Crosstalk between advanced glycation end products (AGEs)-receptor RAGE axis and dipeptidyl peptidase-4-incretin system in diabetic vascular complications

Abstract

Advanced glycation end products (AGEs) consist of heterogenous group of macroprotein derivatives, which are formed by non-enzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids, and whose process has progressed at an accelerated rate under diabetes. Non-enzymatic glycation and cross-linking of protein alter its structural integrity and function, contributing to the aging of macromolecules. Furthermore, engagement of receptor for AGEs (RAGE) with AGEs elicits oxidative stress generation and subsequently evokes proliferative, inflammatory, and fibrotic reactions in a variety of cells. Indeed, accumulating evidence has suggested the active involvement of accumulation of AGEs in diabetes-associated disorders such as diabetic microangiopathy, atherosclerotic cardiovascular diseases, Alzheimer’s disease and osteoporosis. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins, gut hormones secreted from the intestine in response to food intake, both of which augment glucose-induced insulin release, suppress glucagon secretion, and slow gastric emptying. Since GLP-1 and GIP are rapidly degraded and inactivated by dipeptidyl peptidase-4 (DPP-4), inhibition of DPP-4 and/or DPP-4-resistant GLP-1 analogues have been proposed as a potential target for the treatment of diabetes. Recently, DPP-4 has been shown to cleave multiple peptides, and blockade of DPP-4 could exert diverse biological actions in GLP-1- or GIP-independent manner. This article summarizes the crosstalk between AGEs-RAGE axis and DPP-4-incretin system in the development and progression of diabetes-associated disorders and its therapeutic intervention, especially focusing on diabetic vascular complications.

Dipeptidyl peptidase-4 inhibitors and bone metabolism: is vitamin D the link?

“…Cutaneous AGEs accumulation may hinder the photoconversion of provitamin D into vitamin D, mechanism that, in physiological conditions, accounts for 80 % of overall vitamin D balance. Interestingly, linagliptin was shown to prevent the AGE-receptor gene expression [30] and to improve diabetic wound healing in diabetic mice by directly inhibiting DPP4 activity in keratinocytes [31]. Therefore, DPP4-Is may locally improve vitamin D synthesis by modulating AGEs deposition and DPP4 activity in the skin, with favorable effects on bone metabolism.…”

Role of RAGE in Alzheimer’s Disease

“…Several candidate mechanisms that RAGE contributes to chronic diseases have been proposed. Conjugation of RAGE with AGEs induces oxidative stress and subsequently causes the occurrence of proliferative, inflammatory, and fibrotic reactions in a variety of cells (Motoyoshi et al 2014;Yamagishi et al 2015). The pathogenesis is hypothesized to include ligand binding to activate RAGE signals and trigger inflammatory response (Heilmann et al 2014;Zhang et al 2014).…”

Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes

“…There is a pathological crosstalk between the AGE-RAGE system and dipeptidyl peptidase-4 (DPP-4)-incretin axis in the pathogenesis of vascular complications in diabetes (95,96). Glucagonlike peptide-1 directly acts on endothelial cells, mesangila cells and proximal tubular cells via the glucagon-like peptide-1 receptor, and glucagon-like peptide-1 could work as an antiinflammatory and antioxidative agent against AGEs by reducing RAGE expression via activation of cyclic AMP pathways (95,96).…”

“…Glucagonlike peptide-1 directly acts on endothelial cells, mesangila cells and proximal tubular cells via the glucagon-like peptide-1 receptor, and glucagon-like peptide-1 could work as an antiinflammatory and antioxidative agent against AGEs by reducing RAGE expression via activation of cyclic AMP pathways (95,96). Moreover, we have recently found that AGE-RAGE-induced oxidative stress generation stimulates the release of DPP-4 from endothelial cells, which could act on endothelial cells in an autocrine manner via the interaction with mannose 6-phosphate insulin-like growth factor II receptor, further potentiating the deleterious effects of AGEs (97).…”