Genetic and chemically-induced Zebrafish models for the study of diabetes mellitus

Diabetes mellitus (DM) will likely affect over 400 million worldwide by 20301 and is classified as a disease of metabolic dysfunction related to the homeostasis of systemic glucose levels [e.g. elevated glucose levels or what is termed hyperglycemia (HG)].2,3 DM can be subdivided into type-1 DM and type-2 DM. In type-1 DM the ability of insulin to be produced is impaired while in type-2 DM, the ability of the body to respond to insulin is impaired. While management of systemic glucose levels is essential to the health of the patient, the long term secondary complications of diabetes poses an equally critical problem. In this regard, data from the laboratory4–10 and from clinical trials11–23 indicate that complications from the onset of hyperglycemia progress unimpeded via the phenomenon of “metabolic memory” (MM) even when glycemic control is pharmaceutically achieved.11–23 This applies to both type 1 and type 2 diabetes. The underlying molecular mechanisms of hyperglycemic complications and metabolic memory involve: 1) the involvement of excess reactive oxygen species (ROS), 2) the involvement of advanced glycation end products (AGE), and 3) alterations in tissue-wide gene expression patterns.2,3 The heritable nature of metabolic memory24,25 points to involvement of the epigenome. In general terms, the epigenome is comprised of all chromatin modifying processes including DNA methylation and histone modifications allowing cells/organisms to quickly respond to changing environmental stimuli.26–28 Furthermore, these processes allow for quick adaptation to environmental stimuli but also impart the ability of the cell to “memorize” these encounters.24,25 The underlying molecular mechanism/s of MM has been examined via both animal model approaches and in vitro based studies.4–10 These studies have established that the initial hyperglycemia results in permanent aberrant gene expression in DM target tissues such as the: kidney, retina, cardiovascular system, skin as related to wound healing, and impaired blood vessel growth such as seen in wound healing.