Metabolic memory in the autonomic neuropathy of diabetes: implications for pathogenesis and patient care.

Metabolic memory, the concept that historical glycemic control is a major determinant of diabetes complications, is of considerable interest not only to those involved in the care of people with diabetes mellitus but also to a wider audience, those wishing to understand the pathogenesis of hyperglycemia-related target organ damage. This phenomenon has been popularized clinically by the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), which has repeatedly demonstrated the long-term impact of metabolic memory on nephropathy, retinopathy, cardiovascular disease, and peripheral neuropathy in type 1 diabetes mellitus.1–3 An article in this issue of Circulation from the DCCT/EDIC Research Group demonstrates the same phenomenon for cardiac autonomic neuropathy (CAN).4 In the DCCT, intensive glycemic control over an average of 6.5 years achieved a marked reduction in hemoglobin A1c, 1.7% lower than that achieved on conventional therapy, and a reduction in CAN incidence of 53%.5 At the termination of DCCT, all participants were encouraged to adopt intensive glycemic control such that 5 years after DCCT termination, there was no significant difference in hemoglobin A1c between the originally randomized groups. At 13 to 14 years of follow up, CAN incidence subsequent to DCCT termination in those initially randomized to intensive control was reduced by a third compared with those randomized to conventional therapy, even though glycemic control had been identical in these groups for decade before the CAN assessment. Statistical adjustment for historical glycemic control, specifically that achieved during the DCCT itself, abolished the group difference in CAN, supporting the assertion that metabolic memory explained the persistent lower risk of CAN in those originally randomized to intensive glycemic control.