Diabetic neuropathy is a common secondary complication of diabetes mellitus with no effective treatment. It has a complex aetiology, associated with biochemical and structural changes in the nervous system, nerve conduction velocity deficits and altered mechanical and thermal sensitivity. A common feature of both clinical and experimental diabetic neuropathy is degeneration of distal nerve fibres, and a reduced capacity for regeneration of injured axons and/or attenuated collateral branching from undamaged axons. This means that the rate of axonal degeneration eventually exceeds that of regeneration leading to numbness, loss of protective sensation and an increased risk of amputation. In addition, diabetic neuropathy can be accompanied by paresthesias, allodynia and ongoing pain and can therefore impact on patient’s quality of life. We are therefore interested in elucidating the changes at both the cellular and extracellular level that underlie the development of experimental diabetic neuropathy. The main focus of this talk will be the effects of modification of the extracellular matrix (ECM) in diabetes. The ECM not only provides important physical 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. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes. They are best known for their role in degradation of ECM molecules, release of ECM-sequestered cytokines and growth factors, and cleavage and activation of membrane-bound cytokines. We have previously shown that advanced glycation endproducts (AGEs) accumulate in ECM proteins in the endoneurium of rats with streptozotocin-induced diabetes and that glycation of ECM proteins with methylgloxal causes a reduction in both neurotrophin-stimulated and preconditioned neurite-outgrowth from sensory neurons (Duran-Jimenez et al, 2009). Furthermore, reduced MMP-2 expression in the sciatic nerve in diabetes may also contribute to the failure of regeneration in experimental diabetic neuropathy. These changes may provide a potential mechanism for the failure of axonal regeneration and collateral sprouting observed in diabetic neuropathy and represent a target for therapeutic intervention.