Hypoglycaemic neuropathy : Experimental studies in diabetic rats treated witn insulin implants

Sammanfattning: Insulin dependent diabetes mellitus is a metabolic disease that causes secondary complications such as peripheral neuropathy. it is generally believed that diabetic neuropathy is due to chronic hyperglycaemia. In order to understand the pathophysiology of diabetic neuropathy many workers have examined nerves from diabetic rats. While most workers say that animals with high blood glucose levels develop neuropathy, some investigators report that the peripheral nerves are normal in hyperglycaemic rats. Hypoglycaemia may also cause neuropathy. The general aim of the present study is to examine the long-term relation between glycaemia and peripheral neuropathy in diabetic BB/Wor rats. This necessitated establishment of a treatment regime allowing long-term survival of these sick animals.We found that maintenance of diabetic BB/Wor rats on an eu/hyperglycaemic or an eu-/hypoglycaemic regime with insulin implants worked well for our purpose.Unexpectedly, light and electron microscopic examination of plantar nerves in eu-/hyperglycaemic diabetic rats showed a normal picture. But, nerves from eu-/hypoglycemic rats showed severe qualitative changes, interpreted as axonal de- and regeneration. The total number of axons  was subnormal and the myelinated fibres were shifted towards smaller diameters. Hence, eu-/hypoglycaemic diabetic BB/Wor rats but not eu-/hyperglycaemic animals, develop a neuropathy in their plantar nerves.The immunohistochemical occurrence of epidermal protein gene product 9.5 immunoreactive axon profiles was normal in heel skin biopsies from eu/hypoglycaemic rats, but many profiles were short and thin. The content of the neuropeptide calcitonin gene-related peptide in skin biopsies was subnormal. The occurrence of end plate axon terminals labeled with antibodies against the vesicular acetylcholine transporter protein was subnormal in sections from a plantar muscle of eu-/hypoglycaemic rats. Moreover, the end plate axon terminals were abnormally small. Hence, the hypoglycaemic neuropathy seen in plantar nerve trunks of diabetic BB/Wor rats treated with insulin implants is accompanied by mild alterations in the epidermal innervation of plantar skin and a more obviously abnormal nerve terminal pattern in plantar muscle.Electron microscopic examination of L5 dorsal roots from eu/hypoglycaemic rats showed a normal morphology and normal numbers of axons. In L5 ventral roots the picture varied: in 2 rats it was normal and 3 rats showed signs of axonal degeneration. The L5 dorsal root ganglion and the L5 ventral horn showed a normal picture. Hence, eu-/hypoglycaemia affects ventral root axons but not dorsal root axons. Moreover, the degree of ventral root pathology is variable and sensory and motor neuron perikarya are not affected.