Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed. In addition mitochondrial changes recently reported to occur as part of the apoptotic cascade, such as ballooning of mitochondria and disruption of the internal cristae, are seen in diabetic dorsal root ganglion neurons and Schwann cells. Similar changes have been reported in neurons in the presence of oxidative stress. In order to study the neurotoxic effects of high glucose we developed an in vitro model using rat dorsal root ganglion neurons. In dorsal root ganglion cultured in defined medium, addition of moderate glucose levels results in neurite degeneration and apoptosis. These changes are coupled with activation of caspase-3, dependent on the concentration of glucose. The apoptotic changes observed in vitro are similar to those observed in vivo. In contrast, addition of IGF-I, even at physiological concentrations, prevents activation of caspase-3 and neuronal apoptosis in vitro. We suggest that oxidative stress may promote the mitochondrial changes in diabetic animals and lead to activation of programmed cell death caspase pathways. These results imply a new pathogenetic mechanism for diabetic sensory neuropathy.