PUBLICATION
An Association between Insulin Resistance and Neurodegeneration in Zebrafish Larval Model (Danio rerio)
- Authors
- Md Razip, N.N., Mohd Noor, S., Norazit, A., Nordin, N., Sakeh, N.M., Khaza'ai, H.
- ID
- ZDB-PUB-220813-2
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(15): (Journal)
- Registered Authors
- Keywords
- glucose, insulin resistance, neurodegeneration, type 2 diabetes mellitus, zebrafish
- MeSH Terms
-
- Animals
- Claudins/metabolism
- Diabetes Mellitus, Type 2*
- Embryo, Nonmammalian/metabolism
- Glucose/metabolism
- Insulin/metabolism
- Insulin Resistance*
- Larva/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Zebrafish/genetics
- PubMed
- 35955446 Full text @ Int. J. Mol. Sci.
Citation
Md Razip, N.N., Mohd Noor, S., Norazit, A., Nordin, N., Sakeh, N.M., Khaza'ai, H. (2022) An Association between Insulin Resistance and Neurodegeneration in Zebrafish Larval Model (Danio rerio). International Journal of Molecular Sciences. 23(15).
Abstract
Background Type 2 diabetes mellitus has recently been identified as a mediator of neurodegeneration. However, the molecular mechanisms have not been clearly elucidated. We aimed to investigate insulin resistance associated with neurodegenerative events in zebrafish larvae.
Methods Larvae aged 72 h-post-fertilization (hpf) were induced to insulin resistance by immersion in 250 nM insulin and were then reinduced with 100 nM insulin at 96 hpf. This model was validated by a glucose levels assay, qPCR analysis of selected genes (akt, pepck, zglut3 and claudin-5a) and Oil Red-O (ORO) staining of the yolk sac for lipid distribution. The association of insulin resistance and neurodegeneration was validated by malondialdehyde (MDA), glutathione (GSH) assays, and by integrating next-generation sequencing with database for annotation, visualization and integrated discovery (DAVID).
Results There was a significant increase in glucose levels at 180 min in the insulin-resistant group. However, it decreased at 400 min after the re-challenge. Insulin-signaling mediators, akt and pepck, were showed significantly downregulated up to 400 min after insulin immersion (p < 0.05). Meanwhile, claudin-5a assessed blood-brain barrier (BBB) integrity and showed significant deterioration after 400 min of post-insulin immersion. ORO staining remarked the increase in yolk sac size in the insulin-resistant group. After the confirmation of insulin resistance, MDA levels increased significantly in the insulin-resistant group compared to the control group in the following parameters. Furthermore, dysregulated MAPK- and Wnt/Ca2+-signaling pathways were observed in the insulin-resistant group, disrupting energy metabolism and causing BBB injury.
Conclusions We conclude that the insulin-resistant zebrafish larvae alter the metabolic physiology associated with neurodegeneration.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping