biostudies-literatureBrazill JMNIDCR NIH HHSNIDDK NIH HHSNINDS NIH HHSNational Institutes of HealthNIAMS NIH HHSe175159https://www.ebi.ac.uk/biostudies/studies/S-EPMC11143934biostudies-literatureUnknown9(4)Patients with diabetes have a high risk of developing skeletal diseases accompanied by diabetic peripheral neuropathy (DPN). In this study, we isolated the role of DPN in skeletal disease with global and conditional knockout models of sterile-α and TIR-motif-containing protein-1 (Sarm1). SARM1, an NADase highly expressed in the nervous system, regulates axon degeneration upon a range of insults, including DPN. Global knockout of Sarm1 prevented DPN, but not skeletal disease, in male mice with type 1 diabetes (T1D). Female wild-type mice also developed diabetic bone disease but without DPN. Unexpectedly, global Sarm1 knockout completely protected female mice from T1D-associated bone suppression and skeletal fragility despite comparable muscle atrophy and hyperglycemia. Global Sarm1 knockoutJCI insightSarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy.PMC11143934T32 AR060719P30 AR074992R01 NS119812U01 DK116317R00 DE024178R01 NS087632R01-DK132073,U01-DK116317,R00-DE024178,T32- AR060719,R01-NS119812,R01-NS087632,P30-DK020579,P30-AR074992P30 DK020579R01 DK132073Brazill JMMeyer GAMilbrandt JStrickland ABeeve ATScheller ELPark JSDiAntonio AShen IRWee NKLorenz MZhang XMagee KLCraft CSfalseSarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy.Patients with diabetes have a high risk of developing skeletal diseases accompanied by diabetic peripheral neuropathy (DPN). In this study, we isolated the role of DPN in skeletal disease with global and conditional knockout models of sterile-α and TIR-motif-containing protein-1 (Sarm1). SARM1, an NADase highly expressed in the nervous system, regulates axon degeneration upon a range of insults, including DPN. Global knockout of Sarm1 prevented DPN, but not skeletal disease, in male mice with type 1 diabetes (T1D). Female wild-type mice also developed diabetic bone disease but without DPN. Unexpectedly, global Sarm1 knockout completely protected female mice from T1D-associated bone suppression and skeletal fragility despite comparable muscle atrophy and hyperglycemia. Global Sarm1 knockout2024-01-01T00:00:00Z2024 Jan2026-04-08T19:47:05.862Z2026-04-08T14:32:40.246ZS-EPMC111439343817572210.1172/jci.insight.175159