This study confirms our previous results that recovering hypoglycemia with hyperglycemia worsens endothelial function and inflammation, being oxidative stress generation the possible cause of this effect [10
]. We and others have previously suggested that hyperglycemia following hypoglycemia generates an ischemia/reperfusion like situation, generating an oxidative stress [9
]. The role of the oxidative stress is also supported by the data obtained infusing vitamin C.
In this study, for the first time, we report that GLP-1 can partly counterbalance this phenomenon. Recently, the crucial role of GLP-1 in cardiovascular disease has been suggested by both preclinical and clinical studies [19
]. It has been reported that GLP-1 may have cardio-protective effects, being ale of reducing the ischemia/reperfusion injury and also cardiac dysfunction in various animal models and humans [19
]. Several mechanisms may explain the effect of GLP-1 in reducing the damage induced by the ischemia/reperfusion and, between them, the possibility that GLP-1 can reduce oxidative stress and can increase antioxidants, leading to decreased apoptosis [24
]. Therefore, it is reasonable that, in our study, GLP-1 should, reducing oxidative stress generation, improve endothelial dysfunction and inflammation generated by hyperglycemia following hypoglycemia.
It is worthy of interest that vitamin C was more efficacious than GLP-1 in counterbalancing the effects of hyperglycemia post hypoglycemia and that only when both vitamin C and GLP-1 were simultaneously infused this effect is quite completely abolished. It is important to underline how vitamin C and GLP-1 act as antioxidants. Vitamin C has a scavenger action, which means that it “captures” the free radicals when they are already generated [24
]. GLP-1, as other compounds, increases the intracellular antioxidant defenses. This means that they can cooperate on the global oxidative stress generated, because they have a complimentary action. The data show that, even vitamin C has been infused at the supposed maximal antioxidant effect, the alterations in endothelial function and inflammation are still persistent even improved. This means, in our opinion, that some “oxidative stress” still escapes from the action of vitamin C. In this view, it is reasonable that adding another antioxidant, such as GLP-1, which works as antioxidant in a very different way, the effect on oxidative stress and on its related alteration can be further improved.
A possible influence of insulin by itself on the results cannot be excluded, particularly because it has recently been reported that GLP-1 enhances the vasodilator effect of insulin [27
]. However, in our experiments, the amount of insulin infused was the same during all the experiments, therefore, the role of insulin in the study has certainly been minimized. In the same paper by Tesauro et al. [27
], GLP-1 was unable to enhance the effect of vitamin C on endothelial dysfunction. However, our experimental conditions are very different. We studied fifteen people with type 1 diabetes, while the study of Tesauro was focused on only five people with the metabolic syndrome [27
]. Moreover, as underlined by the same authors, no control study, with vitamin C alone, were performed.
It is also worthy of interest the recent report demonstrating that three months of exenatide therapy had similar effects on microvascular endothelial function, markers of inflammation, oxidative stress, and vascular activation, as metformin, in patients with obesity and pre-diabetes [28
], which could question the specific role of GLP-1 analogues in preserving endothelial function. However, it is important to underline that also metformin, as GLP-1 [29
], has an antioxidant power. Therefore this similarity of the effect between the two compounds could may explain the results of this study.
In our opinion this report has also important practical implications. The risk of a cardiovascular disease in type 1 diabetes is very high [30
], and the role of the oxidative stress seems to very relevant in the pathogenesis of these complications in type 1 diabetes [5
]. The interest in understanding if hypoglycemia, which produces an oxidative stress [1
], is a risk factor for cardiovascular disease in type 1 diabetes is increasing, even the epidemiological data are quite conflicting [31
]. We have already suggested the hypothesis that the way in which recovery from hypoglycemia takes place, because may increase the oxidative stress, may condition the cardiovascular outcomes [10
]. It is currently suggested that GLP-1 analogues could be helpful in the management of type 1 diabetes, not only because can contribute to improve the metabolic control and to reduce insulin requirement [14
], but also because GLP-1 can protect type 1 diabetes from hyperglycemia and hypoglycemia-induced oxidative stress, inflammation and endothelial dysfunction [34
]. Our data suggest that another potential good reason to use GLP-1 analogues in the management of type 1 diabetes might be related to their potential to reduce oxidative stress, generated during hyperglycemia following hypoglycemia.
In conclusion, this study confirming the possibility that vitamin C counterbalances the deleterious effects of hyperglycemia post-hypoglycemia underlines the role of the oxidative stress in this phenomenon. At the same time, this study showing that GLP-1 can counterbalance the deleterious effect of the ischemia/reperfusion induced by the recovery from hypoglycemia with hyperglycemia, on oxidative stress generation, inflammation and endothelial dysfunction, supports the usefulness of GLP-1 and its analogues in the management of type 1diabetes.