We establish a mouse model of progressive diabetes induced by conditional NAT1 deficiency in vascular endothelial cells. NAT1 deficiency promotes the activation of RIPK1 owing to a type of post-translational modification mediated by spermidine and deoxyhyupisin synthase termed acetyl-hypusination. Our results suggest that inhibition of RIPK1 could be used to treat type 2 diabetes and vascular inflammation.