Structural-functional interactions in the therapeutic response of diabetic neuropathy.

Studies in experimental diabetic rat attribute the acute reversible nerve conduction defect as well as the early structural abnormalities of the node of Ranvier and myelinated axons to changes in nerve metabolism secondary to hyperglycaemia and activation of the pol yo1 pathway.’-8 The early readily reversible slowing of nerve conduction velocity in the diabetic rats correlates with a decrease in nerve Na,K-ATPase a ~ t i v i t y , ~ which induces a selective conduction block of large rapidly conducting fibres by inactivating voltage-dependent sodium chann e l ~ . ~ A further progressive impairment of nerve conduction velocity correlates with the progressive development of axo-glial dysjunstion, a characteristic structural lesion of the paranodal region in experimental diabetic rats and diabetic human subjects.6,8,’0 This structural defect isassociated with an acutely irreversible marked reduction in nodal sodium permeability.” Impaired Na,K-ATPase activity and axo-glial dysjunction are normalized or prevented by aldose reductase inhibition in the diabetic rat,”,’* in whom axo-glial dysjunction shows a strong correlation with the slowed nerve conduction velocity.’* These data indicate that the nodal delay of the impulse propagation i s associated with axo-glial dysjunction and is superimposed on the slowing of nerve conduction velocity related to abnormalities in nerve fibre metabolism. The neuroanatomical abnormalities associated with peripheral polyneuropathy in diabetic human subjects are similar to those of the diabetic rat including axoglial dysjunction.lo The mechanisms underlying the electrophysiological abnormalities in diabetic patients are less well defined, but it i s believed that they include both metabolic and structural component^.'^ The rapid improvement in nerve conduction velocity following strict glycaemic control probably reflects improvements in nerve metabo l i~m. ’~ Fibre atrophy and progressive loss of myelinated fibres are the structural hallmarks of advanced diabetic neuropathy in human^.'^,'^ Decreased fibre diameter has been suggested as the basis for nerve conduction slowing in human diabetic ne~ropathy . ’~ This laboratory