Advanced glycation end products and oxidative stress in type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a very complex and multifactorial metabolic disease characterized by insulin resistance and β cell failure leading to elevated blood glucose levels. Hyperglycemia is suggested to be the main cause of diabetic complications, which not only decrease life quality and expectancy, but are also becoming a problem regarding the financial burden for health care systems. Therefore, and to counteract the continually increasing prevalence of diabetes, understanding the pathogenesis, the main risk factors, and the underlying molecular mechanisms may establish a basis for prevention and therapy. In this regard, research was performed revealing further evidence that oxidative stress has an important role in hyperglycemia-induced tissue injury as well as in early events relevant for the development of T2DM. The formation of advanced glycation end products (AGEs), a group of modified proteins and/or lipids with damaging potential, is one contributing factor. On the one hand it has been reported that AGEs increase reactive oxygen species formation and impair antioxidant systems, on the other hand the formation of some AGEs is induced per se under oxidative conditions. Thus, AGEs contribute at least partly to chronic stress conditions in diabetes. As AGEs are not only formed endogenously, but also derive from exogenous sources, i.e., food, they have been assumed as risk factors for T2DM. However, the role of AGEs in the pathogenesis of T2DM and diabetic complications-if they are causal or simply an effect-is only partly understood. This review will highlight the involvement of AGEs in the development and progression of T2DM and their role in diabetic complications.

Figures

Figure 1

“Three lines of antioxidative defense” in mammalian cells, modified according to [5]. The first line contains low molecular antioxidants that can scavenge ROS/reactive particles in a purely competitive way, preventing damage from cellular structures like proteins, nucleobases and lipids. The reaction products are mostly significantly less reactive and may in several cases be restored by cellular systems (like vitamin C and tocopherol in a glutathione (GSH)-consuming manner). The most important and abundant low molecular intracellular scavenger is GSH, thus determining the cellular redox-state, defined as the ratio of GSH to its oxidized form, glutathione disulfide (GSSG). Under normal physiological conditions, this ratio is about 1:1000 (GSSG:GSH) or even higher, providing a strongly reducing cellular environment. The second line of defense contains antioxidative enzymes that are able to convert ROS into less reactive particles. This includes the superoxide dismutases (Cu, ZnSOD and MnSOD) as well as catalase. Further important enzymes are glutathione peroxidases, catalyzing the reaction of peroxides (R-OOH) to hydroxyls (R-OH) via GSH-consumption. Besides catalase, glutathione peroxidases are the most important H2O2-detoxifying enzymes. In this group enzymes are also found, which bind redox-active metals—iron is the most important transition metal in mammalian cells—in an inert form. Otherwise, metals like iron (Fe2+) or copper (Cu+) are able to transfer an electron to H2O2 (Fenton reaction), releasing both OH− and the highly reactive hydroxyl radical (•OH). •OH is able to oxidize virtually every organic molecule. The oxidized forms of those metals (Fe3+/Cu2+) are quickly reduced in the cytosolic environment, fuelling the vicious circle. In the last line of defense is a summary of enzymes that are able to restore oxidatively modified amino acids (only methionine and cysteine), thus preventing proteolytic degradation of the whole damaged protein. If repair is not possible, several proteases are available, that can recognize and remove dysfunctional proteins in a proteolytic manner, preventing their intracellular accumulation. The most important one is the proteasomal system, responsible for the degradation of more than 90% of all (oxidatively) damaged proteins, as well as the cathepsins of the lysosomal system. Other catabolic enzymes might also play some role in these defense lines.

Figure 2

Formation of reactive dicarbonyls and AGEs, modified according to [29]. Reactive dicarbonyls including methylglyoxal, glyoxal and 3-deoxyglucosone are formed through several pathways: the Maillard reaction, the polyol pathway, glycolysis, lipid peroxidation or glucose autoxidation. Dicarbonyl compounds react further to form irreversible products, the so-called AGEs.

Figure 3

Mechanisms of AGEs leading to insulin resistance in insulin-sensitive tissues according to [52,78,79,80,84,85,86]. AGEs are involved in mechanisms contributing to insulin resistance due to direct modification of insulin which alters insulin action resulting in impaired glucose uptake, inhibited insulin clearance or further increased insulin secretion. Furthermore, AGEs may contribute to insulin resistance via increased expression of RAGE and reduced expression of AGER1 and SIRT1. AGEs affect insulin signaling and trigger inflammation via stimulation of PKCα and upregulation of TNFα. SIRT1 depletion causes changes in insulin signaling and induces inflammation.

Figure 4

AGE-induced pathways involved in β cell dysfunction according to [98,100,102,103]. Decreased insulin synthesis and reduced insulin secretion are both involved in β cell failure contributing to hyperglycemia. AGEs reduce phosphorylation (P) and induce acetylation (Ac) of FoxO1, thus, FoxO1 translocates into the nucleus and is protected against proteasomal degradation, respectively. In addition, AGEs induce PDX-1 translocation into the cytoplasm and decrease PDX-1 protein expression, finally affecting insulin gene transcription and insulin synthesis. Regarding insulin secretion, AGEs cause inhibition by activation of iNOS and consequent blocking of cytochrome c oxidase activity and ATP depletion. Moreover, AGEs decrease insulin secretion through alterations in the TCA cycle which limits ATP production. ATP depletion inhibits closure of ATP-dependent potassium channels which leads to reduced membrane depolarization and decrease of intracellular calcium concentration inhibiting insulin secretion. (Arrows illustrate direct interactions; dashed arrows illustrate possible targets of AGEs).

Figure 5

Influence of methylglyoxal-modified collagen on cellular functions relevant to diabetic complications, according to [113,116,119,120]. Cells were cultured on methylglyoxal-modified collagen and the effect of AGE-collagen on cellular functions was studied. Dermal fibroblasts grown on modified collagen increase collagen synthesis. Methylglyoxal-modified collagen reduces cell adhesion and migration of mesangial cells, cardiac fibroblast are less adherent. Myofibroblast differentiation is stimulated in cardiac fibroblasts cultured on modified collagen and modifications of basement membrane collagen causes detachment, cell death and reduced angiogenesis of vascular endothelial cells.