DIABETES/METABOLISM RESEARCH AND REVIEWS RESEARCH ARTICLE Diabetes Metab Res Rev 2007; 23: 490–496. Published online 21 February 2007 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.716 Regenerative failure of diabetic nerves bridging transection injuries Douglas W. Zochodne* Gui Fang Guo Brooks Magnowski Mohammed Bangash University of Calgary, Department of Clinical Neurosciences, Hotchkiss Brain Institute, Canada *Correspondence to: Douglas W. Zochodne, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. E-mail: dzochodn@ucalgary.ca Received: 3 November 2006 Revised: 6 November 2006 Accepted: 13 November 2006 Abstract Background Failed regeneration compounds the deficits imposed by diabetes from peripheral neuropathy. In this work, we addressed how diabetes or local glucose toxicity might impact peripheral nerve trunk regeneration and reconstitution across major sciatic nerve transection injuries of rats. Methods Specific conduits, amendable to manipulation of infused glucose concentrations through a T connection, were perfused with 5 or 30 mmol/L glucose in nondiabetics or 5 mmol/L glucose in rats with experimental diabetes. Quantitative early and later regenerative outgrowth was measured. Results Local glucose exposure had no impact on early axon or Schwann cell outgrowth or partnering nor later myelinated axon regeneration. Despite only mildly attenuated early sprouting of axons with Schwann cells, diabetic bridges exhibited massive later failure of reconstitution by 3 weeks after injury. Conclusion Diabetes is associated with severe limitations in regenerative success, despite appropriate early axon outgrowth. Copyright  2007 John Wiley & Sons, Ltd. Keywords peripheral nerve; nerve regeneration; diabetes mellitus; diabetic neuropathy Introduction Neurological deficits develop in a significant proportion of diabetic patients as a result of polyneuropathy. Moreover, such deficits are compounded by a superimposed failure of compensatory regeneration. Mechanisms that may account for diabetic regenerative failure include roles for hyperglycemia itself, for exaggerated polyol flux through the aldose reductase pathway, for relative ischemia of the regenerative microenvironment, for precarious neurotrophic support, for inappropriate advanced glycosylation endproducts (AGE)-receptor for AGEs (RAGE) signalling and for oxidative or nitrergic stress. The topic has been reviewed in depth elsewhere [1,2]. While regenerative failure has been observed with several types of nerve lesions including crush and transection [3], what steps in the regenerative process are most impaired is debated. For example, a failure of early axon outgrowth has been considered a primary deficit from which slowing of each subsequent step is magnified. Against this possibility, however, has been the finding that early axon outgrowth, for example, after crush, had only limited deficits [4]. In this work, we asked whether manipulation of glucose concentrations within the local milieu in vivo of regenerating axons might alter regrowth. Copyright  2007 John Wiley & Sons, Ltd.