Several epidemiological and prospective studies suggest that an early intensive control of hyperglycaemia is able to decrease the risk of diabetic micro- and macro-vascular complications. A growing body of experimental evidence supports the concept that the risk for diabetes complications may be linked to oxidative stress, non-enzymatic glycation of proteins, epigenetic changes, and chronic inflammation, laying the foundation for the “metabolic memory” theory. From a clinical point of view, this theory supports the need for a very early aggressive treatment, with the goal of normalizing metabolic control as soon as possible. It may also prove beneficial to introduce therapeutic agents that are able to reduce reactive species and glycation, in addition to presenting better control of glucose levels in patients with diabetes, in order to minimize long-term diabetes complications. In this review, we evaluate the effect of glucose intake and metabolism in the light of this theory.

Atherosclerosis is one of the main complications of diabetes involving multiple causative factors. Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with both diabetes and atherosclerosis. Although the pathological link between diabetes and atherosclerosis is well-established, better comprehension of the underlying mechanisms is of utmost importance to identify novel potential molecular targets. It is difficult to separate the effects of hyperglycaemia from those of other atherogenic factors: recent evidence shows that they share many common mechanisms, such as endothelial activation and inflammation, mitochondrial oxidative stress, changes in extracellular matrix components and disruption of cellular defence systems. The plausible hypothesis of the ‘common soil’ between diabetes and atherosclerosis seems to be born from a unique ‘ancestor’: the nuclear factor κB, a transcription factor able to guide multiple molecular processes. It seems that this master regulator triggers either some hyperglycaemia-induced effects on the endothelial function, or the expression of certain microRNAs (in particular miR-126, -21 and miR-146a-5p) involved in favouring atherosclerosis. Here, we review the latest evidence and proposed mechanisms, aiming to understand the link between diabetes and atherosclerosis.

Several studies suggest that, together with glucose variability, the variability of other risk factors, as blood pressure, plasma lipids, heart rate, body weight, and serum uric acid, might play a role in the development of diabetes complications. Moreover, the variability of each risk factor, when contemporarily present, may have additive effects. However, the question is whether variability is causal or a marker. Evidence shows that the quality of care and the attainment of the target impact on the variability of all risk factors. On the other hand, for some of them causality may be considered. Although specific studies are still lacking, it should be useful checking the variability of a risk factor, together with its magnitude out of the normal range, in clinical practice. This can lead to an improvement of the quality of care, which, in turn, could further hesitate in an improvement of risk factors variability.