Targeting Molecular Chaperones in Diabetic Peripheral Neuropathy

1.1 Diabetic peripheral neuropathy Diabetes Mellitus (DM) is estimated to affect 347 million patients globally as of 2008 (Danaei et al., 2011) and this number is expected to double by 2030 (Wild et al., 2004). DM results from the failure of our body to generate and/or respond to insulin, the principal hormone regulating uptake of glucose from the blood stream, leading to abnormally high blood glucose levels, termed hyperglycemia. Sensory neurons absorb glucose as a direct function of extracellular glucose concentration instead of insulin-mediated glucose uptake and are particularly susceptible to the cumulative metabolic insults imposed by chronic hyperglycemia (Tomlinson and Gardiner, 2008). This damage leads to secondary microvascular complications that contribute to the progression of diabetic neuropathy. Diabetic peripheral neuropathy (DPN) is the most prevalent complication of DM (Tahrani et al., 2010), also comprises the most common form of peripheral neuropathy globally, surpassing leprosy in this aspect (Harati, 2010; Martyn and Hughes, 1997). Depending on the case definitions used, 30-70% of patients with either type 1 or type 2 DM are diagnosed with some form of peripheral neuropathy (National Institutes of Diabetes and Digestive and Kidney Diseases). A distal symmetric sensorimotor polyneuropathy is the most frequent manifestation of DPN. Patients with this form of DPN are predisposed to foot ulceration and increased risk of amputation; ulcerative complications from DPN account for approximately 87% of non-traumatic lower extremity amputations. In addition to this traumatic medical event, DPN is also a major contributing factor to the development of joint deformities, limb threatening ischemia as well as other various neurological dysfunctions (Harati, 2010). This greatly reduces the quality of life in people with DM through increased disability and is assuming more hospitalizations than all other diabetic complications combined (Mahmood et al., 2009). As a consequence, approximately $15 billion are spent on DPN annually in the US, causing a major drain on healthcare expenditure (Rathmann and Ward, 2003). With the staggering individual, social and economic burden brought about by DPN-associated morbidity and mortality, development of effective treatments that prevent and/or reverse DPN are needed but currently unmet.