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Hyperglycemia coupled with loss of insulin signaling (type 1 diabetes) and/or insulin resistance (type 2 diabetes) including dysregulation of lipid metabolism and dyslipidemia, lead to systemic inflammation and vicious cycles of oxidative/nitrosative stress, endoplasmic and mitochondrial stress, and accumulating cellular damage ( Mechanism related therapies Pre-clinical studies have provided a wide array of potential mechanisms and effective treatments for DPN ( If combination therapy is the best approach what evidence is there to suggest a specific combination of agents

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