title: Role of microRNAs in the age-associated decline  of pancreatic beta cell function in rat islets.
abstract: OBJECTIVE
  Ageing can lead to reduced insulin sensitivity and loss of pancreatic beta cell function, predisposing individuals to the development of diabetes. The aim of this study was to assess the contribution of microRNAs (miRNAs) to age-associated beta cell dysfunction.
  
  
  METHODS
  The global mRNA and miRNA profiles of 3- and 12-month-old rat islets were collected by microarray. The functional impact of age-associated differences in miRNA expression was investigated by mimicking the observed changes in primary beta cells from young animals.
  
  
  RESULTS
  Beta cells from 12-month-old rats retained normal insulin content and secretion, but failed to proliferate in response to mitotic stimuli. The islets of these animals displayed modifications at the level of several miRNAs, including upregulation of miR-34a, miR-124a and miR-383, and downregulation of miR-130b and miR-181a. Computational analysis of the transcriptomic modifications observed in the islets of 12-month-old rats revealed that the differentially expressed genes were enriched for miR-34a and miR-181a targets. Indeed, the induction of miR-34a and reduction of miR-181a in the islets of young animals mimicked the impaired beta cell proliferation observed in old animals. mRNA coding for alpha-type platelet-derived growth factor receptor, which is critical for compensatory beta cell mass expansion, is directly inhibited by miR34a and is likely to be at least partly responsible for the effects of this miRNA.
  
  
  CONCLUSIONS
  Changes in the level of specific miRNAs that occur during ageing affect the proliferative capacity of beta cells. This might reduce their ability to expand under conditions of increased insulin demand, favouring the development of type 2 diabetes.
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Tugay
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland.
authors.forename: Claudiane
authors.initials: C
authors.lastname: Guay
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Marques
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Florent
authors.initials: F
authors.lastname: Allagnat
authors.affiliation: Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Locke
authors.affiliation: Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland. romano.regazzi@unil.ch.
authors.forename: Romano
authors.initials: R
authors.lastname: Regazzi
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D059467:Transcriptome; D014162:Transfection
chemical_list: D007328:Insulin; C548144:MIRN124 microRNA, rat; C569198:MIRN130 microRNA, rat; C581717:MIRN181 microRNA, rat; C560944:MIRN34 microRNA, rat; C000611600:MIRN383 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger