The metabolic syndrome and neuropathy: therapeutic challenges and opportunities

Abstract

The metabolic syndrome and neuropathy are common conditions, especially in the elderly, that are associated with significant morbidity. Furthermore, the metabolic syndrome is reaching epidemic proportions across the world. Current evidence supports the association of the metabolic syndrome and its individual components with neuropathy. Several clinical trials have demonstrated that treating hyperglycemia, a component of the metabolic syndrome, has a significant effect on reducing the incidence of neuropathy in those with type 1 diabetes. However, glucose control has only a marginal effect on preventing neuropathy in those with type 2 diabetes, suggesting that other factors may be driving nerve injury in these patients. Emerging evidence supports the metabolic syndrome as including risk factors for neuropathy. Interventions exist for treatment of all of the metabolic syndrome components, but only glucose control has strong evidence to support its use and is widely employed. Our understanding of the biology of metabolic nerve injury has rapidly expanded over the past several years. Mechanisms of injury include fatty deposition in nerves, extracellular protein glycation, mitochondrial dysfunction, and oxidative stress. Additionally, the activation of counter-regulatory signaling pathways leads to chronic metabolic inflammation. Medications that target these signaling pathways are being used for a variety of diseases and are intriguing therapeutic agents for future neuropathy clinical trials. As we move forward, we need to expand our understanding of the association between the metabolic syndrome and neuropathy by addressing limitations of previous studies. Just as importantly, we must continue to investigate the pathophysiology of metabolically induced nerve injury.

Figure 1

Signaling pathways underlying nutrient excess and metabolic neuropathy. Hyperglycemia and hyperlipidemia incite a feed-forward cycle of cellular damage with production of reactive oxygen species leading to cellular oxidative stress, mitochondrial dysfunction and parallel endoplasmic reticulum (ER) stress. These changes not only lead to direct neuronal injury but also promote nutrient excess-mediated insulin resistance, initiating tissue inflammation, which in turn exacerbates insulin resistance and mediates injury cascades. There is leukocyte recruitment with the production of tissue damaging inflammatory chemokines and activation of Jun N-terminal kinases (JNK) and inhibitor of nuclear factor Kb (IKb) kinase B (IKKb) triggering further insulin resistance, inflammatory responses and tissue damage. JNK and IKKb also mediate NFκB activation leading to production of inflammatory and tissue damaging signals. Collectively these diverse but interlinked pathways reinforce a destructive cycle of cellular impairment and damage linking nutrient excess to metabolic neuropathy.