The balance of evidence supports the concept that programmed cell death (PCD) occurs in cells of the peripheral nervous system (PNS) in the presence of diabetes, elevated glucose levels, or insulin deprivation. The morphological appearance of apoptosis, the severity of cell death, and the mechanism of cell death might vary between different cell types in the PNS and between different mammalian models of diabetes. However, most cells show evidence of mitochondrial (Mt) damage and some, if not all, the features of the original morphological descriptions of apoptosis. PCD has mainly been described in cell culture and animal models of diabetes, although there is also morphological evidence of apoptosis in Schwann cells from human sural nerve. Evidence of PCD or organellar damage often exceeds the observed dorsal root ganglion neuronal loss. Apoptosis represents only the final pathological observation in this state of organellar failure or suboptimal organelle function. It is likely that even nonapoptotic neurons exhibit impaired metabolic function and protein synthesis and this dysregulation will in part induce neuropathy. One potential mechanism for induction of apoptosis in the PNS is diabetes-induced generation of reactive oxygen species and dysregulation of Mt function. During Mt dysfunction, several essential players of apoptosis, including procaspases and cytochrome-c are released into the cytosol and result in the formation of multimeric complexes that induce apoptotic cell death. Antioxidants and certain regulators of the inner Mt membrane potential, for example B-cell lymphoma (BCL) proteins, uncoupling proteins, and growth factors might prevent apoptosis in the PNS. The primary precipitating events leading to apoptosis in the PNS need to be clearly delineated if it is to be understood how to intervene or prevent the most common complication of diabetes, namely neuropathy.

Key Words: Apoptosis; programmed cell death; diabetes; neuropathy; oxidative stress; mitochondria; growth factors; uncoupling proteins; BCL.

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