Blunted cortisol and altered antioxidant defense as biomarkers of systemic stress in hyperglycemic Zebrafish

Emerging evidence links hyperglycemia, a "hallmark of diabetes mellitus" not only to peripheral metabolic dysfunction but also to its detrimental impact on brain health, often contributing to stress-related pathologies such as depression and cognitive decline. Zebrafish, with their well-characterized vascular system and behavioral assays, offer a unique model to study the impacts of sucrose-induced hyperglycemia. This study aims to investigates the effects of sucrose-induced hyperglycemia on stress mechanisms in type 2 diabetes using the zebrafish.

Male zebrafish were divided into two groups: control, and 55.5mM sucrose immersed. Over two weeks, these were subjected to behavioural assays- the novel tank test (NTT) and the light/dark test (LDT). The NTT assessed anxiety-related behaviour by measuring the time spent in different vertical zones of a novel tank, while the light/dark test evaluated anxiety responses based on the time spent in illuminated versus dark compartments. Trajectory body coordinates and tail kinematics were quantified using ZebraZoom software to asses locomotor metrics status. Cortisol levels were measured to assess HPA axis function. Antioxidant enzymes, including superoxide dismutase (SOD) and catalase (CAT), were quantified to evaluate oxidative stress.

The results revealed that zebrafish exposed to sucrose exhibited significant hyperglycemia (**p < 0.01) and behavioural changes compared to those on control. Specifically, in the NTT, the hyperglycemic group demonstrated heightened anxiety-like behaviour, spending more time at the bottom zone of the tank. In the light/dark test, male zebrafish showed increased anxiety by spending more time in the dark compartment. Hyperglycemic zebrafish showed a significant blunting of the cortisol response, indicating impaired stress regulation. Additionally, SOD activity was increased, while CAT activity was decreased, suggesting an imbalance in antioxidative defense mechanisms.

The zebrafish system effectively models the negative impacts of sucrose-induced hyperglycemia, providing valuable insights into the stress mechanisms associated with type 2 diabetes. These findings demonstrate that hyperglycemia alters both endocrine stress response and antioxidant systems, potentially serving as biomarkers of systemic stress.