Ranirestat

Ranirestat, an aldose reductase inhibitor evaluated in several randomised controlled trials (RCTs) in diabetic peripheral neuropathy (DPN). However, to date, no meta-analysis has evaluated the efficacy and safety of ranirestat in DPN. We undertook this meta-analysis to address this knowledge gap. Detailed search of electronic databases for RCTs published till December 2021 was done at Cochrane register, Medline, PubMed, Embase, clinicaltrials.gov, ctri.nic.in, global health and Google Scholar using the Boolean search strategy: ((ranirestat) OR (aldose reductase inhibitor)) AND ((diabetes) OR (“diabetes mellitus”)). The primary outcome was to evaluate changes in nerve conduction velocities (NCV) of different nerves. The secondary outcomes were to evaluate alterations in amplitudes, F-wave latencies of nerves, modified Toronto Clinical Neuropathy Score (mTCNS) and adverse events. Data from 5 studies involving 1461 patients with DPN was analysed to establish the impact of ranirestat (20-40 mg/day) as compared to placebo on different electrophysiologic outcomes over a median follow-up of 52 weeks. Patients receiving ranirestat had significantly greater improvement in proximal median sensory NCV [MD 0.77 m/s (95%CI: 0.50–1.05); P < 0.01; I2 = 26%], distal median sensory NCV [MD 0.91 m/s (95%CI: 0.87–0.95); P < 0.01; I2 = 0%], median motor NCV [MD 0.63 m/s (95%CI: 0.60–0.66); P < 0.01; I2 = 0%], tibial motor NCV [MD 0.46 m/s (95%CI: 0.43–0.49); P < 0.01; I2 = 0%] and peroneal motor NCV [MD 0.80 m/s (95%CI: 0.66–0.93); P < 0.01; I2 = 0%]. mTCNS was not significantly different among groups. Treatment-emergent adverse events [risk ratio (RR) 0.85 (95%CI: 0.63–1.14); P = 0.28; I2 = 0%] and severe adverse events [RR 1.35 (95%CI: 0.86–2.11); P = 0.20; I2 = 0%] were comparable across study groups. In people with established DPN with long-standing diabetes, ranirestat is safe and effective in improving electrophysiologic but not clinical DPN.

Recurrent infections are one of the common morbidities in Type 2 Diabetes (T2D) subjects. Bidirectional activation of innate immune cells such as neutrophils and glucose metabolism in T2D conditions leads to a pro-inflammatory milieu and reduced neutrophil function, which can be a potential cause for recurrent infections. In pathological conditions of sterile inflammation associated T2D, neutrophils form constitutive extracellular traps (NETs) due to hyperglycemia and respond poorly to infections. The present study was aimed at understanding the cellular and metabolic consequences, and NETs formation in T2D. We show that glucose induces NADPH oxidase derived reactive oxygen species and further citrullinates the histones to form weaker NETs leading to reduced response to lipopolysaccharide (LPS). Untargeted metabolomics analysis in neutrophils cultured under high glucose and from T2D subjects revealed enrichment of polyol pathway intermediates (1-anhydrosorbitol) and reduced glutathione metabolism products (cysteinylglycine). NADPH is an absolute requirement for three independent pathways of formation of 1-anhydrosorbitol via aldose reductase under excess glucose, induction of glutathione synthesis and glucose induced NETs formation. During T2D and in presence of high glucose, there is a competition for NADPH between these processive reactions, which leads to its insufficiency to produce NETs in response to LPS. Interestingly, supplementation of NADPH and pharmacological inhibitor of aldose reductase, ranirestat, restored NETs formation in presence of LPS. Our study provides novel insights on the metabolic reprogramming of neutrophils, which may lead to susceptibility of T2D subjects to infections.