Advanced glycation end products (AGE) and diabetes: cause, effect, or both?

Abstract

Despite new and effective drug therapies, insulin resistance (IR), type 2 diabetes mellitus (T2D) and its complications remain major medical challenges. It is accepted that IR, often associated with over-nutrition and obesity, results from chronically elevated oxidant stress (OS) and chronic inflammation. Less acknowledged is that a major cause for this inflammation is excessive consumption of advanced glycation end products (AGEs) with the standard western diet. AGEs, which were largely thought as oxidative derivatives resulting from diabetic hyperglycemia, are increasingly seen as a potential risk for islet β-cell injury, peripheral IR and diabetes. Here we discuss the relationships between exogenous AGEs, chronic inflammation, IR, and T2D. We propose that under chronic exogenous oxidant AGE pressure the depletion of innate defense mechanisms is an important factor, which raises susceptibility to inflammation, IR, T2D and its complications. Finally we review evidence on dietary AGE restriction as a nonpharmacologic intervention, which effectively lowers AGEs, restores innate defenses and improves IR, thus, offering new perspectives on diabetes etiology and therapy.

Figure 1

Native and exogenous sources of oxidants, a most notable one being food derived AGEs, contribute to cellular and tissue injury in chronic diabetes.

Figure 2

AGE restriction protects islet structure and function in mice genetically predisposed to type 1 (A) and type 2 diabetes (B). Non-obese diabetic (NOD) mice (A), and db/db +/+ mice (B) were exposed to either standard or Low-AGE diet for life. Pancreatic islets from mice on AGE-restriction did not display the mononuclear cell infiltration, typical of NOD mice fed a standard diet (AGE-rich) (H&E mag.x400,). Similarly, islets from age-matched db/db+/+ mice, after AGE-restriction, showed intact insulin production compared to those on regular diet. (insulin staining, mag.x400).

Figure 3

Dietary AGEs can impair insulin secretion in pancreatic islet β-cells. Pro-oxidant AGEs can induce iNOS, and the generation of mitochondrial ROS, suppressing cytochrome-C levels and ATP generation, reducing insulin release. They can also suppress the deacetylase SIRT1, which regulates UCP2, thus impairing membrane depolarization and β-cell secretory function.

Figure 4

Traditional and non-traditional pathways to T1/T2D and complications. A, Over-nutrition promotes obesity and insulin resistance as well as increased OS, inflammation and β-cell injury leading to diabetes by unclear mechanisms. B, Modern diet, typically rich in animal food products, is also generally subject to heat-exposure. The resulting excess of oxidant AGEs include flavorful appetite-enhancing substances, which simultaneously promote food over-consumption and obesity, as well as insulin resistance, beta-cell injury and diabetes (type 1 or 2).

Figure 4

Traditional and non-traditional pathways to T1/T2D and complications. A, Over-nutrition promotes obesity and insulin resistance as well as increased OS, inflammation and β-cell injury leading to diabetes by unclear mechanisms. B, Modern diet, typically rich in animal food products, is also generally subject to heat-exposure. The resulting excess of oxidant AGEs include flavorful appetite-enhancing substances, which simultaneously promote food over-consumption and obesity, as well as insulin resistance, beta-cell injury and diabetes (type 1 or 2).

Figure 5

Partial list of known properties of AGER1, the best characterized anti-AGE receptor involved in the removal of AGEs, as well as in the maintenance of host defenses controlling their pro-inflammatory effects. Loss of function of AGER1 in chronic diabetes and other conditions of sustained oxidant AGE pressure is thought as one way by which depleted host defenses and anti-oxidant mechanisms can lead to the maladaptive inflammatory responses underlying diabetes and its complications.