NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice.

Abnormal NAD+ signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD+ precursors could alleviate DPN symptoms through increasing the NAD+ levels and activating the sirtuin-1 (SIRT1) protein. To test this, we exposed cultured Dorsal Root Ganglion neurons (DRGs) to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which increased the levels of NAD+, the SIRT1 protein, and the deacetylation activity that is associated with increased neurite growth. A SIRT1 inhibitor blocked the neurite growth induced via NR or NMN. We then induced neuropathy in C57BL6 mice with streptozotocin (STZ) or a high fat diet (HFD) and administered NR or NMN for two months. Both the STZ and HFD mice developed neuropathy, which was reversed through the NR or NMN administration: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored. The NAD+ levels and SIRT1 activity were reduced in the DRGs from diabetic mice but were preserved with the NR or NMN treatment. We also tested the effect of NR or NMN administration in mice that overexpress the SIRT1 protein in neurons (nSIRT1 OE) and found no additional benefit from the addition of the drug. These findings suggest that supplementing with NAD+ precursors or activating SIRT1 may be a promising treatment for DPN.

A Double Hit to Ubiquitination Leading to a New Diagnosis of VEXAS Syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) syndrome is a newly defined illness that bridges hematology, oncology, and rheumatology. Its pathophysiology originates in a mutation in the UBA1 gene that leads to a defect in ubiquitination resulting in a severe systemic inflammatory syndrome. It is associated with significant morbidity and mortality; however, data are scarce due to limited cases described in the literature. Here we describe a case of a male in his 60s who was referred to hematology-oncology due to progressive dyspnea, poor oral intake, and weight loss. He was diagnosed with relapsing polychondritis 2 years prior; however, his symptoms did not improve despite treatment. He was ultimately diagnosed with VEXAS syndrome with a mutation in UBA1 (ubiquitin-like modifier activating enzyme 1) and a concurrent SQSTM1 mutation. In addition, the coexistence of two mutations in the ubiquitination pathway in the same patient has not been reported to date. This patient and the treatment course were compared to pre-existing literature to increase awareness and improve the medical management of VEXAS syndrome.

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

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.