The fusion of proinsulin-expressing bone marrow cells with neurons could be a key event in the development of diabetic neuropathy, according to a recent report by Lawrence Chan and colleagues.

Diabetic peripheral neuropathy is the leading cause of non-traumatic limb amputations. The symptoms can be widespread, from numbness, pain and tingling of the extremities to problems with the digestive tract, bladder infections and impotence. But the chain of events that leads to nerve damage in diabetes is not well described, and current treatments are designed to relieve discomfort and prevent further tissue damage.

The main risk factor for diabetic neuropathy is hyperglycaemia, and the progression of neuropathy depends on the degree of glycaemic control in type 1 and type 2 diabetes. How hyperglycaemia leads to diabetic complications, including neuropathy, is unclear, but a number of factors have been implicated in the process.

Chan and colleagues had previously found proinsulin- and insulin-positive cells — which are normally confined to the pancreas — in various organs in mouse and rat models of diabetes, and had shown that most of these extrapancreatic insulin-producing cells originated in the bone marrow. In their latest study, the researchers discovered that in diabetic mice and rats with neuropathy, bone-marrow-derived cells that expressed proinsulin fused with neurons in the sciatic nerve and dorsal root ganglion, leading to cellular dysfunction and accelerated apoptosis.

The hybrid cells expressed proinsulin and tumour necrosis factor-α (TNFα), a cytokine that is known to be involved in peripheral neuropathy, and only neurons marked by proinsulin expression showed abnormal calcium homeostasis and apoptosis. Crucially, the researchers showed that the treatment of diabetic rats with insulin led to a reduction in the number of proinsulin-positive cells and prevented the prolongation of motor nerve conduction velocity — a sign of neuropathy — confirming that the appearance of these cells was due to hyperglycaemia.

How the mechanism described by Chan and colleagues relates to several other factors that have been implicated in diabetic neuropathy, including oxidative stress and growth factor deficiency, remains an open question.