The incidence and severity of neuropathy in patients with diabetes is worsened by poor hyperglycaemic control, indicating high glucose levels to be a primary causative factor. Distal sensory polyneuropathy (DPN) is the most common of the peripheral nerve disorders associated with diabetes (~54% of type 1 diabetic patients develop DPN). DPN can be accompanied by: pain, tingling and burning sensations; heightened sensitivity; numbness; and ultimately loss of sensation, which may lead to tissue damage. It is a debilitating condition, with no effective treatment.The degeneration of sensory nerve terminals in the skin, and subsequent failure of reinnervation is a key pathological feature of DPN. The cause of this regenerative deficit is complex – a combination of phenotypic change, oxidative stress, reduced growth factors, impaired synthesis and axonal transport of cytoskeletal components, and associated biochemical changes including formation of advanced glycation endproducts (AGEs.
The success of sensory nerve regeneration depends largely on two factors: the presence of a permissive growth environment and the intrinsic growth capacity of the neuron. The extracellular matrix (ECM) not only provides important physical structure and support for cells and tissue, but also has a crucial role in regulating cell behaviour, mediating survival, proliferation, differentiation and migration via interaction with specific cell adhesion receptors such as the integrins. Therefore, modification ECM proteins in disease, such as by glycation in diabetes, can severely impact on cell function.
Dr Gardiner’s group have recently shown that AGEs accumulate in ECM proteins of peripheral nerve in experimental diabetes, and that glycation of the ECM proteins laminin and fibronectin, with either glucose or methylglyoxal, increases AGE residue content of these proteins and dramatically impairs regeneration of sensory neurons in vitro. They hope to elucidate the changes in the sensory nervous system in diabetes, to develop effective therapeutic strategies for treating diabetic neuropathy.