title: Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function.
abstract: 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.
authors: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Meagan R
authors: MR
authors: Pitcher
authors: Christopher S
authors: CS
authors: Ward
authors: E Melissa
authors: EM
authors: Arvide
authors: Christopher A
authors: CA
authors: Chapleau
authors: Lucas
authors: L
authors: Pozzo-Miller
authors: Andreas
authors: A
authors: Hoeflich
authors: Manaswini
authors: M
authors: Sivaramakrishnan
authors: Stefanie
authors: S
authors: Saenger
authors: Friedrich
authors: F
authors: Metzger
authors: Jeffrey L
authors: JL
authors: Neul
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D008136:Longevity / Q000187:drug effects; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D007334:Insulin-Like Growth Factor I