Ricerc@Sapienza

While AGEs have been long recognized as factors in the pathogenesis of diabetic vascular complications, their importance in insulin resistance and type 2 diabetes development is of more recent concern. In particular, the relevance of AGEs of dietary origin as a factor in cardiometabolic diseases has been a growing area of investigation (Luévano-Contreras et al, Curr Diab Rep 2017). The highly processed foods composing the UMD are rich in RCS and AGEs, as these glycotoxins are produced due to common procedures such as heating, sterilizing, or ionizing (O¿Brien & Morrissey Crit Rev Food Sci Nutr 1989). Since it was observed that the prevalence of chronic health conditions is continuously increasing in parallel with the increase of the exposure to dietary AGEs, a role for food-derived AGEs in type 2 diabetes, cardiovascular disease and cancer has been proposed (Uribarri et al, Diabetes Care 2002). However, the real pathophysiological relevance of ingested AGEs is controversial. In particular, some areas demand further research, such as the absorption mechanisms and metabolic fate of dietary AGEs, the analytical measurement of AGEs in foods, and the impact of AGEs on healthy individuals (Luévano-Contreras et al, Curr Diab Rep 2017). Regarding the importance of exogenous AGEs ingested with the diet, a recent study demonstrated that AGE intake is positively associated with levels of free plasma and urinary AGEs, but not with their corresponding protein-bound AGEs (Scheijen et al, Clin Nutr 2018). This is because AGE-modified proteins, as well as native proteins, are digested into amino acids and small peptides. Consequently, the preformed AGEs present in food enter the circulation largely in the free form (i.e. glycated aminoacids and short peptides) and are excreted in the urine. This implies that dietary AGEs may not contribute to the endogenous pool of biologically active AGEs, since only protein-bound AGEs can be retained in the body, accumulate in tissues, and induce inflammation and ROS production through RAGE activation. Collectively, these observations suggest that the noted association between UMD, circulating levels of AGEs, and cardiometabolic disorders might be actually mediated by other factors characterizing the UMD, including the high GI and consequent postprandial dysmetabolism.
In addition to being generated during food processing, AGEs can also be produced in biological systems through nonenzymatic glycation, a chemical reaction consisting in the adduction of a reducing sugar to another biomolecule, such as a protein, lipid, or DNA. The glycation process occurs slowly at 37¿C, and it takes several weeks to generate AGEs in the presence of high glucose levels. Therefore, endogenous formed AGEs have always been considered important factors contributing to diabetic complications (Giacco & Brownlee, Circ Res 2010; Peppa et al, Clin Diab 2003), but not to diabetes development and vascular disease in nondiabetic subjects. However, a large body of evidence has shown that AGEs, including CML and CEL, can be quickly generated through the reaction between intermediate metabolites of cellular glucose and lipid metabolism (i.e., the reactive dicarbonyls MGO, GO and 3-DG) and biomolecules (Schalkwijk et al, Physiol. Rev 2020). This open up the possibility that a UMD diet may trigger rapid generation of endogenous AGEs by inducing exaggerated post-prandial spikes in blood glucose and consequent accumulation of their dycarbonyl precursors. This may explain the association between dietary intake of AGEs (which content is high in UMD) and circulating levels of AGE-modified proteins observed in some studies (Chao et al, Eur J Nutr 2020). Consistent with this hypothesis, increased blood levels of the AGE precursors MGO, GO and 3-DG have been demonstrated after a glucose load in individuals with type 2 diabetes and impaired glucose metabolism (Maessen et al, Diabetes Care 2015). By investigating the relationship between post-challenge glucose excursions and RCS/AGE formation, this project may propose a mechanism linking glucose spikes with oxidative stress, which has been considered the main culprit of the metabolic and vascular effects related with postprandial dysmetabolism in lean and metabolically healthy subjects.
Finally, it was hypothesized that, when repeated frequently over longer periods, transient modifications of insulin sensitivity and atherogenic changes characterizing postprandial dysmetabolism (Nilsson et al, Am J Clin Nutr 2007) may lead to abnormal glucose homeostasis and atherosclerotic cardiovascular disease (O¿Keefe et al, JACC 2008). By investigating the impact of glucose spikes on production of AGEs, which levels tend to accumulate over time, this project may also suggest a mechanism linking recurrent postprandial acute inflammatory and atherogenic changes with the development of persistent glucose dysmetabolism and vascular damage.