The conundrum of diabetic neuropathies-Past, present, and future

Abstract

Diabetic neuropathy (DN) remains arguably the most prevalent chronic complication in people with both type 1 and type 2 diabetes, including in youth, despite changes in the current standards of clinical care. Additionally, emerging evidence demonstrates that neuropathy affects a large proportion of people with undiagnosed diabetes and/or prediabetes, as well as those with obesity. Here we summarize the latest epidemiology of DN, recent findings regarding the pathophysiology of the disease, as well as current outcome measures for screening and diagnosis, in research and clinical settings. The authors discuss novel perspectives on the impact of social determinants of health in DN development and management, and the latest evidence on effective therapies, including pharmacological and nonpharmacological therapies for neuropathic pain. Throughout the publication, we identify knowledge gaps and the need for future funding to address these gaps, as well as needs to advocate for a personalized care approach to reduce the burden of DN and optimize quality of life for all affected individuals.

Keywords: Autonomic neuropathies; Diabetic peripheral neuropathy; Epidemiology; Mechanisms; Novel risk factors; Personalized care implementation.

Figure 1:

Diabetic neuropathy pathogenesis. Hyperglycaemia and dyslipidaemia, together with altered insulin signalling, lead to several pathological alterations in neurons, glia and vascular cells that can lead to nerve dysfunction and ultimately, neuropathy, including DNA damage, endoplasmic reticulum stress, mitochondrial dysfunction, neurodegeneration and loss of neurotrophic signalling, and can trigger macrophage activation. The importance of these pathways in the development of neuropathy varies with cell type, disease profile and time, as distinct cell types are more or less susceptible to injury depending on the metabolic impairments. AGE, advanced glycation end-product; FFAs, free fatty acids; Glucosamine-6-P, glucosamine 6-phosphate; LDL, low-density lipoprotein; LOX1, oxidized LDL receptor 1; RAGE, AGE-specific receptor; ROS, reactive oxygen species; TLR4, Toll-like receptor 4; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine. Reproduced from: Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, Bril V, Russell JW, Viswanathan V. Diabetic neuropathy. Nat Rev Dis Primers. 2019 Jun 13;5(1):42. doi: 10.1038/s41572-019-0097-9. PMID: 31197183; PMCID: PMC7096070.

Figure 2:

Mechanisms and clinical consequences of cardiovascular autonomic neuropathy (CAN) in diabetes