Epalrestat br Acknowledgements Support provided by projects

Acknowledgements Support provided by projects PTDC/SAU-MIC/115178/2009 and PEst-OE/QUI/UI0612/2011 from the Fundação para a Ciência e a Tecnologia, Portugal.
Diabetes Mellitus Diabetes mellitus is a chronic, multisystem metabolic disorder caused by a combination of environmental and genetic factors and characterized by hyperglycemia. The World Health Organization estimates that 220 million people worldwide currently have diabetes. Type 2 Epalrestat is the most prevalent form and accounts for 90% to 95% of these cases. According to the Centers for Disease Control and Prevention, 25.8 million children and adults currently suffer from diabetes mellitus in the United States. Importantly, 35% of the adult population is estimated to have prediabetes or metabolic syndrome, a condition with higher than normal blood glucose and impaired insulin sensitivity that has yet to reach diagnostic criteria for diabetes mellitus. Individuals with prediabetes are at a higher potential for developing type 2 diabetes mellitus. Hence, a staggering 79 million adults are at risk for developing type 2 diabetes mellitus. Although type 1 diabetes mellitus accounts for a far smaller percentage, 5% to 10% of cases, the incidence has been steadily rising in the past decades to nearly 5% annually in the United States. Hence, both type 1 and type 2 diabetes mellitus remain growing problems throughout the world. Despite the differences in etiology, clinical presentation, and disease prevalence, secondary complications, such as heart disease, stroke, retinopathy, nephropathy, and neuropathy, occur in both type 1 and 2 diabetes mellitus. As a result of the continual rise in diabetes mellitus, secondary complications continue to be a large economic burden in the United States and across the world.3, 4 Of these, diabetic neuropathy is the most common complication of long-term diabetes mellitus.3, 5, 6 The Centers for Disease Control and Prevention estimates that 60% to 70% of diabetic patients will develop diabetic neuropathy symptoms with the prevalence increasing with the duration of diabetes mellitus. Patients with diabetic neuropathy are at an increased risk for developing ulcers, recurrent foot infections, and Charcot joints, bony destruction, and deformation resulting from repetitive, traumatic injury, often associated with reduced sensation in the feet.5, 7 Consequently, diabetic neuropathy is the cause of 50% to 75% of nontraumatic amputations. Diabetic neuropathy has a profound impact on patients’ quality of life and is responsible for most diabetes-associated morbidity and mortality. Diabetic neuropathy is a collection of syndromes, either focal or diffuse in nature, affecting sensory, motor, and/or autonomic peripheral neurons.5, 6 These disorders can range from clinical to subclinical and differ in their anatomical distribution, clinical course, and spectrum of symptoms. The most prevalent of the syndromes is distal symmetrical sensorimotor polyneuropathy, referred to as diabetic neuropathy in this review, that results from damage to peripheral sensory nerves and accounts for nearly 80% of diabetic neuropathy cases. One hallmark of diabetic neuropathy is the symmetrical loss of distal skin innervation resulting from degeneration of small cutaneous nerve fibers. Diabetes-induced nerve damage causes a dying-back of distal axons that begins in the feet and progresses proximally in a stocking-and-glove distribution.8, 9 Diabetic peripheral neuropathy has an insidious onset and is chronic and progressive in nature; therefore, diabetic neuropathy often results in severe, irreversible symptoms after longstanding diabetes mellitus. Sural nerve biopsies from diabetic patients also demonstrate loss of small unmyelinated C-fibers and small myelinated Aδ fibers in early stages of diabetic neuropathy with progressive involvement of large myelinated Aβ fibers with duration of disease.10, 11 Despite histological and ultrastructural findings of axonal regeneration, collateral sprouting, and remyelination within peripheral nerves, impaired nerve regeneration has been documented.13, 14 However, regeneration is ultimately unable to compensate for the continued vicious cycle of damage and neurodegeneration of sensory neurons.13, 15