Vicious spirals of repeating self-accelerating oxidative stress and dysregulated redox and information signaling as possible causes of type 2 diabetes. Schema of cell events that occur at type 2 diabetes development, as related to oxidative stress and impaired redox homeostasis and signaling, dysfunctional insulin signaling in peripheral tissues, and autocrine insulin signaling in failing pancreatic β cells. Considered “vicious spirals” (depicted by black spirals) of progressive oxidative stress leading to oxidation of proteins, lipids, and DNA, notably mitochondrial DNA, all resulting in further turn of self-accelerating metabolic deterioration and specifically impairment of the glucose sensing. Progressive oxidative stress also impairs redox signaling and autocrine insulin signaling which further deteriorates fitness of β cells and their housekeeping mechanisms, specifically autophagy and mitochondria-specific autophagy, mitophagy, besides initiating an inappropriate apoptosis. Another component of oxidative stress comes from the intake of excessive fatty acids and lipid peroxidation products, generally termed as lipotoxicity. Yet another component results from elevated blood glucose as is known as glucotoxicity further accelerating cell oxidative stress, impairing cell maintenance, dysregulating information signaling and leading to advanced glycation end products (AGEs), (yet further accelerating oxidative stress and other cell stresses), activating polyol pathway and thus again contributing to pro-oxidation redox homeostasis, activating hexosamine pathway and dysregulating crucial survival pathways including insulin receptor (autocrine) signaling, and finally enhancing glycosylation and forming antiparallel crossed β-pleated sheet structure called amylin-derived islet amyloid, promoting β cell cytotoxicity.
