Although the observations on metabolic functions, such as increased insulin sensitivity in TcMAC21 mice from this study are consistent with the only other study using this mouse model (Sarver et al., 2023a), it is important to note that people with DS exhibit insulin resistance (Fonseca et al., 2005), which challenges the use of the TcMAC21 mouse model for metabolic disease in DS. This evidence concerns the gene INS and metabolic disease.