| First Author | Pitcher MR | Year | 2013 |
| Journal | Hum Mol Genet | Volume | 22 |
| Issue | 13 | Pages | 2626-33 |
| PubMed ID | 23462290 | Mgi Jnum | J:198235 |
| Mgi Id | MGI:5495886 | Doi | 10.1093/hmg/ddt111 |
| Citation | Pitcher MR, et al. (2013) Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function. Hum Mol Genet 22(13):2626-33 |
| abstractText | Rett syndrome (RTT), an X-linked postnatal disorder, results from mutations in Methyl CpG-binding protein 2 (MECP2). Survival and breathing in Mecp2(NULL/Y) animals are improved by an N-terminal tripeptide of insulin-like growth factor I (IGF-I) treatment. We determined that Mecp2(NULL/Y) animals also have a metabolic syndrome and investigated whether IGF-I treatment might improve this phenotype. Mecp2(NULL/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 Mecp2(NULL/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 treated Mecp2(NULL/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. |
