479-P: Imeglimin Improves Hyperglycemia-Induced Mitochondrial Dysfunction and Increases SIRT1 and NAD⁺ Biosynthesis in Schwann Cells

Hyperglycemia-induced oxidative stress is a major cause of the pathogenesis of diabetic neuropathy, and hyperglycemia-induced mitochondrial ROS production is considered as a significant mechanism of increased oxidative stress. On the other hand, imeglimin is the first in a new glimin class of anti-diabetic drugs targeting mitochondrial bioenergetics. In addition, imeglimin has been reported to enhance insulin secretion by increasing nicotinamide adenine dinucleotide (NAD⁺) levels in rat islets via the salvage pathway involving nicotinamide phosphoribosyltransferase (NAMPT). Moreover, NAD⁺ has been shown to modulate sirtuin and PGC1α, which in turn ameliorate mitochondrial dysfunction. We investigated the effects of imeglimin on high glucose-induced cell death and mitochondrial dysfunction in Schwann cells. In addition, the effects of imeglimin on NAD⁺ levels, NAMPT activity, the rate-limiting enzyme in the salvage pathway for NAD⁺ synthesis, and SIRT1 expression, a longevity gene, were evaluated. Immortalized adult mouse Schwann (IMS32) cells were cultured in 5.5 mM normal glucose (NG) and 25 mM high glucose (HG) medium. Compared to NG, HG decreased cell viability and increased mitochondrial oxidative stress. HG decreased mitochondrial membrane potential, increased mitochondrial oxygen consumption rate (OCR), increased activity of complex I and decreased ATP levels. Imeglimin ameliorated the reduction in cell viability and improved these mitochondrial dysfunctions. In addition, imeglimin increased NAMPT activity and NAD⁺ levels in IMS32 cells under HG conditions. Furthermore, imeglimin also ameliorated the reduction in SIRT1 expression by HG. These results suggest that imeglimin may prevent diabetic neuropathy by attenuating hyperglycemia-induced mitochondrial dysfunction and cell death in Schwann cells, at least in part, through the enhancement of SIRT1 and NAD⁺ biosynthesis.