Ginsenoside Rb1 attenuates diabetic peripheral neuropathy pathology by functioning as a potent activator of...

Diabetic peripheral neuropathy (DPN) is a severe diabetic complication closely associated with diabetic foot that is a major risk factor for amputation and mortality. Hyperglycemia disrupts the tricarboxylic acid (TCA) cycle, thereby coupling metabolic disorders to DPN pathogenesis. However, the underlying mechanisms remain unclear.

This study aimed to explore the role of isocitrate dehydrogenase 1 (IDH1), a key TCA cycle enzyme, in DPN pathogenesis using clinical samples and mouse models.

Serum and sciatic nerve (SN) tissues from patients with DPN, individuals without diabetes, and type 1/2 diabetic mice with DPN were analyzed. IDH1 activators were screened from the lab in-house compound library. To investigate the mechanism underlying the regulation of IDH1 in DPN pathogenesis, a proteomics-based assay using the discovered IDH1 activator as a probe was performed and verified in the SN tissues of DPN mice, clinical samples and IDH1-knockdown DPN mice that were generated using adeno-associated virus php.s-IDH1-RNAi.

IDH1 activity and its catalytic product, α-ketoglutarate, were pathologically repressed in patients with DPN and model mice. Ginsenoside Rb1 (Rb1) was identified as an IDH1 activator and could counteract the methylglyoxal (a diabetes-associated metabolite)-mediated IDH1 inhibition. Rb1-mediated pharmacological activation of IDH1 effectively alleviated DPN pathology by improving ribosomal dysfunction, enhancing mitochondrial biogenesis and suppressing neuroinflammation.

Our findings highlight the potent role of TCA cycle dysfunction in DPN progression and reveal that pharmacological IDH1 activation is a promising therapeutic strategy against DPN, while Rb1 shows high potential for treating this disease.