Glucagon-like peptide-1 receptor agonist prevents pulmonary fibrosis following acute COVID-19 infection associated with type 2 diabetes

作者：Runhong Zhou, Ming Yue, Qing Shen, Na Liu, Yuting Chen, Pui Wang, Kyungmin Kim, Ranyao Yang, Honglin Chen, Kwok-Yung Yuen, Kelvin Kai‐Wang To, Aimin Xu, Zhiwei Chen · 发表于：Journal of Virology · 年份：2026 · DOI：10.1128/jvi.00401-26 · 研究领域：COVID-19 Clinical Research Studies、Long-Term Effects of COVID-19、Pharmacological Receptor Mechanisms and Effects

ABSTRACT Post-acute sequelae of COVID-19 (PASC) poses a major health burden after SARS-CoV-2 infection. Although type 2 diabetes (T2D) is associated with PASC, the mechanism of T2D-mediated PASC in the lung remains elusive. Here, we found that people with T2D (PWT2D) exhibited significantly upregulated fibrosis-related genes in monocytes, which positively correlated with pulmonary fibrosis-related biomarkers up to 3 months after acute SARS-CoV-2 infection. Using db/db mice to model human T2D, we found consistently that SARS-CoV-2 infection resulted in upregulation of fibrosis-related genes in lung macrophages and persistent pulmonary fibrosis. Moreover, the macrophage-depletion demonstrated that pro-inflammatory macrophages in db/db mice were determinants for inducing pulmonary fibrosis post-infection. Importantly, the anti-T2D glucagon-like peptide-1 receptor agonist (GLP1-RA) reprogramed macrophage responses to SARS-CoV-2 by normalizing fibrosis-related genes, significantly reducing the pulmonary fibrosis in a glucose-independent manner. These findings demonstrated that SARS-CoV-2-induced proinflammatory macrophages are detrimental factors in T2D-mediated PASC, which can be prevented by GLP1-RA. IMPORTANCE Some COVID-19 patients develop pulmonary post-acute sequelae of COVID-19 (PASC) with clinical symptoms lasting for years. Critically, the incidence of pulmonary PASC in PWT2D is four times higher than that in those without T2D. However, the immune mechanisms underlying pu...