Genetic and Epigenomic Modifiers of Diabetic Neuropathy

Abstract

Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.

Epigenetics in Obesity and Diabetes Mellitus: New Insights

“…There, 17 genes were found to be differentially expressed between both types of patients ( p = <0.0005), two of which (MTHFSD and LMAN2L) were partially non-coding. In addition, the TUBA4B gene was overexpressed in the DPN samples; however, this study has inconsistent results [ 78 ], and, like other publications, the studies are limited due to the variability of epigenetic mechanisms in these patients [ 79 ].…”

“…Diabetic neuropathy is a very complex complication of T2D that can appear as diabetic peripheral neuropathy (DPN), diabetic autonomic neuropathy, or uremic neuropathy [ 78 , 79 , 80 ]. DPN is caused by chronic hyperglycemia, leading to peripheral nerve damage and subsequent foot ulceration, Charcot neuropathy, possible amputation, and death [ 79 ].…”

Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

“…The proposed mechanism for pathogenesis is mitochondrial dysfunction, altered mitochondrial transport, and microtubule instability [ 124 ]. The study of HDACis in diabetic neuropathy is yielding very promising results [ 112 , 125 ]. Ricolinostat, an oral, selective HDAC6i is being investigated in a phase 2 clinical trial for diabetic neuropathic pain (see Table 3 ) [ 126 ].…”

Lipotoxic Proximal Tubular Injury: A Primary Event in Diabetic Kidney Disease

“…MTHFR, an enzyme in folate cycle and homocysteine metabolism, indirectly regulates lipid metabolism. MTHFR 1298A/C variant is closely associated with DN ( 38 ). Moreover, miRNAs may affect the effects of hypolipidemic drugs.…”