Possible Role Of Uncoupling Proteins As Protectors From Hyperglycemia-Induced Neuropathy

Diabetic neuropathy may be induced by oxidative stress, possibly as a consequence of the hyperglycemic situation. Uncoupling proteins (UCPs) have been reported to function as anti-oxidants by decreasing the production of reactive oxygen species (ROS). These mitochondrial carrier proteins are located in the inner membrane of mitochondria and upon activation, they dissipate proton gradients, which generates heat instead of ATP. In humans, UCP2 and UCP3 are believed to play a role as energy dissipaters and aberrant function could underlie metabolic defects seen in both obesity and non-insulin dependent diabetes (NIDDM). In this study we have shown that human neuroblastoma SH-SY5Y cells expressed UCP2 and UCP3 natively and that the expression was upregulated by insulin and IGF-I via the IGF-I receptor. In highly differentiated SH-SY5Y cells, which were cultured in hyperglycemic N2-medium (30 mM and 60 mM glucose) containing 8.6 nM insulin, the number of neurites per cell and total cellular protein levels/dish were significantly decreased, as compared to cells grown in N2-medium containing 17 mM glucose. This effect was abolished when the cells were grown with 10 nM IGF-I at 30 mM glucose and decreased at 60 mM glucose. Furthermore, in hyperglycemic cells, the IGF-I-induced increase in UCP3 protein levels was inhibited. Non-differentiated cells responded to hyperglycemic situations by increased rate of proliferation, leaving cell morphology intact. We conclude that differentiated SH-SY5Y cells can serve as an in vitro model for hyperglycemic neurons and that IGF-I protects the cells from hyperglycemia-induced neuropathy, suggestively by the involvement of UCP3.