Author:
Wang Zhen,Zhang Guolin,Fu Jixian,Li Guangxing,Zhao Zhihao,Choe HyokChol,Ding Kaiyue,Ma Junnan,Wei Jing,Shang Dong,Zhang Lin
Abstract
AbstractThe 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.
Funder
Dalian Medical University Foundation for Teaching Reform Project of Undergraduate Innovative Talents
Natural Science Foundation of Liao Ning Province
National Natural Science Foundation of China
Liaoning Revitalization Talents Program
Natural Science Foundation of Liaoning Province
Distinguished Young Scholars in Dalian
Publisher
Springer Science and Business Media LLC
Reference65 articles.
1. Woodmansey, C. et al. Incidence, demographics, and clinical characteristics of diabetes of the exocrine pancreas (Type 3c): A retrospective cohort study. Diabetes Care 40, 1486–1493 (2017).
2. Zhi, M. et al. Incidence of new onset diabetes mellitus secondary to acute pancreatitis: A systematic review and meta-analysis. Front. Physiol. 10, 637 (2019).
3. Petrov, M. S. & Basina, M. Diagnosis of endocrine disease: Diagnosing and classifying diabetes in diseases of the exocrine pancreas. Eur. J. Endocrinol. 184, R151–R163 (2021).
4. Wang, F., Gupta, S. & Holly, E. A. Diabetes mellitus and pancreatic cancer in a population-based case-control study in the San Francisco Bay Area. California. Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 15, 1458–1463 (2006).
5. Pannala, R. et al. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 134, 981–987 (2008).