Dataset Information

MicroRNA-7a regulates pancreatic ? cell function.

ABSTRACT: Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic ? cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of ? cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in ? cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates ? cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in ? cells developed diabetes due to impaired insulin secretion and ? cell dedifferentiation. Interestingly, perturbation of miR-7a expression in ? cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine ? cell mass. Furthermore, we found that miR-7a levels are decreased in obese/diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated ? cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic ? cells and support a role for miR-7 in the adaptation of pancreatic ? cell function in obesity and type 2 diabetes.

SUBMITTER: Latreille M

PROVIDER: S-EPMC4038573 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MicroRNA-7a regulates pancreatic β cell function.

Latreille Mathieu M Hausser Jean J Stützer Ina I Zhang Quan Q Hastoy Benoit B Gargani Sofia S Kerr-Conte Julie J Pattou Francois F Zavolan Mihaela M Esguerra Jonathan L S JL Eliasson Lena L Rülicke Thomas T Rorsman Patrik P Stoffel Markus M

The Journal of clinical investigation 20140501 6

Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic β cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of β cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in β cells. Using Mir7a2 deficient mic ...[more]

PMID: 24789908

Similar Datasets

Project description:Background:Transcription factor 7-like 2 (TCF7L2), which previously known as TCF-4, is a major form of transcription factor involved in the downstream WNT signaling and exhibits the strongest association to diabetes susceptibility. Although we still do not know mechanistically how TCF7L2 exerts its physiological functions on pancreatic endocrine cells, it had been suggested that TCF7L2 may directly affect ?-cell function by regulating the activation of PI3K/AKT signaling pathway. Methods:MIN6 cells were transfected with TCF7L2 knockdown virus or lenti-TCF7L2 virus for 48 h to evaluate the contribution of TCF7L2 to the PI3K/AKT signaling pathway and pancreatic ?-cell function. This was confirmed by measuring the expression of PI3K p85 and p-Akt by western blotting and insulin secretion by enzyme-linked immunosorbent assay (ELISA), respectively. Chromatin immunoprecipitation (ChIP) and polymerase chain reaction (PCR) experiments were performed to explore the genomic distribution of TCF7L2-binding sites in the promoter of PIK3R1, the affinity between which was analyzed by the luciferase reporter assay. Results:In the present study, we strikingly identified that TCF7L2 could profoundly inhibit the expression of PIK3R1 gene and its encoding protein PI3K p85, which then could lead to the activation of PI3K/AKT signaling and stimulate insulin secretion in pancreatic ?-cells. However, the integrity and stability of evolutionarily conserved TCF7L2-binding motif plays a very crucial role in the binding events between transcription factor TCF7L2 and its candidate target genes. We also found that the affinity of TCF7L2 to the promoter region of PIK3R1 alters upon the specific binding sites, which further provides statistical validation to the necessity of TCF7L2-binding motif. Conclusions:This study demonstrated that TCF7L2 is closely bound to the specific binding regions of PIK3R1 promoter and prominently controls the transcription of its encoding protein p85, which further affects the activation of PI3K/AKT signaling pathway and insulin secretion.

Dataset Information

MicroRNA-7a regulates pancreatic ? cell function.

Publications

MicroRNA-7a regulates pancreatic β cell function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets