疫荧光染色提示B2M的改变主要发生在α细胞和β细胞。总体而言，该研究表明，逐渐增加的免疫细胞浸润是 DP 患者血糖恶化的一个重要因素，并且还强调了 B2M 作为一种生物标志物。