Advanced glycation end-products: modifiable environmental factors profoundly mediate insulin resistance

Abstract

Advanced glycation end-products are toxic by-products of metabolism and are also acquired from high-temperature processed foods. They promote oxidative damage to proteins, lipids and nucleotides. Aging and chronic diseases are strongly associated with markers for oxidative stress, especially advanced glycation end-products, and resistance to peripheral insulin-mediated glucose uptake. Modifiable environmental factors including high levels of refined and simple carbohydrate diets, hypercaloric diets and sedentary lifestyles drive endogenous formation of advanced glycation end-products via accumulation of highly reactive glycolysis intermediates and activation of the polyol/aldose reductase pathway producing high intracellular fructose. High advanced glycation end-products overwhelm innate defenses of enzymes and receptor-mediated endocytosis and promote cell damage via the pro-inflammatory and pro-oxidant receptor for advanced glycation end-products. Oxidative stress disturbs cell signal transduction, especially insulin-mediated metabolic responses. Here we review emerging evidence that restriction of dietary advanced glycation end-products significantly reduces total systemic load and insulin resistance in animals and humans in diabetes, polycystic ovary syndrome, healthy populations and dementia. Of clinical importance, this insulin sensitizing effect is independent of physical activity, caloric intake and adiposity level.

Keywords: AGEs; Western diet; glycation; insulin resistance; oxidative stress.

Fig. 1

Redox Homeostasis and Oxidative Stress. Many known factors contribute to redox homeostasis in human physiology. On the left are those that increase oxidation with opposing anti-oxidant mechanisms on the right. ^†Uric acid and RAGE are antioxidants at low concentrations and pro-oxidant and markers of oxidative stress at high concentrations.

Fig. 2

Sources of Systemic AGEs. Known pathways to physiologic load of toxic advanced glycation end-products (AGEs). Hyperglycemia and hypercaloric diets drive endogenous formation while dietary AGEs enter the system pre-formed with heat-treated foods.