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miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models

Kim, JW; You, YH; Jung, S; Suh-Kim, H; Lee, IK; Cho, JH; Yoon, KH
Diabetologia, 56(4):847-855, 2013
Journal Title
AIMS/HYPOTHESIS: 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/INTERPRETATION: 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.
MeSH terms
AnimalsBasic Helix-Loop-Helix Transcription Factors/*metabolismBinding SitesCell LineDiabetes Mellitus, Type 2/metabolism/pathologyDisease Models, Animal*Gene Expression Regulation*Gene SilencingGlucose Tolerance TestInsulin/metabolismInsulin-Secreting Cells/cytologyMiceMicroRNAs/genetics/*metabolismNerve Tissue Proteins/*metabolismRatsRats, Sprague-Dawley
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