title: miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models.
abstract: OBJECTIVE
  The loss of beta cell function is a critical factor in the development of type 2 diabetes. Glucotoxicity plays a major role in the progressive deterioration of beta cell function and development of type 2 diabetes mellitus. Here we demonstrate that microRNA (miR)-30a-5p is a key player in early-stage glucotoxicity-induced beta cell dysfunction.
  
  
  METHODS
  We performed northern blots, RT-PCR and western blots in glucotoxicity-exposed primary rat islets and INS-1 cells. We also measured glucose-stimulated insulin secretion and insulin content. In vivo approaches were used to evaluate the role of miR-30a-5p in beta cell dysfunction.
  
  
  RESULTS
  miR-30a-5p expression was increased in beta cells after exposure to glucotoxic conditions, and exogenous miR-30a-5p overexpression also induced beta cell dysfunction in vitro. miR-30a-5p directly suppressed expression of Beta2/NeuroD (also known as Neurod1) by binding to a specific binding site in its 3'-untranslated region. After restoration of Beta2/NeuroD expression by knockdown miR-30a-5p or transfection of the Beta2/NeuroD gene, beta cell dysfunction, including decreased insulin content, gene expression and glucose-stimulated insulin secretion, recovered. Glucose tolerance and beta cell dysfunction improved on direct injection of Ad-si30a-5p into the pancreas of diabetic mice.
  
  
  CONCLUSIONS
  Our data demonstrate that miR-30a-5p-mediated direct suppression of Beta2/NeuroD gene expression is an important initiation step of glucotoxicity-induced beta cell dysfunction.
authors: Department of Endocrinology and Metabolism, Seoul St Mary's Hospital, The Catholic University of Korea, # 505, Banpo-Dong, Seocho-Gu, Seoul 137-040, Korea.
authors: J-W
authors: JW
authors: Kim
authors: Y-H
authors: YH
authors: You
authors: S
authors: S
authors: Jung
authors: H
authors: H
authors: Suh-Kim
authors: I-K
authors: IK
authors: Lee
authors: J-H
authors: JH
authors: Cho
authors: K-H
authors: KH
authors: Yoon
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007328:Insulin; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; C556157:MIRN30 microRNA, rat; C534715:Mirn30d microRNA, mouse; C093564:Neurogenic differentiation factor 1