Inflammation as a Therapeutic Target for Diabetic Neuropathies

Abstract

Diabetic neuropathies (DNs) are one of the most prevalent chronic complications of diabetes and a major cause of disability, high mortality, and poor quality of life. Given the complex anatomy of the peripheral nervous system and types of fiber dysfunction, DNs have a wide spectrum of clinical manifestations. The treatment of DNs continues to be challenging, likely due to the complex pathogenesis that involves an array of systemic and cellular imbalances in glucose and lipids metabolism. These lead to the activation of various biochemical pathways, including increased oxidative/nitrosative stress, activation of the polyol and protein kinase C pathways, activation of polyADP ribosylation, and activation of genes involved in neuronal damage, cyclooxygenase-2 activation, endothelial dysfunction, altered Na(+)/K(+)-ATPase pump function, impaired C-peptide-related signaling pathways, endoplasmic reticulum stress, and low-grade inflammation. This review summarizes current evidence regarding the role of low-grade inflammation as a potential therapeutic target for DNs.

Keywords: Chronic inflammation; Diabetic neuropathy; Inflammatory cytokines; Peripheral nerve dysfunction.

Fig. 1

The link between chronic inflammation in diabetes and peripheral nerve fiber damage and loss. Hyperglycemia coupled with loss of insulin signaling and insulin resistance, along with 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. Glucotoxicity, insulinopenia, and lipotoxicity produce neuronal oxidative/nitrosative stress and activate multiple downstream kinases such as protein kinase C (PKC), mitogen activated protein kinase (MAPK), and jun N-terminal kinase (JNK), as well as redox-sensitive transcriptional factors, including NF-κB. These factors play a critical role in triggering a cascade of cytokine and chemokine production, including pro-inflammatory interleukin-1β, interleukin-2, interleukin-6, interleukin-8 (IL-1β, IL-2, IL-6, IL-8), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), and chemokine (C-X-C motif) ligand 1 (CXCL1). Cytokines and chemokines not only enhance existing inflammatory and immune responses but also promote activation of the wide array of downstream cellular oxidative/nitrosative stresses, promoting even more neuronal damage