A Zebrafish Model of Diabetes Mellitus and Metabolic Memory

Abstract

Diabetes mellitus currently affects 346 million individuals and this is projected to increase to 400 million by 2030. Evidence from both the laboratory and large scale clinical trials has revealed that diabetic complications progress unimpeded via the phenomenon of metabolic memory even when glycemic control is pharmaceutically achieved. Gene expression can be stably altered through epigenetic changes which not only allow cells and organisms to quickly respond to changing environmental stimuli but also confer the ability of the cell to "memorize" these encounters once the stimulus is removed. As such, the roles that these mechanisms play in the metabolic memory phenomenon are currently being examined.We have recently reported the development of a zebrafish model of type I diabetes mellitus and characterized this model to show that diabetic zebrafish not only display the known secondary complications including the changes associated with diabetic retinopathy, diabetic nephropathy and impaired wound healing but also exhibit impaired caudal fin regeneration. This model is unique in that the zebrafish is capable to regenerate its damaged pancreas and restore a euglycemic state similar to what would be expected in post-transplant human patients. Moreover, multiple rounds of caudal fin amputation allow for the separation and study of pure epigenetic effects in an in vivo system without potential complicating factors from the previous diabetic state. Although euglycemia is achieved following pancreatic regeneration, the diabetic secondary complication of fin regeneration and skin wound healing persists indefinitely. In the case of impaired fin regeneration, this pathology is retained even after multiple rounds of fin regeneration in the daughter fin tissues. These observations point to an underlying epigenetic process existing in the metabolic memory state. Here we present the methods needed to successfully generate the diabetic and metabolic memory groups of fish and discuss the advantages of this model. Video LinkThe video component of this article can be found at

Anatomic and molecular characterization of the endocrine pancreas of a teleostean fish: Atlantic wolffish (Anarhichas lupus)

“…Since the last decade, teleost species have become important as model systems in different areas of hormonal, metabolic, and immunologic research (Intine et al 2013;McGonnell and Fowkes 2006). One advantage of using teleost fish in studies of diabetes mellitus is that the pancreatic endocrine cells are separated from the pancreatic exocrine tissue and can be easily isolated and harvested.…”

Animal Models of Diabetic Retinopathy

“…Induction of DR by STZ has been observed in multiple models including mice, rabbits, pigs, rats, dogs, zebrafish, and monkeys [31,[63][64][65][66][67][68][69][70]. STZ is now generally preferred over alloxan, as it is more effective in recapitulating the diabetic disease state, though both drugs are still commonly used [41].…”

“…Adult zebrafish, 4-6 months of age, injected with multiple doses of STZ intraperitoneally or through direct caudal fin injection over one or several weeks, develop hyperglycemia and within 3 weeks, and display inner plexiform layer (IPL) thinning, photoreceptor segment layer (PSL) thinning, cone receptor dysfunction, and neuronal damage by 4 weeks [69,70]. This model is maintained approximately 80 days after induction of diabetes [70].…”

Type 2 Diabetes Mellitus (T2DM): Biological Overview from Pathways to Organelles and its Translation toward a Torpid Wound Healing Process

“…Thus the initial hyperglycemic hit translates into a permanently harmful cellular imprinting identified since 1993 as "metabolic memory". In other words, this term represents the ability to sustain and perpetuate diabetic complications involving epigenetic events [77]. show that a number of gene/proteins appear to be "imprinted" as to predispose or to lead to insulin resistance and T2DM.…”