title: MicroRNA-124a is hyperexpressed in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion.
abstract: OBJECTIVE
  MicroRNAs are a class of negative regulators of gene expression, which have been shown to be involved in the development of endocrine pancreas and in the regulation of insulin secretion. Since type 2 diabetes (T2D) is characterized by beta cell dysfunction, we aimed at evaluating expression levels of miR-124a and miR-375, both involved in the control of beta cell function, in human pancreatic islets obtained from T2D and from age-matched non-diabetic organ donors.
  
  
  METHODS
  We analyzed miR-124a and miR-375 expression by real-time qRT-PCR in human pancreatic islets and evaluated the potential role of miR-124a by overexpressing or silencing such miRNA in MIN6 pseudoislets.
  
  
  RESULTS
  We identified a major miR-124a hyperexpression in T2D human pancreatic islets with no differential expression of miR-375. Of note, miR-124a overexpression in MIN6 pseudoislets resulted in an impaired glucose-induced insulin secretion. In addition, miR-124a silencing in MIN6 pseudoislets resulted in increased expression of predicted target genes (Mtpn, Foxa2, Flot2, Akt3, Sirt1 and NeuroD1) involved in beta cell function. For Mtpn and Foxa2, we further demonstrated the actual binding of miR-124a to their 3UTR sequences by luciferase assay.
  
  
  CONCLUSIONS
  We uncovered a major hyperexpression of miR-124a in T2D islets, whose silencing resulted in increased expression of target genes of major importance for beta cell function and whose overexpression impaired glucose-stimulated insulin secretion, leading to the hypothesis that an altered miR-124a expression may contribute to beta cell dysfunction in type 2 diabetes.
authors.affiliation: Fondazione Umberto Di Mario ONLUS, c/o Toscana Life Science Park, Siena, Italy, sebastianiguido@gmail.com.
authors.forename: Guido
authors.initials: G
authors.lastname: Sebastiani
authors.forename: Agnese
authors.initials: A
authors.lastname: Po
authors.forename: Evelina
authors.initials: E
authors.lastname: Miele
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ventriglia
authors.forename: Elena
authors.initials: E
authors.lastname: Ceccarelli
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Francesco
authors.initials: F
authors.lastname: Dotta
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D015854:Up-Regulation
chemical_list: D007328:Insulin; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D005947:Glucose