Metabolic memory: Evolving concepts.

The relationships of glycemic control over time with the development of complications have been investigated in several studies, but new areas of debate continue to arise. Does glycemic control have greater benefit when attained earlier than when attained later in the natural history of diabetes? Is it simply the duration of better or worse levels of glycemia that lead a given individual to have fewer or greater levels of complications? Might glycemic control have similar benefit throughout the duration of diabetes until irreversible damage occurs, perhaps varying by organ system (neurologic, renal, retinal, cardiovascular)? Specific benefits or adverse effects of treatment agents may further complicate the interpretation of what has been characterized as "metabolic memory." The notion of metabolic memory was based on findings of the Diabetes Control and Complications Trial (DCCT) of type 1 diabetes (T1D), in which the initial 2% HbA1c separation between the groups of patients randomized to intensive or conventional control was lost during the follow up Epidemiology of Diabetes Interventions and Complications (EDIC) study, when the two groups of participants returned to standard treatment and showed similar HbA1c levels but the initial intensively treated group continued to have lower rates of development of microvascular and, subsequently, macrovascular complications. Similarly, a decade after the conclusion of the UK Prospective Diabetes Study (UKPDS), patients with type 2 diabetes (T2D) in the intensive therapy group, despite showing similar levels of glycemic control to those receiving standard care, continued to have significant reductions in microvascular endpoints and reductions in myocardial infarction and all-cause mortality. A 6-year follow up of the Veteran's Administration Diabetes Trial suggested that the formerly intensively controlled subset were more likely to maintain an estimated glomerular filtration rate >60 ml/min/1.73m2 than those randomized to standard control. However, the UKPDS blood pressure control trial showed a reduction in complications, but no difference between the intervention and control groups was seen during the follow-up of this portion of the study, suggesting that no such "memory" exists for these interventions. The molecular mechanisms underlying these long-term effects of prior periods of better or worse glycemic control continue to be investigated. Extended periods of exposure to high glucose levels persistently dysregulated fibrotic and inflammatory genes in endothelial and vascular smooth muscle cells. Furthermore, epigenetic processes may contribute to metabolic memory, with evidence that post-translational histone methylation and changes in microRNA may persist after exposure to high glucose levels is terminated. In this context, it is of note that the zebrafish model of T1D exhibits regeneration of the pancreas, becoming euglycemic after a period of hyperglycemia, but with evidence in this model that delay in skin wound healing persists indefinitely even after multiple rounds of fin regeneration, suggesting a long-lasting adverse effect of prior hyperglycemia. Such epigenetic differences were reported in genes related to the nuclear factor-κB inflammatory pathway and to diabetes complications in a study of intensive versus conventional treatment patients followed from the DCCT. A further mechanism that has been suggested is a role of dysregulated mitochondrial biogenesis contributing to deterioration of retinopathy even after a period of good glycemic control continues. Interestingly, in this issue of the Journal, Pantalone et al. present a study that touches upon our first question, failing to find a relationship between the HbA1c level measured at the time of diabetes diagnosis and subsequent outcome. The study analyzed relationships between glycemic control and complications among >30 000 people with newly diagnosed T2D followed for the subsequent decade. Might the level of HbA1c at the time of diagnosis simply reflect a brief period of glycemic exposure, so that it would not be expected to be of consequence? The ratio of undiagnosed to diagnosed diabetes in National Health and Nutrition Surveys (NHANES) carried out from 1999 to 2010, and from 2011 to 2012, is roughly 1: 2, suggesting that at the time of initial diagnosis diabetes often may be present for a substantial period, implying that prediagnosis exposure to elevated glucose levels has a bearing on subsequent outcome. Bianchi and del Prato suggest an interesting interpretation of "bad glycemic legacy" based on the Veterans Administration Diabetes Trial (VADT). In that study, 1791 military veterans with a mean diabetes duration of 11.5 years and poor diabetes control, with baseline HbA1c 9.4%, and assigned to intensive or standard treatment arms showed no overall differences in macrovascular or microvascular endpoints after a median follow-up of 5.6 years. Perhaps, then, uncontrolled glycemia of long duration may not be offset by subsequent intensive control, but intensive treatment from the time of diagnosis, even with "bad glycemic legacy" (but of short duration), will be effective in decreasing risk of later complications. Does the retrospective study by Pantalone et al. hint at a different aspect of metabolic memory, namely that poor control of glycemia at baseline does not affect the development of complications later if it is effectively managed subsequently? That effects of initial hyperglycemia could be dispelled with excellent glycemic control? Such an interpretation gives cause for optimism and can be used in empowering people developing diabetes to participate in their care. Analysis of more datasets with serial measures of HbA1c may allow us to further understand these relationships, and certainly the underlying molecular mechanisms of metabolic memory deserve further investigation.

RCT Entities:   Population Interventions Outcomes