Endoplasmic reticulum (ER) plays a central role in the synthesis of proteins and their post-translational modification by folding newly synthesized proteins through the formation of disulfide bonds, which is necessary for their final stable conformational state. ER homeostasis is stressed when the influx of newly synthesized unfolded or misfolded polypeptide chains exceeds the ER capacity for repair and refolding. ER stress in diabetes can be caused by various factors that inhibit protein folding, such as glucose, nonesterified cholesterol, oxidized phospholipids, saturated fatty acids, and ROS. Chronic ER stress leads to the death of pancreatic beta-cells, increases hyperglycemia, and is the main etiology of diabetes. Atherosclerosis (AS) is a chronic inflammatory disease that underlies the pathology of ischemic cardiovascular and cerebrovascular diseases. It has been documented that both endoplasmic reticulum (ER) stress and NLRP3 inflammasomes influence the progression of AS. The ER stress response in endothelial cells leads to inflammation and cell death in diabetes-related vascular diseases. ER stress also plays a key role in the onset of atherosclerosis in diabetes, which is a major consequence of endothelial dysfunction. Several independent risk factors for cardiovascular diseases, namely hyperhomocysteinemia, obesity, and dyslipidemia, as well as hyperglycemia, are also associated with ER stress, which indicates its integrating function in atherogenesis. The etiological role of low-level tissue inflammation in the formation of insulin resistance and beta-cell dysfunction in type 2 diabetes is commonly recognized. Among innate immune receptors, NLRP3 plays a critical role in tissue inflammation associated with lipid overload or obesity. The research showed that ER stress is involved in inflammation and that ER plays a key role in the activation of NLRP3-inflammasomes, which trigger secretion of proinflammatory cytokines, such as IL-1 beta and IL-18. Metformin, an AMPK activator, inhibits ER stress and restores endothelial cell function in diabetes. Metformin inhibits NLRP3 inflammasome activation under ER stress through suppression of IL-6 and MCP-1 production induced by high glucose levels, lower TXNIP expression, and activation of autophagy via AMPK.
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