Metabolic memory refers to the persistence of diabetic complications even after maintained glycaemic control.

The concept of metabolic memory arose from the results of multiple large-scale clinical trials, which showed that after diabetes onset, diabetes complications persist and progress even when glycaemic control is restored through pharmaceutical intervention. Early glycaemic interventions prevent diabetic complications and has a marked decrease in cardiovascular disease (CVD) endpoints in patients that received either standard or intensive treatment following their diagnosis. Metabolic memory involves four mechanisms: epigenetics, oxidative stress, non-enzymatic glycation of proteins and chronic inflammation.

Different mechanisms are involved in metabolic memory, including mitochondrial DNA damage, protein kinase C activation, and the polyol pathway, increased production of advanced glycation end products (AGEs). AGEs (non-enzymatic glycation end products), glycation of mitochondrial proteins, and oxidative stress have been found to explain, at least in part, the ‘glycometabolic theory’.

Although hyperglycaemia remains a hallmark in the pathophysiology of chronic diabetes complications, it is now clear that therapies should also address several factors only partially related to glycaemic control. These factors appear to be related to an imbalance between oxidative stress and antioxidant capacity, which could be the link between hyperglycaemia and the multiple biochemical cascades that lead to diabetes complications.

Two temporally separated phases may be behind the role of AGEs in the genesis of microvascular damage. In the early years of the disease, a linear relationship between hyperglycaemia, increased oxidative stress, and excessive AGE formation could be hypothesised.

Later, a persistent respiratory chain protein glycation and DNA damage in the mitochondria could generate a hyperglycaemia-independent vicious cycle, in which oxidative stress is self-supporting, and AGEs ‘feed’ this process.

The effects of this metabolic imbalance could include changes in the composition and structure of the extracellular matrix, mediated by inflammatory processes induced by receptor binding of AGEs or oxidative stress. Subsequent fibrosis and the extension of the extracellular structures interfere with capillary blood flow, reducing capillary density. These structural changes could cause endothelial dysfunction and then atherosclerosis.

Epigenetic mechanisms have been hypothesised to be a crucial interface between genetic and environmental factors to explain metabolic memory. Hyperglycaemia can induce a variety of epigenetic changes that persist for days after the normalisation of glucose levels, mainly through the involvement of inflammatory genes.

Among the epigenetic mechanisms studied in metabolic memory, DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated. In particular, high glucose levels can alter the activity of PTHMs and DNA methyltransferases, with irreversible changes over time. These modifications may explain the long-term harmful effects of metabolic memory.

References

• Unai Galicia-Garcia, Asier Benito-Vicente, Shifa Jebari, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020;21(17): 6275. Published online 2020 Aug 30. doi: 10.3390/ijms21176275.
• Roberto Testa, Anna Rita Bonfigli, Francesco Prattichizzo et al. The “Metabolic Memory” Theory and the Early Treatment of Hyperglycemia in Prevention of Diabetic Complications. Nutrients 2017; 9(5): 437. Published online 2017 Apr 28. doi: 10.3390/nu9050437.