在患有外分泌胰腺(DP)疾病的患者中,对内分泌胰腺的损害导致血糖恶化减少,最终导致胰腺外分泌型糖尿病(DEP)。本研究旨在探讨DP患者血糖恶化的机制。并确定有用的生物标志物,以提高临床实践意识为最终目标。本研究中DP患者的基因表达谱从基因表达综合数据库获得。原始研究将DP患者定义为以下三类之一:非糖尿病(ND),糖耐量受损(IGT)和DEP,对应于血糖正常,早期和晚期血糖恶化,分别。在确保质量控制后,发现队列包括8ND,20IGT,和12DEP,而验证队列包括27ND,15IGT,20DEP基因集富集分析(GSEA)采用差异表达基因(DEGs),而免疫细胞浸润使用单样品基因组富集分析(ssGSEA)确定。此外,进行相关分析以建立临床特征与免疫细胞浸润之间的联系。最小绝对收缩和选择算子回归和随机森林相结合,以识别指示DP患者血糖恶化的生物标志物。通过独立的队列和动物实验进一步验证了这些生物标志物。随着血糖恶化,在DP患者中,胰岛的生物学过程如营养代谢和复杂的免疫反应被破坏.ACOT4、B2M、ACKR2上调,而CACNA1F的表达下调。胰岛微环境中免疫细胞浸润与年龄呈显著正相关,体重指数(BMI),患者2小时的HbA1c和血糖。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著正相关。定量实时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。总的来说,研究表明,逐渐增加的免疫细胞浸润是DP患者血糖恶化的重要原因,它还强调了B2M作为生物标志物。
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.