NAD+ Precursors Repair Mitochondrial Function in Diabetes and Prevent Experimental Diabetic Neuropathy

Abstract

Axon degeneration in diabetic peripheral neuropathy (DPN) is associated with impaired NAD+ metabolism. We tested whether the administration of NAD+ precursors, nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), prevents DPN in models of Type 1 and Type 2 diabetes. NMN was administered to streptozotocin (STZ)-induced diabetic rats and STZ-induced diabetic mice by intraperitoneal injection at 50 or 100 mg/kg on alternate days for 2 months. mice The were fed with a high fat diet (HFD) for 2 months with or without added NR at 150 or 300 mg/kg for 2 months. The administration of NMN to STZ-induced diabetic rats or mice or dietary addition of NR to HFD-fed mice improved sensory function, normalized sciatic and tail nerve conduction velocities, and prevented loss of intraepidermal nerve fibers in skin samples from the hind-paw. In adult dorsal root ganglion (DRG) neurons isolated from HFD-fed mice, there was a decrease in NAD+ levels and mitochondrial maximum reserve capacity. These impairments were normalized in isolated DRG neurons from NR-treated mice. The results indicate that the correction of NAD+ depletion in DRG may be sufficient to prevent DPN but does not significantly affect glucose tolerance, insulin levels, or insulin resistance.

Xbp1 promotes odontoblastic differentiation through modulating mitochondrial homeostasis

“…The therapy of primary and secondary mitochondrial diseases characterized by mitochondrial dysfunction was still a clinical conundrum. Recently, UPR mt modulation, such as NR treatment, functioned as a promising therapeutic target already verified in treating mitochondrial diseases such as diabetes, osteoarthritis, and neurodegenerative diseases 62–64 . In our study, we chose NR as the therapeutic reagent for mitochondrial dysfunction in shXbp1 cells, further confirming the recovery of odontoblastic differentiation potential after NR treatment.…”

“…Recently, UPR mt modulation, such as NR treatment, functioned as a promising therapeutic target already verified in treating mitochondrial diseases such as diabetes, osteoarthritis, and neurodegenerative diseases. [62][63][64] In our study, we chose NR as the therapeutic reagent for mitochondrial dysfunction in shXbp1 cells, further confirming the recovery of odontoblastic differentiation potential after NR treatment. The deficient expression of Hspa9 was also increased to a normal level.…”

Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy

“…NR is orally bioavailable, has an excellent toxicity profile (55), and is safe for use in human clinical trials (56,57). It has shown efficacy in animal models (25,26) and would be an excellent choice for treatment of human DN. However, based on our data, its efficacy may be limited when given to subjects with advanced disease.…”

“…SIRT1 is an NAD + -dependent protein deacetylase which acts as a metabolism sensor in a variety of metabolic processes. Decreased activity or expression levels of SIRT1 have been observed in various tissues of diabetic patients possibly due to decreased systemic NAD + biosynthesis (21)(22)(23)(24) or increased NAD + degradation (25,26). SIRT1 deacetylates a number of proteins e.g.…”

“…Decreased activity or expression of SIRT1 has been observed in various tissues of diabetic patients possibly due to decreased systemic NAD + biosynthesis [23][24][25][26] or increased NAD + degradation. 27,28 SIRT1 deacetylates a number of proteins e.g. FoxO, p53 and PGC1α, and regulates transcription of their downstream targets.…”