1435-P: Imeglimin and Nicotinamide Mononucleotide Ameliorate High Glucose–Induced Mitochondrial Dysfunction and Senescence in Schwann Cells

Introduction and Objective: Oxidative stress and mitochondrial dysfunction play a pivotal role in the pathogenesis of diabetic neuropathy. We previously reported that hyperglycemia and glucose fluctuations induce mitochondrial dysfunction and cell death in immortalized adult mouse Schwann (IMS32) cells. Recently, the oral glucose-lowering drug imeglimin has been shown to attenuate ROS generation and improve mitochondrial function in hepatocytes. In addition, nicotinamide mononucleotide (NMN), a precursor of NAD+, has emerged as a key regulator of energy metabolism and cellular senescence. In this study, we investigated the effects of imeglimin and NMN on high glucose-induced mitochondrial dysfunction and cellular senescence in Schwann cells. Methods: IMS32 cells were cultured under either normal glucose (5.5 mM) or high glucose (25 mM). The levels of mitochondrial oxidative stress and intracellular NAD+ were measured. The protein expression levels of the longevity gene Sirt1 and the mitochondrial biogenesis-related factors PGC1α and TFAM were evaluated. Senescent cells were identified by senescence-associated β-galactosidase (SA-β-gal) staining. Results: Imeglimin and NMN suppressed high glucose-increases in mitochondrial oxidative stress. Imeglimin significantly increased intracellular NAD+ levels. Both agents restored the high glucose-induced downregulation of Sirt1, PGC1α, and TFAM expression and attenuated the increase in SA-β-gal-positive cells. Conclusion: These findings suggest that the accumulation of senescent Schwann cells may contribute to the development and progression of diabetic neuropathy. Imeglimin and NMN improved high glucose-induced mitochondrial dysfunction and suppressed cellular senescence in Schwann cells, suggesting its potential therapeutic benefits for diabetic neuropathy. Disclosure A. Kato: None. W. Nihei: None. H. Yako: None. N. Nakamura: None. K. Naruse: None. T. Himeno: None. Y. Kato: None. J. Nakamura: None. H. Kamiya: Research Support; Current; Boehringer Ingelheim International GmbH, CBC, Daiichi Sankyo, EA Pharma, Eli Lilly and Company, Fukuda Denshi, Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., MSD, Mochida Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Parexel International, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Current; Abbott Japan Co., Ltd., Array BioPharma Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Chugai Pharmaceutical Co., Ltd., EA Pharma, Eli Lilly and Company, Eisai Inc., Fukuda Denshi, GlaxoSmithKline plc., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Novo Nordisk, Mitsubishi Tanabe Pharma Corporation, MSD, Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Viatris Inc. K. Sango: None. K. Kato: Speaker's Bureau; Current; Daiichi Sankyo.