A Narrative Review of Zebrafish Models of Diabetes Mellitus

Diabetes mellitus is a major chronic metabolic disease characterized by persistent hyperglycemia resulting from impaired insulin secretion, impaired insulin action, or both, and is associated with microvascular and macrovascular complications. Although rodent models remain central to diabetes research, zebrafish (Danio rerio) have emerged as a powerful complementary vertebrate model because of their genetic and physiological conservation with humans, rapid development, optical transparency during early life stages, high fecundity, low maintenance cost, and suitability for high-throughput drug screening. Several reviews have addressed specific aspects of zebrafish diabetes research, but fewer provide an integrated comparison across the major genetic, chemical, and dietary models while also emphasizing translational relevance, model selection, and practical limitations. This narrative review, therefore, provides a comparative overview of the major zebrafish diabetes models and their principal applications. We group models into genetic models with predominant beta-cell dysfunction or insulin deficiency and those with predominant insulin resistance or type 2 diabetes-like metabolic dysfunction; chemical models including beta-cell-toxic agents such as streptozotocin and alloxan, as well as metabolically oriented glucose immersion and endocrine-disruptor exposures; and dietary models based on overfeeding and high-fat, high-glucose, or combined cholesterol-glucose regimens. Across these model classes, we compare induction strategy, principal phenotype, relevance to type 1 versus type 2 diabetes, strengths, limitations, and typical research applications in drug discovery, regeneration, pharmacogenomics, and studies of complications. We also emphasize that there is no universally accepted single diagnostic glycemic threshold for diabetes in zebrafish; instead, model validation usually relies on sustained elevation of glucose relative to controls together with functional or mechanistic readouts such as glucose tolerance, insulin signaling, beta-cell mass, and lipid-metabolic changes. Despite important physiological differences from mammals and the strong regenerative capacity of zebrafish, the model provides a scalable vertebrate platform for mechanistic and early translational diabetes research.