OBJECTIVE-Results from the Diabetes Control ComplicationsTrial (DCCT) and the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) Study and more recently from the U.K. Prospective Diabetes Study (UKPDS) have revealed that the deleterious end-organ effects that occurred in both conventional and more aggressively treated subjects continued to operate Ͼ5 years after the patients had returned to usual glycemic control and is interpreted as a legacy of past glycemia known as "hyperglycemic memory." We have hypothesized that transient hyperglycemia mediates persistent geneactivating events attributed to changes in epigenetic information. RESEARCH DESIGN AND METHODS-Models of transienthyperglycemia were used to link NFB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyltransferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFB-p65 chromatin. RESULTS-The sustained upregulation of the NFB-p65 gene as a result of ambient or prior hyperglycemia was associated with increased H3K4m1 but not H3K4m2 or H3K4m3. Furthermore, glucose was shown to have other epigenetic effects, including the suppression of H3K9m2 and H3K9m3 methylation on the p65 promoter. Finally, there was increased recruitment of the recently identified histone demethylase LSD1 to the p65 promoter as a result of prior hyperglycemia.CONCLUSIONS-These studies indicate that the active transcriptional state of the NFB-p65 gene is linked with persisting epigenetic marks such as enhanced H3K4 and reduced H3K9 methylation, which appear to occur as a result of effects of the methyl-writing and methyl-erasing histone enzymes. Diabetes 58:1229-1236, 2009 V ascular complications are the major source of morbidity and mortality in diabetes and are considered, based on both epidemiological data and from more mechanistic studies, to occur primarily as a result of the long-term deleterious effects of hyperglycemia. Interestingly, these vascular complications often persist and may progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Results in both type 1 and type 2 diabetes, as observed in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study and in the recent follow-up of the U.K. Prospective Diabetes Study (UKPDS), have revealed that end-organ effects that occurred in both conventional and intensified glycemic control groups continued to operate Ͼ5 years after the patients had returned to their usual level of glycemic control (1,2). These studies suggest that the injurious effects of exposure to high glucose levels persist for many years after these episodes of altered metabolic control and this is typically referred to as either "hyperglycemic memory" (3) or the legacy effect (4). Recently, several clinical trials, including the ADVANCE (5) and ACCORD studies (6), failed to demonstrate that intensified glycemic control for 3-5 years markedly reduced ...

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