Olsen, A.S., Sarras, M.P., Leontovich, A., and Intine, R.V. (2012) Heritable Transmission of Diabetic Metabolic Memory in Zebrafish Correlates With DNA Hypomethylation and Aberrant Gene Expression. Diabetes. 61(2):485-491.
Metabolic memory (MM) is the phenomenon whereby diabetes complications persist and progress after glycemic recovery is achieved.
Here, we present data showing that MM is heritable and that the transmission correlates with hyperglycemia-induced DNA hypomethylation
and aberrant gene expression. Streptozocin was used to induce hyperglycemia in adult zebrafish, and then, following streptozocin
withdrawal, a recovery phase was allowed to reestablish a euglycemic state. Blood glucose and serum insulin returned to physiological
levels during the first 2 weeks of the recovery phase as a result of pancreatic β-cell regeneration. In contrast, caudal fin
regeneration and skin wound healing remained impaired to the same extent as in diabetic fish, and this impairment was transmissible
to daughter cell tissue. Daughter tissue that was never exposed to hyperglycemia, but was derived from tissue that was, did
not accumulate AGEs or exhibit increased levels of oxidative stress. However, CpG island methylation and genome-wide microarray
expression analyses revealed the persistence of hyperglycemia-induced global DNA hypomethylation that correlated with aberrant
gene expression for a subset of loci in this daughter tissue. Collectively, the data presented here implicate the epigenetic
mechanism of DNA methylation as a potential contributor to the MM phenomenon.