Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function

Academic Article

Abstract

  • 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 insulinlike 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 treated Mecp2NULL/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. © The Author 2013. Published by Oxford University Press.
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    Digital Object Identifier (doi)

    Author List

  • Pitcher MR; Ward CS; Arvide EM; Chapleau CA; Pozzo-Miller L; Hoeflich A; Sivaramakrishnan M; Saenger S; Metzger F; Neul JL
  • Start Page

  • 2626
  • End Page

  • 2633
  • Volume

  • 22
  • Issue

  • 13