Aging (chronic age-related diseases); ii. metabolic (hyperglycemia advanced glycation end products and its receptor (AGE/RAGE) interactions and hyperinsulinemia-insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis-vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.
Hyperglycemia increased the mRNA expression and protein levels of malondialdehyde (MDA), superoxide dismutase (SOD), monocyte chemoattractant protein‑1 (MCP‑1), intercellular adhesion molecule‑1 (ICAM‑1), fibronectin (FN), collagenase type 1 (COL‑1), HMGB1, RAGE and NF‑κB, and the effects could be reversed by dapagliflozin in a concentration‑dependent manner.
There is growing evidence that chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs) which exerts its effect via interaction with the receptor for advanced glycation end products (RAGE).
Presently, we provide a translationally oriented review of key studies evaluating the aberrant effects of hyperglycemia on two major signaling pathways linked to debilitating cellular and systemic effects via targeted disruption of mitochondrial bioenergetics: (1) advanced glycation end-products (AGEs)/and their cognate receptor for advanced glycation end-products (RAGEs), and (2) the hexosamine biosynthetic pathway (HBP).
Although the absence of RAGEs from birds has yet to be confirmed at the protein level, other differences between humans and birds may also be important in accounting for the ability of birds to live with chronic hyperglycemia.
Our study is also the first to establish a distinct role of hyperglycemia and hypercholesterolemia in osteochondrogenic differentiation of SMCs and determined these cells as a major source contributing to cartilaginous and calcifying lesions of T2DM blood vessels, possibly mediated by RAGE.
The Receptor for Advanced Glycation End-products (RAGE) belongs to the family of pattern-recognition receptors and is significantly involved in the molecular mechanisms mediating pro-inflammatory action of hyperglycemia in diabetes.