Distal neuropathy in experimental diabetes mellitus

Abstract

Although nerve conduction slowing is a well-accepted abnormality in rats with acute experimental diabetes, reports of neuropathological changes in diabetic rat nerves have been inconsistent. To examine this further, we studied electrophysiological and morphological features of posterior tibial nerves and their distal branches from four-week streptozotocin-induced diabetic rats and matched controls. Diabetic rat posterior tibial motor conduction was slowed (mean +/- 1 SD, 34.8 +/- 3.1 m/sec; controls, 41.2 +/- 2.5 m/sec), and evoked muscle response amplitudes were only half of control values. Using quantitative techniques, we documented a diminution in number of the largest myelinated fibers in otherwise normal mid posterior tibial nerves, with an increase in the smaller sizes, indicating either a degree of axonal atrophy or impaired fiber growth during development. The principal pathological finding was active breakdown of myelinated fibers in the most distal motor twigs of hindfoot muscles supplied by posterior tibial branches, with preservation of fibers in more proximal segments of these nerves. This anatomical lesion in diabetic nerves could account for both oberved conduction slowing and lowered muscle response amplitudes. A consistent feature in both diabetic and control mid lateral plantar nerves was a zone of demyelination that apparently occurs at this natural site of nerve entrapment in rats. Taken together, the pathological abnormalities of peripheral nerve in acute experimental diabetes are best explained as resulting from a distal axonopathy.

Animal Models of Peripheral Neuropathies

“…Soon after the initial development of the streptozotocin-induced diabetes mellitus model, investigators recognized that the pathological changes in the peripheral nerves of these rats mirrored what has been seen in patients with DPN; they exhibited axonal atrophy, axonal degeneration, and demyelination [19][20][21]. These findings, however, were not very consistent across different models, and only a careful study was able demonstrate that streptozotocin-induced diabetic rats had distal axonal degeneration similar to human DPN, in which the degeneration starts in the most distal nerves in a "dying-back" fashion [22]. In typical streptozotocininduced diabetic rats, the peroneal nerves may not show obvious signs of large myelinated axonal degeneration, but they often show axonal atrophy, which requires careful nerve morphometric studies that are tedious and time consuming.…”

“…In typical streptozotocininduced diabetic rats, the peroneal nerves may not show obvious signs of large myelinated axonal degeneration, but they often show axonal atrophy, which requires careful nerve morphometric studies that are tedious and time consuming. In addition, the distal most parts of the peroneal nerves, within the intramuscular branches, show signs of axonal degeneration [22] complicating quantitation in drug development studies that rely on evaluation of many nerves in a feasible manner.…”

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

“…Diabetic rats display tactile allodynia and the increased sensitivity of rats has been difficult to relate to the insensate neuropathy that occurs in the majority of humans with diabetic neuropathy. Moreover, the rapid appearance of the hypersensitivity in rats has not been easily attributable to diabetes-induced abnormalities in peripheral nerve (Brown et al, 1980;Courteix et al, 1993;Calcutt et al, 1996;Sima et al, 1998;Fox et al, 1999;Khan et al, 2002). It is not clear why STZ-induced diabetic rats and mice develop such divergent responses to mechanical stimuli.…”

Peripheral neuropathy in selectively-inbred spontaneously diabetic rats: Electrophysiological, morphometrical and freeze-replica studies.

“…The results suggested that the delayed nerve conduction velocity was most related to diabetic dysmetabolism and independent of the structural changes of peripheral nerves being in the course of distal axonopathy. peripheral neuropathy; nerve conduction velocity; spontaneously diabetic rats; morphometry; freeze-replica Growing interest in the pathophysiology of the nervous system in diabetes mellitus has raised a large body of important reports on the nervous system abnormalities in diabetes, but yielding conflicting results (Hildebrand et al 1968;Jakobsen 1976Jakobsen , 1979 Yagihashi et al 1979a;Brown et al 1980;Robertson and Sima 1980). In experimental diabetes, it has been established that delayed…”

“…The present study was designed (1) to clarify the sequential changes of nerve conduction velocity of SDR, (2) to detect morphometrical changes of peripheral nerve structures in SDR and (3) to clarify the membrane abnormalities of internodal myelin and Schwann cell membranes in SDR.…”