ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Diabetes: Molecular Mechanisms
Age-and diet-dependent progression of retinal microvascular injury in GCK-MODY under metabolic stress
Yadi Huang 1
YangLiu Liu 1
Yiqing Wang 1
Xuan Liu 1
Shuhui Ji 2
Shanshan Chen 1
Hua Shu 1
Yu Fan 1
Ming Liu 1
Xin Li 1
1. Tianjin Medical University General Hospital, Tianjin, China
2. The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
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Abstract
Background: Maturity-onset diabetes of the young type 2 (GCK-MODY), caused by heterozygous inactivating mutations in the glucokinase (GCK) gene, is generally considered a mild and stable form of diabetes with a relatively low risk of chronic complications. However, whether GCK deficiency predisposes to retinal microvascular injury under metabolic stress remains unclear. Methods: A GCK-Q26L knock-in mouse model (GCKMut) was used to evaluate age-and diet-dependent alterations in retinal morphology and molecular pathology under normal diet (ND) and high-fat diet (HFD) conditions at 28, 40, and 60 weeks. Retinal structure and vasculature were examined by H&E staining and trypsin digestion. Oxidative stress, inflammation, and apoptosis were assessed using dihydroethidium fluorescence, Western blotting, and immunohistochemistry. Correlation analyses were performed to determine the relationship between NOX2 expression and inflammatory/apoptotic markers. Results: Under ND, retinal morphology and microvasculature were comparable between GCKMut and WT mice at 28, 40, and 60 weeks. In contrast, after prolonged HFD exposure, 60-week-old GCKMut mice exhibited clear microvascular injury, characterized by increased acellular capillaries and pronounced pericyte loss. At this late stage, retinal ROS levels were elevated, accompanied by NOX2 upregulation and increased expression of IL-1β and TNF-α. Apoptotic signaling was concurrently enhanced, as reflected by increased cleaved caspase-3 and a higher Bax/Bcl-2 ratio. Consistently, NOX2 protein levels correlated positively with inflammatory and apoptotic markers. Conclusions: This study demonstrates that GCK inactivation can predispose to retinal microvascular injury under prolonged metabolic stress. These findings support a NOX2-centered oxidative stress–linked inflammatory and apoptotic axis in late-stage retinal injury and highlight potential therapeutic targets for risk reappraisal in GCK-MODY.
Summary
Keywords
Apoptosis, Diabetic Retinopathy, GCK-MODY, Inflammation, Oxidative Stress
Received
12 November 2025
Accepted
18 February 2026
Copyright
© 2026 Huang, Liu, Wang, Liu, Ji, Chen, Shu, Fan, Liu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yu Fan; Ming Liu; Xin Li
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