Contribution of oxidative stress and impaired biogenesis of pancreatic β-cells to type 2 diabetes.

SIGNIFICANCE: Type 2 diabetes development involves multiple changes inβ-cells, related to the oxidative stress and impaired redox signaling, beginning frequently by sustained overfeeding due to the resulting lipotoxicity and glucotoxicity. Uncovering relations among the dysregulated metabolism, impaired β-cell "well being", biogenesis, or crosstalk with peripheral insulin resistance is required for elucidation of type 2 diabetes etiology. Recent Advances: It has been recognized that the oxidative stress, lipotoxicity and glucotoxocity cannot be separated from numerous other cell pathology events, such as the attempted compensation ofβ-cell for the increased insulin demand and dynamics ofβ-cell biogenesis and its "reversal" at dedifferentiation, i.e. from the concomitantly decreasing isletβ-cell mass (also due to transdifferentiation) and low-grade islet or systemic inflammation.

CRITICAL ISSUES: At prediabetes, the compensation responses ofβ-cells, attempting to delay the pathology progression - when exaggerated - set a new state, in which a self-checking redox signaling related to the expression of Ins gene expression is impaired. The resulting altered redox signaling, diminished insulin secretion responses to various segretagogues including glucose, may lead to excretion of cytokines or chemokines byβ-cells or excretion of endosomes. They could substantiate putative stress signals to the periphery. Subsequent changes and lasting glucolipotoxicity promote islet inflammatory responses and further pathology spiral.

FUTURE DIRECTIONS: should bring an understanding of theβ-cell selfchecking and related redox signaling, including the putative stress signal to periphery. Strategies to cure/prevent type 2 diabetes could be based on the substitution of the "wrong" signal by the "correct" self-checking signal.