Diabetes is a disease of altered metabolism and chemistry of both carbohydrates and lipids. Normally, the absorption of carbohydrates stimulates insulin secretion and the translocation of GLUT 4 from muscle and adipose tissue's intracellular compartments to the cell's surface in order to increase cellular uptake of glucose. However, due to insulin resistance (IR) in T2DM muscle and adipose tissue are unable to bring glucose inside their cells, which causes blood glucose levels to rise (hyperglycemia). Consequently, cells that are unable to decrease the rate of glucose transported inside the cell become damaged. Specifically, this is seen in three cell types: the capillary endothelial cells of the retina, mesanglial cells in renal glomerulus, and neurons and Schwann cells of peripheral nerves; representing microvascular complications retinopathy, nephropathy, and neuropathy. However, injury to macrovascular tissue as evidenced in atherosclerosis, cardiomyopathy, and peripheral arterial disease is preceded by elevated of free fatty acids (FFAs) and low-density lipoproteins (LDLs); precursors for the formation of foam cells and fatty streaks that eventually lead to arterial insufficiency. Crucially, at the center of each of these pathologies is the formation of advanced glycation endproducts (AGEs).
Advanced glycation endproducts (AGEs), or glycotoxins, are modification of proteins and lipids that become glycated and oxidized through a non-enzymatic reaction with reducing sugars (glucose, fructose, and galactose). Once formed, AGEs may bind to its receptor to disrupt normal cell function or glycate proteins in the extracellular matrix to inhibit cell growth and secretory abilities. AGEs have been demonstrated to activate inflammatory and pro-oxidant mechanisms, impair cell-signaling pathways, accumulate inside and outside the cell as well as in serum and skin, and alter cellular structure and function apart from overnutrition or genetic susceptibility.Consequently, the formation of AGEs is accelerated in diabetes because of increased availability of reducing sugars, implicating glycotoxins in the pathogenesis of vascular complications in T2DM.
