The role of glycation in the pathogenesis of diabetic polyneuropathy

Abstract

The most common neuropathy associated with diabetes mellitus is a distal sensory polyneuropathy. The relative importance of the direct effects of prolonged glycaemia on nervous tissue compared with indirect damage resulting from changes in blood vessels is not known. Although the importance of glycaemia is confirmed by a study showing that the incidence of neuropathy is greatly reduced by strict glycaemic control, many of the details of the deleterious effects of glycaemia on the peripheral nervous system (PNS) are not understood. These may be the result of direct damage to any of the cells in the PNS or the disruption of neuronal metabolism, axonal transport mechanisms, or repair capabilities; in addition, they may result from the effects of glycation on PNS connective tissue or a combination of some or all of the above mentioned mechanisms. The relative importance of these various mechanisms by which diabetes damages the PNS is a matter of conjecture. Therapeutic approaches targeting a specific mechanism such as those utilising aldose reductase inhibitors, or advanced glycation endproduct inhibitors have met with limited success. Clearly, it is difficult to design a treatment for diabetic neuropathy while its pathogenesis is still poorly understood.

Figure 1

Transverse section of a radial nerve from a 42 year old woman with distal sensory symmetric polyneuropathy. There are circular clusters of regenerative sprouts (arrows) and the endoneurial microvessels are encircled by thickened basal lamina. Resin section, stained with thionin and acridine orange. Original magnification, ×200.

Figure 2

Electron microscopy of a regenerative cluster shows the persistent basal laminal tube (arrow) around myelinated and unmyelinated axonal sprouts (asterisks). Radial nerve, 47 year old man with distal sensory symmetric polyneuropathy. Contrasted with lead and uranyl acetate. Bar, 1 μm.

Figure 3

Light micrograph of resin section of sural nerve from 48 year old woman with distal sensory symmetric polyneuropathy. The endoneurial microvessels have extensively enlarged basal laminal ensheathment. Few myelinated fibres have survived in this case. Stained with thionin and acridine orange. Original magnification, ×400.

Figure 4

Electron micrograph showing that the widened basal laminal ensheathment around endoneurial blood vessels consists of basal lamina (arrow) and collagen fibrils, and contains pericyte processes (p). Same case as fig 2 ▶. Bar, 1 μm.

Figure 5

(A) Electron microscopy of a section through the whole thickness of the perineurium of a radial nerve fascicle from a 39 year old man with distal sensory symmetric polyneuropathy; the epineurial face is at the top. The basal lamina of the perineurial cells is extensively widened (asterisks). The small electron dense bodies are deposits of calcium apatite. Bar, 1 μm. (B) Electron microscopy of the perineurium from a normal control subject with approximately the same numbers of perineurial laminae. The basal laminae are much thinner. Bar, 1 μm.