Abstract
<title>Abstract</title> <p>Diabetic peripheral neuropathy (DPN) is a common and disabling complication of diabetes encompassing both sensory and autonomic subtypes. Using a genetic type 2 diabetic (db/db) mouse model, we investigated the role of SARM1 (sterile alpha and TIR motif-containing protein 1) in the development and progression of DPN, with a specific focus on potential subtype-specific effects and underlying mechanisms. We demonstrate that genetic deletion of SARM1 prevents the progression of sudomotor denervation and dysfunction — a key indicator of autonomic neuropathy. Furthermore, SARM1 deficiency attenuates sensory neuropathy, as evidenced by preserved intraepidermal sensory nerve fiber density, thermal pain sensitivity, and sensory and motor nerve conduction velocities. Mechanistically, SARM1 deletion confers protection against diabetic peripheral neuropathy by preserving mitochondrial function. This effect is evidenced in the sciatic nerve by a reduction in mitochondrial DNA deletion burden and the maintenance of key respiratory parameters—including basal and maximal respiration, as well as ATP production. Our results identify SARM1 as a critical pathogenic factor in DPN that impacts both somatic and autonomic nerves, with a particularly pronounced neuroprotective benefit for the autonomic system. These findings position SARM1 inhibition as a promising therapeutic strategy for DPN, offering the potential to alleviate both sensory and autonomic neuropathy.</p>