Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function

Hum Mol Genet. 2013 Jul 1;22(13):2626-33. doi: 10.1093/hmg/ddt111. Epub 2013 Mar 5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Body Weight / drug effects
  • Disease Models, Animal
  • Female
  • Heart Rate / drug effects
  • Hyperinsulinism / genetics
  • Hyperinsulinism / metabolism
  • Insulin-Like Growth Factor I / administration & dosage*
  • Longevity / drug effects
  • Male
  • Metabolic Syndrome / drug therapy
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism*
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice
  • Mice, Knockout


  • Methyl-CpG-Binding Protein 2
  • Insulin-Like Growth Factor I