<i>Sarm1</i> Gene Deficiency Attenuates Diabetic Peripheral Neuropathy in Mice.

Abstract

Diabetic peripheral neuropathy (DPN) is the most common complication in both type 1 and type 2 diabetes, but any treatment toward the development of DPN is not yet available. Axon degeneration is an early feature of many peripheral neuropathies, including DPN. Delay of axon degeneration has beneficial effects on various neurodegenerative diseases, but its effect on DPN is yet to be elucidated. Deficiency of <i>Sarm1</i> significantly attenuates axon degeneration in several models, but the effect of <i>Sarm1</i> deficiency on DPN is still unclear. In this study, we show that <i>Sarm1</i> knockout mice exhibit normal glucose metabolism and pain sensitivity, and deletion of the <i>Sarm1</i> gene alleviates hypoalgesia in streptozotocin-induced diabetic mice. Moreover, <i>Sarm1</i> gene deficiency attenuates intraepidermal nerve fiber loss in footpad skin; alleviates axon degeneration, the change of g-ratio in sciatic nerves, and NAD⁺ decrease; and relieves axonal outgrowth retardation of dorsal root ganglia from diabetic mice. In addition, <i>Sarm1</i> gene deficiency markedly diminishes the changes of gene expression profile induced by streptozotocin in the sciatic nerve, especially some abundant genes involved in neurodegenerative diseases. These findings demonstrate that <i>Sarm1</i> gene deficiency attenuates DPN in mice and suggest that slowing down axon degeneration is a potential promising strategy to combat DPN.