Diabetic neuropathy: what does the future hold?

Abstract

Frustratingly, disease-modifying treatments for diabetic neuropathy remain elusive. Glycaemic control has a robust effect on preventing neuropathy in individuals with type 1 but not in those with type 2 diabetes, which constitute the vast majority of patients. Encouragingly, recent evidence points to new metabolic risk factors and mechanisms, and thus also at novel disease-modifying strategies, which are desperately needed. Obesity has emerged as the second most important metabolic risk factor for neuropathy (diabetes being the first) from consensus findings of seven observational studies in populations across the world. Moreover, dyslipidaemia and altered sphingolipid metabolism are emergent novel mechanisms of nerve injury that may lead to new targeted therapies. Clinical history and examination remain critical components of an accurate diagnosis of neuropathy. However, skin biopsies and corneal confocal microscopy are promising newer tests that have been used as outcome measures in research studies but have not yet demonstrated clear clinical utility. Given the emergence of obesity as a neuropathy risk factor, exercise and weight loss are potential interventions to treat and/or prevent neuropathy, although evidence supporting exercise currently outweighs data supporting weight loss. Furthermore, a consensus has emerged advocating tricyclic antidepressants, serotonin-noradrenaline (norepinephrine) reuptake inhibitors and gabapentinoids for treating neuropathic pain. Out-of-pocket costs should be considered when prescribing these medications since their efficacy and tolerability are similar. Finally, the downsides of opioid treatment for chronic, non-cancer pain are becoming increasingly evident. Despite these data, current clinical practice frequently initiates and continues opioid prescriptions for patients with neuropathic pain before prescribing guideline-recommended treatments.

Keywords: Diabetes; Dyslipidaemia; Exercise; Neuropathy; Obesity; Opioids; Pain; Skin biopsy; Sphingolipids; Weight loss.

Fig. 1

Diabetic neuropathy pathogenesis. Hyperglycaemia and dyslipidaemia lead to several pathological alterations in neurons, Schwann cells, glia and vascular cells, including ER stress, DNA damage, mitochondrial dysfunction, neurodegeneration and apoptosis and, ultimately, neuropathy. The importance of these pathways in the development of neuropathy varies with cell type, disease profile and time. Distinct cell types are more or less susceptible to injury depending on the metabolic impairments. LOX1, oxidised LDL receptor 1; RAGE, AGE-specific receptor; ROS, reactive oxygen species; TLR4, Toll-like receptor 4. Adapted from [11] with permission from Springer Nature. This figure is available as a downloadable slide