Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity. However, the precise mechanisms responsible for the combined impact of corona virus disease 2019 (COVID-19) and diabetes have not yet been elucidated, and effective treatment options for SARS-CoV-2-infected diabetic patients remain limited. To investigate the disease pathogenesis, K18-hACE2 transgenic (hACE2 Tg) mice with a leptin receptor deficiency (hACE2-Lepr -/-) or high-fat diet (hACE2-HFD) background were generated. The two mouse models were intranasally infected with a 5×10 5 median tissue culture infectious dose (TCID 50) of SARS-CoV-2, with serum and lung tissue samples collected at 3 days post-infection. The hACE2-Lepr -/- mice were then administered a combination of low-molecular-weight heparin (LMWH) (1 mg/kg or 5 mg/kg) and insulin via subcutaneous injection prior to intranasal infection with 1×10 4 TCID 50 of SARS-CoV-2. Daily drug administration continued until the euthanasia of the mice. Analyses of viral RNA loads, histopathological changes in lung tissue, and inflammation factors were conducted. Results demonstrated similar SARS-CoV-2 susceptibility in hACE2 Tg mice under both lean (chow diet) and obese (HFD) conditions. However, compared to the hACE2-Lepr +/+ mice, hACE2-Lepr -/- mice exhibited more severe lung injury, enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α, and increased apoptosis. Moreover, combined LMWH and insulin treatment effectively reduced disease progression and severity, attenuated lung pathological changes, and mitigated inflammatory responses. In conclusion, pre-existing diabetes can lead to more severe lung damage upon SARS-CoV-2 infection, and LMWH may be a valuable therapeutic approach for managing COVID-19 patients with diabetes.
糖尿病和肥胖患者在感染严重急性呼吸系统综合征冠状病毒2型（severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）后往往出现更严重的症状且预后较差。然而，为何出现这种现象，新型冠状病毒肺炎（corona virus disease 2019, COVID-19）与糖尿病相互影响的潜在致病机制尚未阐明，临床上针对SARS-CoV-2感染的糖尿病患者的有效治疗方案仍然有限。为了探索其发病机制，该研究分别构建了具有瘦素受体基因敲除背景（hACE2-Lepr -/-）和高脂饮食（high-fat diet, HFD）背景（hACE2-HFD）的K18-hACE2转基因（hACE2 Tg）小鼠模型。通过滴鼻感染SARS-CoV-2，感染后每日观察小鼠临床表现、监测体重变化、血糖变化，并在安乐死后采集小鼠肺脏组织检测肺脏中病毒载量及肺脏病理变化，以确定两种小鼠模型对新冠病毒易感性。为了探究肝素对SARS-CoV-2感染的糖尿病患者的治疗效果，对hACE2-Lepr -/-小鼠在鼻内感染SARS-CoV-2之前，先经皮下注射低剂量（1 mg/kg）和高剂量（5 mg/kg）的低分子肝素 （low-molecular-weight heparin, LMWH），每日持续给药直至小鼠安乐死。实验过程中监测小鼠体重、临床表征、血糖变化，同时采集小鼠肺脏组织，检测肺脏组织中病毒载量、肺组织病理学变化和炎症因子水平。结果表明，hACE2 Tg小鼠在正常饮食状态和肥胖（HFD）状态下对 SARS-CoV-2的易感性相似。然而，与hACE2-Lepr +/+小鼠相比，hACE2-Lepr -/-小鼠表现出更严重的肺损伤，炎症因子如缺氧诱导因子1α（hypoxia-inducible factor-1α, HIF-1α）的表达增加，细胞凋亡增强。此外，LMWH与胰岛素联合治疗后可有效减少糖尿病小鼠的疾病进展和严重程度，减轻肺部病理变化和炎症反应。总之，糖尿病可能会在SARS-CoV-2感染后导致更严重的肺损伤，而 LMWH联合胰岛素可能是治疗患有糖尿病的COVID-19患者的一种有价值的治疗方法。.
Keywords: Antiviral therapy; Diabetes; Heparin; Mouse model; SARS-CoV-2.