Toledo Frederico G S, Li Yisheng, Wang Fuchenchu, Bellin Melena D, Brand Randall, Cusi Kenneth, Fisher William, Kudva Yogish C, Park Walter G, Saeed Zeb I, Yadav Dhiraj, Considine Robert V, Graham Sarah C, Andersen Dana K, Serrano Jose, Goodarzi Mark O, Hart Phil A
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Diabetologia. 2025 Sep 24. doi: 10.1007/s00125-025-06543-y.
AIMS/HYPOTHESIS: Pancreatic ductal adenocarcinoma-related diabetes mellitus (PDAC-DM) is a paraneoplastic syndrome with a poorly understood pathophysiology. PDAC-DM is often clinically confused with type 2 diabetes, resulting in delayed cancer detection and poorly individualised hyperglycaemia treatment. We investigated whether these forms of diabetes can be distinguished at the metabolic level.
Adults with either cancer treatment-naive PDAC-DM (n=28) or type 2 diabetes (n=97), and with diabetes onset within 3 years, underwent mixed-meal tolerance tests to investigate glucose metabolism. Outcomes included insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), beta cell function (oral disposition index), insulin clearance, and postprandial glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) responses.
Compared with type 2 diabetes, individuals with PDAC-DM showed ~2.5-fold greater insulin sensitivity, ~81% lower insulin secretion and ~40% lower beta cell function. Insulin clearance was higher in the PDAC-DM group than the type 2 diabetes group, with and without adjustment for insulin sensitivity. Glucagon and GLP-1 levels increased after a meal in both groups, but levels were higher in the PDAC-DM group. GIP levels were similar between groups. The metabolic differences between groups persisted after adjustment for age, sex and BMI.
CONCLUSIONS/INTERPRETATION: PDAC-DM and type 2 diabetes are metabolically distinct, with different defects responsible for hyperglycaemia. PDAC-DM is characterised predominantly by insulin deficiency and displays higher insulin sensitivity than type 2 diabetes. There are also differences in alpha cell regulation and insulin clearance compared with type 2 diabetes. These findings identify biological characteristics that may have implications for individualised treatment of PDAC-DM and guide diagnostic biomarker discovery for early PDAC diagnosis.
目的/假设：胰腺导管腺癌相关糖尿病（PDAC-DM）是一种副肿瘤综合征，其病理生理学机制尚不清楚。PDAC-DM在临床上常与2型糖尿病混淆，导致癌症检测延迟和高血糖治疗个体化不足。我们研究了这两种糖尿病形式在代谢水平上是否可以区分。
对未接受过癌症治疗的PDAC-DM患者（n=28）和2型糖尿病患者（n=97），且糖尿病发病时间在3年内的成年人进行混合餐耐量试验，以研究葡萄糖代谢。结果包括胰岛素敏感性（松田指数）、胰岛素分泌（胰岛素生成指数）、β细胞功能（口服处置指数）、胰岛素清除率以及餐后胰高血糖素、胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）反应。
与2型糖尿病相比，PDAC-DM患者的胰岛素敏感性高约2.5倍，胰岛素分泌低约81%，β细胞功能低约40%。无论是否调整胰岛素敏感性，PDAC-DM组的胰岛素清除率均高于2型糖尿病组。两组餐后胰高血糖素和GLP-1水平均升高，但PDAC-DM组水平更高。两组间GIP水平相似。在调整年龄、性别和BMI后，两组间的代谢差异仍然存在。
结论/解读：PDAC-DM和2型糖尿病在代谢上是不同的，高血糖的原因存在不同缺陷。PDAC-DM主要特征为胰岛素缺乏，且比2型糖尿病表现出更高的胰岛素敏感性。与2型糖尿病相比，α细胞调节和胰岛素清除率也存在差异。这些发现确定了可能对PDAC-DM个体化治疗有影响的生物学特征，并指导早期PDAC诊断的生物标志物发现。
