Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function

… mg/kg (10 ml/kg). Animal assessment. Twice weekly weight and temperature and
weekly heart rate via pulse oximetry using MouseOx (STARR Life Sciences) was
recorded, as described previously (13). In the presentation of … Rett syndrome (RTT), an X-linked postnatal disorder, results from mutations in Methyl CpG-binding protein 2 (MECP2). Survival and breathing in Mecp2NULL/Y animals are improved by an N-terminal tripeptide of insulin-like growth factor I (IGF-I) treatment. We determined that Mecp2NULL/Y animals also have a metabolic syndrome and investigated whether IGF-I treatment might improve this phenotype.Mecp2NULL/Y mice were treated with a full-length IGF-I modified with the addition of polyethylene glycol (PEG-IGF-I), which improves pharmacological properties. Low-dose PEG-IGF-I treatment slightly improved lifespan and heart rate in Mecp2NULL/Y mice; however, high-dose PEG-IGF-I decreased lifespan. To determine whether insulinotropic off-target effects of PEG-IGF-I caused the detrimental effect, we treatedMecp2NULL/Y mice with insulin, which also decreased lifespan. Thus, the clinical benefit of IGF-I treatment in RTT may critically depend on the dose used, and caution should be taken when initiating clinical trials with these compounds because the beneficial therapeutic window is narrow.

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