ABSTRACT Recently, diabetes mellitus (DM) has shown rapid global increases with about five million deaths annually. Animal models are imperative to understand disease mechanisms and develop diagnostic, preventive, and therapeutic interventions in translational research. Rodent and mini-pig models have been established and widely used for DM research. However, domestic pig models are limited in spite of advantages such as pharmacokinetic and physiopathological availability. This study examines the potential use of domestic pigs expressing recombinant human erythropoietin (rhEPO) as disease and therapeutic response models for DM. We previously generated transgenic pigs (n = 16, EPO Tg) in which rhEPO was expressed and circulated in all organs. Thirty-two pigs, including 16 controls, were fed high fat (HF) diets for 42 weeks. Subsequently, blood samples for chemical and metabolic analysis were collected after fasting for 24 h and glucose loading for oral glucose tolerance tests (OGTTs). We found increased activation of the PI3 K/Akt signaling pathway under hypoxic conditions after rhEPO treatment, and HF diet-inducible-obesity in the EPO Tg and control pigs. OGTTs showed lower fasting glucose levels in the EPO Tg pigs than in controls before and after the HF diet, suggesting that rhEPO may affect glucose concentrations. Insulin and C-peptide concentrations responded slowly to glucose administration and returned to initial levels after 2 h. The blood test results suggest that EPO might affect metabolic and chemical components such as glucose, high-density lipoprotein, glucagon, triglyceride, and free fatty acid. Our findings support the use of rhEPO transgenic domestic pigs as model animals for translational DM research.

中文翻译：

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表达重组人促红细胞生成素的转基因家猪在糖尿病转化研究中的潜在用途

摘要 最近，糖尿病 (DM) 在全球范围内迅速增加，每年约有 500 万人死亡。动物模型对于理解疾病机制和在转化研究中开发诊断、预防和治疗干预措施至关重要。啮齿动物和迷你猪模型已经建立并广泛用于 DM 研究。然而，尽管具有药代动力学和病理生理学可用性等优点，但家猪模型仍受到限制。本研究考察了表达重组人促红细胞生成素 (rhEPO) 的家猪作为 DM 的疾病和治疗反应模型的潜在用途。我们以前生成了转基因猪（n = 16，EPO Tg），其中rhEPO 在所有器官中表达和循环。32 头猪，包括 16 头对照，饲喂高脂肪 (HF) 饮食 42 周。随后，在禁食 24 小时和葡萄糖负荷后收集用于化学和代谢分析的血液样本用于口服葡萄糖耐量试验 (OGTT)。我们发现在低氧条件下，rhEPO 处理后 PI3 K/Akt 信号通路的激活增加，EPO Tg 和对照猪的 HF 饮食诱导肥胖。OGTT 显示 EPO Tg 猪的空腹血糖水平低于 HF 饮食前后的对照组，表明 rhEPO 可能影响葡萄糖浓度。胰岛素和 C 肽浓度对葡萄糖给药反应缓慢，2 小时后恢复到初始水平。血液测试结果表明，EPO 可能会影响代谢和化学成分，如葡萄糖、高密度脂蛋白、胰高血糖素、甘油三酯和游离脂肪酸。