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Review
. 2022 Sep 15:9:1002710.
doi: 10.3389/fmolb.2022.1002710. eCollection 2022.

Endogenous advanced glycation end products in the pathogenesis of chronic diabetic complications

Misganaw Asmamaw Mengstie  1 , Endeshaw Chekol Abebe  1 , Awgichew Behaile Teklemariam  1 , Anemut Tilahun Mulu  1 , Melaku Mekonnen Agidew  1 , Muluken Teshome Azezew  2 , Edgeit Abebe Zewde  2 , Assefa Agegnehu Teshome  3
Affiliations
Review

Endogenous advanced glycation end products in the pathogenesis of chronic diabetic complications

Misganaw Asmamaw Mengstie et al. Front Mol Biosci. .

Abstract

Diabetes is a common metabolic illness characterized by hyperglycemia and is linked to long-term vascular problems that can impair the kidney, eyes, nerves, and blood vessels. By increasing protein glycation and gradually accumulating advanced glycation end products in the tissues, hyperglycemia plays a significant role in the pathogenesis of diabetic complications. Advanced glycation end products are heterogeneous molecules generated from non-enzymatic interactions of sugars with proteins, lipids, or nucleic acids via the glycation process. Protein glycation and the buildup of advanced glycation end products are important in the etiology of diabetes sequelae such as retinopathy, nephropathy, neuropathy, and atherosclerosis. Their contribution to diabetes complications occurs via a receptor-mediated signaling cascade or direct extracellular matrix destruction. According to recent research, the interaction of advanced glycation end products with their transmembrane receptor results in intracellular signaling, gene expression, the release of pro-inflammatory molecules, and the production of free radicals, all of which contribute to the pathology of diabetes complications. The primary aim of this paper was to discuss the chemical reactions and formation of advanced glycation end products, the interaction of advanced glycation end products with their receptor and downstream signaling cascade, and molecular mechanisms triggered by advanced glycation end products in the pathogenesis of both micro and macrovascular complications of diabetes mellitus.

Keywords: advanced glycation end products; diabetes complication; glycation; hyperglycemia; receptor advanced glycation end products.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Activation process of NF-κB transcription factor through an AGE-RAGE signaling pathway. Activation of RAGE through AGE interaction transduces a signal for the phosphorylation of IkB by IKK. Phosphorylated IkB then could be detached from the cytosolic NF-kB transcription factor. Multiple genes such as cytokines, chemokines, and adhesion molecules are activated when active and free NF-kB translocate into the nucleus. These proteins trigger oxidative stress, inflammation, and cellular damage, all of which contribute to diabetic complications.
FIGURE 2
FIGURE 2
General mechanism of AGEs in diabetic chronic complications. Hyperglycemia is the most common cause of the synthesis of endogenous advanced glycation products in diabetic patients. The general mechanism of advanced glycation end-products in diabetic vascular complications is due to the activation of multiple signal transduction pathways as a result of RAGE/AGE interaction or through cross-link formation with cellular proteins. Activation of RAGE leads to the activation of Nox-1, ERKs, Janus kinase, MAPK, and activation of NF-κB. When those pathways are activated, oxidative stress (decreased NOS, increased ROS, and increased NADPH oxidase) and inflammatory factors are activated. Cross-link (adduct) formation on the other hand altered the three-dimensional structure of protein consequently impairing cellular function. As a result of the combined effect, diabetic vascular complications such as retinopathy, neuropathy, nephropathy, and atherosclerosis develop.
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