Figure 1: Molecular ingredients in T2DM and its complications pathophysiology. Studies based on cultured cells, gene transcriptional expression and epigenetic regulation have progressed to show that a number of gene/proteins appear to be “imprinted” as to predispose or to lead to insulin resistance and T2DM. Epidemiological studies have also shown the negative impact of environmental factors as life and diet styles. High glucose burden has proved to be toxic to cultured cells as to multiorgan systems under both acute and chronic exposure conditions. A line of evidences has shown that in humans and experimental animals, hyperglycemia is the proximal trigger for the activation of acute phase hepatic reactants and pro-inflammatory cytokines elevation in circulation. In a perpetuative vicious circle, the pro-inflammatory cytokines perturbs insulin receptor signal transduction and thus amplifies hyperglycemia. A cross-activation has been described between the receptor for advanced glycation-end products (RAGE) and the cytokines mediating the state of low grade inflammation in diabetes. Mounting evidences leave no room to doubt on the deleterious role of the advanced glycation-end products (AGE) accumulation. AGEs induce inflammation, apoptosis and cellular aging. On the other hand, hyperglycemia per se as in combination with pro-inflammatory cytokines reduces the cellular pool of anti-oxidant reserves and creates a pro-oxidant environment by the mitochondrial over-production of reactive oxygen species (ROS). These free radicals hamper the mitochondrial oxidative phosphorylation and provoke DNA damages. Under these oxidant and toxic environment, the cells activate signaling pathways and transcription factors that when their “fine tuning” is out of control lead to further amplification of cellular damages. In parallel, other gene/proteins involved in cells defense, anabolism, and survival become downregulated. It is worth noting to mention that hyperglycemia itself is toxic enough to reduce the expression of some of these genes or its derived proteins as e-NOS. As a consequence, cells become predisposed to onset a precocious senescent program, become refractory to programmed turnover and prone to apoptosis. These “cellular illness” translates into tissue and organs irreversible complications.