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The "Metabolic Memory": Is More Than Just Tight Glucose Control Necessary to Prevent Diabetic Complications?

Warwick Medical School (A.C.), University of Warwick, Coventry CV2 2DX, United Kingdom; Istituto Nazionale Ricovero e Cura Anziani (A.C.), Diabetes Unit, 60129 Ancona, Italy; and Department of Cell Biology (M.A.I., J.E.T.), University of Oklahoma Health Sciences Center, Oklahoma, City, Oklahoma 73104

Address all correspondence and requests for reprints to: Prof. Antonio Ceriello, Warwick Medical School, Clinical Science Research Institute, Clinical Science Building, University Hospital–Walsgrave Campus, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom. E-mail: antonio.ceriello{at}warwick.ac.uk.

Context: The concept of a "metabolic memory," that is of diabetic vascular stresses persisting after glucose normalization, has been supported both in the laboratory and in the clinic and in both type 1 and type 2 diabetes.

Evidence Acquisition: Using PubMed, we searched for publications on diabetic micro- and macrovascular complications using terms such as persistence, prolongation, sustained, and "memory" and focusing on the mechanistic basis behind this metabolic memory.

Evidence Synthesis: We found that as early as the mid-1980s this memory phenomenon was described in diabetic animals and isolated cells exposed to high glucose followed by normalized glucose and then, beginning around 2002, in results from large clinical trials such as the Diabetes Complications and Control Trial–Epidemiology of Diabetes Interventions and Complications and the United Kingdom Prospective Diabetes Study. Furthermore, mechanisms for propagating this memory appear focused on the nonenzymatic glycation of cellular proteins and lipids and on an excess of cellular reactive oxygen and nitrogen species, in particular originating at the level of glycated mitochondrial proteins and perhaps acting in concert with one another to maintain stress signaling independent of glucose levels.

Conclusions: The emergence of this metabolic memory suggests the need for early aggressive treatment aiming to "normalize" metabolic control together perhaps with the addition of agents which reduce cellular reactive species and glycation in order to minimize long-term diabetic complications.

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