Pathogenesis of diabetic neuropathy: bad to the bone.

Insulin and proinsulin are normally produced only by the pancreas and thymus. We detected in diabetic rodents the presence of extra pancreatic proinsulin-producing bone marrow-derived cells (PI-BMDCs) in the BM, liver, and fat. In mice and rats with diabetic neuropathy, we also found proinsulin-producing cells in the sciatic nerve and neurons of the dorsal root ganglion (DRG). BM transplantation experiments using genetically marked donor and recipient mice showed that the proinsulin-producing cells in the DRG, which morphologically resemble neurons, are actually polyploid proinsulin-producing fusion cells formed between neurons and PI-BMDCs. Additional experiments indicate that diabetic neuropathy is not simply the result of nerve cells being damaged directly by hyperglycemia. Rather, hyperglycemia induces fusogenic PI-BMDCs that travel to the peripheral nervous system, where they fuse with Schwann cells and DRG neurons, causing neuronal dysfunction and death, the sine qua non for diabetic neuropathy. Poorly controlled diabetes is indeed bad to the bone.