Dietary Sugars and Endogenous Formation of Advanced Glycation Endproducts: Emerging Mechanisms of Disease

Abstract

The rapid increase in metabolic diseases, which occurred in the last three decades in both industrialized and developing countries, has been related to the rise in sugar-added foods and sweetened beverages consumption. An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation Endproducts (AGEs). AGEs can be ingested with high temperature processed foods, but also endogenously formed as a consequence of a high dietary sugar intake. Animal models of high sugar consumption, in particular fructose, have reported AGE accumulation in different tissues in association with peripheral insulin resistance and lipid metabolism alterations. The in vitro observation that fructose is one of the most rapid and effective glycating agents when compared to other sugars has prompted the investigation of the in vivo fructose-induced glycation. In particular, the widespread employment of fructose as sweetener has been ascribed by many experimental and observational studies for the enhancement of lipogenesis and intracellular lipid deposition. Indeed, diet-derived AGEs have been demonstrated to interfere with many cell functions such as lipid synthesis, inflammation, antioxidant defences, and mitochondrial metabolism. Moreover, emerging evidence also in humans suggest that this impact of dietary AGEs on different signalling pathways can contribute to the onset of organ damage in liver, skeletal and cardiac muscle, and the brain, affecting not only metabolic control, but global health. Indeed, the most recent reports on the effects of high sugar consumption and diet-derived AGEs on human health reviewed here suggest the need to limit the dietary sources of AGEs, including added sugars, to prevent the development of metabolic diseases and related comorbidities.

Keywords: NLRP3; Nrf2; advanced glycation end products; fructose; glucose; lipogenesis; mitochondrial dysfunction; oxidative stress; sphingolipids.

Scheme 1

Fructose and glucose metabolism and proposed effects for dietary sugar-induced glycation. Fructose bypasses the rate limiting step of glycolysis leading to a faster generation of dicarbonyl precursors than glucose. AGE accumulation in tissues can interfere with many protein functions contributing to the onset of metabolic diseases and related comorbidities.

Scheme 2

The polyol pathway. In conditions of excess of glucose, as occurring in diabetes, glucose undertakes the polyol pathway to be converted to fructose through the consecutive action of aldose reductase and sorbitol dehydrogenase. This alternative pathway for the metabolism of glucose leads to the increase in fructose levels in tissues of diabetic patients and of the NADH/NAD+ ratio that contrasts GAP-dehydrogenase activity leading to accumulation of the triose phosphates GAP and DHAP, precursors of the dicarbonyls compounds glyoxal (GO) and methylglyoxal (MGO).