title: The Drosophila insulin-degrading enzyme restricts growth by modulating the PI3K pathway in a cell-autonomous manner.
abstract: Mammalian insulin-degrading enzyme (IDE) cleaves insulin, among other peptidic substrates, but its function in insulin signaling is elusive. We use the Drosophila system to define the function of IDE in the regulation of growth and metabolism. We find that either loss or gain of function of Drosophila IDE (dIDE) can restrict growth in a cell-autonomous manner by affecting both cell size and cell number. dIDE can modulate Drosophila insulin-like peptide 2 levels, thereby restricting activation of the phosphatidylinositol-3-phosphate kinase pathway and promoting activation of Drosophila forkhead box, subgroup O transcription factor. Larvae reared in high sucrose exhibit delayed developmental timing due to insulin resistance. We find that dIDE loss of function exacerbates this phenotype and that mutants display increased levels of circulating sugar, along with augmented expression of a lipid biosynthesis marker. We propose that dIDE is a modulator of insulin signaling and that its loss of function favors insulin resistance, a hallmark of diabetes mellitus type II.
authors.affiliation: Instituto Leloir, Buenos Aires C1405BWE, Argentina National Scientific and Technical Research Council, Buenos Aires C1033AAJ, Argentina Centro FONDAP de Regulación del Genoma, Facultad de Ciencias, Universidad de Chile, Santiago 7800024, Chile Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1053ABJ, Argentina.
authors.forename: Diego
authors.initials: D
authors.lastname: Galagovsky
authors.forename: Maximiliano J
authors.initials: MJ
authors.lastname: Katz
authors.forename: Julieta M
authors.initials: JM
authors.lastname: Acevedo
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sorianello
authors.forename: Alvaro
authors.initials: A
authors.lastname: Glavic
authors.forename: Pablo
authors.initials: P
authors.lastname: Wappner
mesh_terms: D000818:Animals; D048429:Cell Size; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007339:Insulysin / Q000235:genetics* / Q000378:metabolism; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D009479:Neuropeptides; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal / Q000166:cytology / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D007339:Insulysin; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; C544178:ILP2 protein, Drosophila