# Age- and diet-dependent progression of retinal microvascular injury in GCK-MODY under metabolic stress

## TL;DR

This study shows that GCK-MODY mice develop retinal damage under long-term high-fat diets, revealing a new link between metabolic stress and eye complications.

## Contribution

The study identifies a NOX2-driven pathway linking oxidative stress, inflammation, and apoptosis in retinal injury under metabolic stress in GCK-MODY.

## Key findings

- GCKMut mice on high-fat diets showed retinal microvascular injury at 60 weeks.
- Elevated ROS, NOX2, and inflammatory markers were observed in late-stage retinal damage.
- NOX2 levels correlated with increased inflammation and apoptosis in GCKMut mice.

## Abstract

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.

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.

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.

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.