This study confirms that hypoglycemia induces endothelial dysfunction, oxidative stress, and inflammation. However, it also shows that the way in which recovery from hypoglycemia takes place may also have an effect on cardiovascular risk. When recovery from hypoglycemia is obtained reaching normoglycemia, the deleterious effects of the previous hypoglycemia are mainly counterbalanced, whereas when recovery is obtained reaching hyperglycemia, endothelial function, oxidative stress, and inflammation are further worsened.
In recent years, hyperglycemia and hypoglycemia have both been confirmed as affecting atherothrombosis and inflammation (1
). However, the role of hypoglycemia in this setting has received particular attention. Two epidemiologic studies have determined that hypoglycemia results in an increased risk of cardiovascular disease and all-cause mortality (16
), whereas the increase in cardiovascular mortality in people with type 2 diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (18
) and possibly in the Veterans Affairs Diabetes Trial (VADT) (19
) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) (20
) studies has caused concern, because intensive treatment had tripled the frequency of severe hypoglycemia.
The situation remains unclear, however. In the ACCORD trial, epidemiologic analyses were perplexing; for example, earlier severe hypoglycemic episodes were a risk factor for death and occurred three times as often as in the intensive glycemic treatment group, but the excess of deaths in that group was not accounted for by those subjects who had suffered earlier episodes of severe hypoglycemia (21
). In the ADVANCE trial, severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes; however, although it is possible that severe hypoglycemia contributes to adverse outcomes, the data indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events (20
). None of these studies devoted attention to how patients recovered from hypoglycemia, and these kinds of data are probably not available. For the first time, our data raise the interesting hypothesis that the way in which recovery from hypoglycemia takes place may, on the one hand, have a role in determining the outcomes, and, on the other, in confusion regarding the interpretation of results.
The way by which recovery from hypoglycemia through hyperglycemia worsens the situation is, convincingly, an increase in oxidative stress. When hyperglycemia after hypoglycemia was accompanied by the simultaneous infusion of the antioxidant vitamin C, the expected improvement in oxidative stress was accompanied by a simultaneous improvement in endothelial function and inflammation. This finding is consistent with the evidence reported in cells and animals (9
), suggesting that hyperglycemia after hypoglycemia produces a “reperfusion-like” effect (22
In our opinion, it is interesting that recovery from hypoglycemia with normoglycemia in control subjects and in people with type 1 diabetes was not completely without negative effects. In both groups, even improved endothelial function, inflammation, and oxidative stress were not completely recovered, suggesting that hypoglycemia regardless might produce a sort of legacy effect, even for a short period. The concept of “legacy” or “metabolic memory” is well recognized in hyperglycemia and indicates the possibility of a long-lasting deleterious effect persisting for some time after glucose normalization (23
). This concept is not new at all to hypoglycemia; for example, baroreflex sensitivity and sympathetic response to hypotension are attenuated after previous hypoglycemia (24
). Interestingly, oxidative stress is the mediator of the hyperglycemia-induced metabolic memory (23
). Moreover, the “memory” phenomenon, after heart ischemia–reperfusion, is also well known: alterations of metabolism in the heart may last for even days after a period of ischemia–reperfusion (22
). It is possible that after hypoglycemia, alterations similar to those occurring in the reperfused heart are produced in endothelial cells. This is supported by the similarity of the pathways activated in the two situations, as reported in basic experiments (25
In conclusion, our study shows for the first time that the way in which recovery from hypoglycemia takes place could have a dramatic impact on cardiovascular risk in diabetes, suggesting that in clinical practice, a gradual correction of blood glucose in patients with hypoglycemia may be preferred to a more rapid correction and hyperglycemia. This hypothesis, of course, needs to be confirmed in large-scale, specifically designed clinical trials. However, because hypoglycemia as a risk factor for cardiovascular disease has become increasingly evident (1
) and because hypoglycemia is a frequent event in the life of people with diabetes, we believe that our study may already give a rationale for a more careful treatment of hypoglycemia in daily practice.