Formation of Fructose-Mediated Advanced Glycation End Products and Their Roles in Metabolic and Inflammatory Diseases

Abstract

Fructose is associated with the biochemical alterations that promote the development of metabolic syndrome (MetS), nonalcoholic fatty liver disease, and type 2 diabetes. Its consumption has increased in parallel with MetS. It is metabolized by the liver, where it stimulates de novo lipogenesis. The triglycerides synthesized lead to hepatic insulin resistance and dyslipidemia. Fructose-derived advanced glycation end products (AGEs) may be involved via the Maillard reaction. Fructose has not been a main focus of glycation research because of the difficulty in measuring its adducts, and, more importantly, because although it is 10 times more reactive than glucose, its plasma concentration is only 1% of that of glucose. In this focused review, I summarize exogenous and endogenous fructose metabolism, fructose glycation, and in vitro, animal, and human data. Fructose is elevated in several tissues of diabetic patients where the polyol pathway is active, reaching the same order of magnitude as glucose. It is plausible that the high reactivity of fructose, directly or via its metabolites, may contribute to the formation of intracellular AGEs and to vascular complications. The evidence, however, is still unconvincing. Two areas that have been overlooked so far and should be actively explored include the following: 1) enteral formation of fructose AGEs, generating an inflammatory response to the receptor for AGEs (which may explain the strong association between fructose consumption and asthma, chronic bronchitis, and arthritis); and 2) inactivation of hepatic AMP-activated protein kinase by a fructose-mediated increase in methylglyoxal flux (perpetuating lipogenesis, fatty liver, and insulin resistance). If proven correct, these mechanisms would put the fructose-mediated Maillard reaction in the limelight again as a contributing factor in chronic inflammatory diseases and MetS.

Keywords: AMPK; Maillard reaction; RAGE; advanced glycation; arthritis; asthma; diabetes; fructose; inflammation; metabolic syndrome.

FIGURE 1

Fructose metabolism in hepatocytes. Numbers indicate key reactions and are explained in text. Glut, glucose transporter; P, phosphate.

FIGURE 2

The sorbitol pathway as an intracellular source, and dietary sources of fructose and AGEs. Question marks indicate areas in which our knowledge or evidence is scant. Dietary fructose is mainly kept at the liver at first pass; therefore, the role of circulating fructose in AGE formation is questionable. AGE, advanced glycation end product; Fru-AGE, fructose-advanced glycation end product; GI, gastrointestinal; G-6-P, glucose-6-phosphate.

FIGURE 3

The Maillard reaction by glucose (A) and fructose (B) produce different early and late glycation products. Fru-AGE, fructose-advanced glycation end product; Glc-AGE, glucose-derived advanced glycation end product.

FIGURE 4

Two areas of fructose-mediated Maillard reaction that have been overlooked. Enteral formation of fructose AGEs, generating an RAGE inflammatory response (A); inactivation of hepatic AMPK by a fructose-mediated increase in methylglyoxal flux (B). AcCoA, acetyl coenzyme A; AGE, advanced glycation end product; AMPK, AMP-activated protein kinase; MG, methylglyoxal; RAGE, receptor for advanced glycation end products.