Might genetics play a role in understanding and treating diabetic polyneuropathy?

Abstract

Despite the high prevalence and impact on quality of life, costs, and survival, there are still unresolved issues regarding diabetic polyneuropathy (DPN): the lack of definite knowledge of its pathogenesis; the limited preventive action of glycaemic control in type 2 diabetes; and the unavailability of evidence-based effective disease-modifying treatment. How can genetics provide the tools to address these gaps? Ziegler et al for the GDS Group explore the novel hypothesis that genetic variability in transketolase (TKT) might contribute to susceptibility to DPN in patients with newly diagnosed type 1 and type 2 diabetes (well characterised for DPN). Transketolase diverts excess glycolytic metabolites from the hexosamine, protein kinase C, and advanced glycation endproduct pathways to the pentose phosphate pathway, with a protective effect against hyperglycaemia-induced damage. Moreover, thiamine and its derivative benfotiamine are among the few disease-modifying agents still under consideration as DPN treatment. The authors find significant associations of single-nucleotide polymorphisms of the TKT gene with the Total Symptom Score and thermal thresholds, in particular in male participants with type 2 diabetes. Moreover, they measure plasma methylglyoxal (a glycating agent, whose availability is hindered by TKT) without however finding a relation with TKT single-nucleotide polymorphisms. The link found between TKT genetic variability and nerve function measures is considered here in the context of DPN genetic studies and of experimental and clinical findings regarding thiamine and benfotiamine. The conclusion is that available data supports the decision to maintain focus on both the search for DPN genetic biomarkers and the therapeutic attempts to target thiamine, TKT, and methylglyoxal.

Diabetic Cardiovascular Neuropathy

“…A suppression of TKT activity, and subsequent down-regulation of the hexose monophosphate (HMP) shunt, resulting in accumulation of glyceraldehyde 3-phosphate (GA3P), fructose 6-phosphate (F6-P), and dihydroxyacetone phosphate (DHAP) may be at least one mechanism in the development of diabetes-induced vascular damage and other comorbidities [182][183][184][185]. It is hypothesized that genetic variability in TKT might contribute to susceptibility to early DPN [186,187]. TKT is indeed pertinent to the pathogenesis of diabetic microangiopathic complications.…”

“…When activated in the cell by thiamine, TKT determines the diversion of F6-P and GA3P to the pentose-phosphates pathway (PPP), in this way it exercises a protective effect against three pathogenetic mechanisms of microvascular complications, i.e. the glucose-driven hexosamine, PKC, and advanced glycation end products (AGE's) pathways [188,187]. The connection between genetic variability of TKT and nerve function measures in newly diagnosed diabetic patients were demonstrated, which can favour the identification of patients with a deficiency in TKT defensive mechanisms (and as such suitable candidates for therapeutic intervention) [188,187].…”

“…the glucose-driven hexosamine, PKC, and advanced glycation end products (AGE's) pathways [188,187]. The connection between genetic variability of TKT and nerve function measures in newly diagnosed diabetic patients were demonstrated, which can favour the identification of patients with a deficiency in TKT defensive mechanisms (and as such suitable candidates for therapeutic intervention) [188,187]. Therefore, changes in thiamine levels may be masked by an increase in THTR expression [189].…”

“…The identification of the association of polymorphisms related to the genes of thiamine and TKT with DPN might be a first step in defining a DPN genetic risk profile with potential therapeutic repercussions. There is moderate evidence from preclinical experimental models that high-dose thiamine and BFT (1) inhibit the HMP, AGE's formation, and diacylglycerol-PKC through the TKT activation; (2) target at various surrogate markers of hyperglycaemia-induced pathological processes and (3) can delay the progression of microangiopathic complications [187].…”

“…Clinical trials in both diabetic nephropathy and DPN have shown some effect on microalbuminuria and symptomatic DPN, although with some controversy due to their limitations such as low number, poor design, short duration, confounding bias of dietary source of thiamine, different phenotypes, and inadequately defined outcomes [187]. Thus, there is still a need for high-quality, well-designed clinical trials of appropriate size and duration to bridge the gap in evidence and to allow final recommendations to be established on the use of thiamine and BFT as a disease-modifying treatment of diabetic complications [187].…”