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MicroRNA-194 modulates glucose metabolism and its skeletal muscle expression is reduced in diabetes

Latouche, Celine, Natoli, Alaina, Reddy-Luthmoodoo, Medini, Heywood, Sarah E., Armitage, James A. and Kingwell, Bronwyn A. 2016, MicroRNA-194 modulates glucose metabolism and its skeletal muscle expression is reduced in diabetes, PLoS one, vol. 11, no. 5, pp. 1-20, doi: 10.1371/journal.pone.0155108.

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Title MicroRNA-194 modulates glucose metabolism and its skeletal muscle expression is reduced in diabetes
Author(s) Latouche, Celine
Natoli, Alaina
Reddy-Luthmoodoo, Medini
Heywood, Sarah E.
Armitage, James A.
Kingwell, Bronwyn A.
Journal name PLoS one
Volume number 11
Issue number 5
Start page 1
End page 20
Total pages 20
Publisher Public Library of Science (PLOS)
Place of publication San Francisco, Calif.
Publication date 2016-05-10
ISSN 1932-6203
Summary BACKGROUND: The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated.

METHODS: Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy.

RESULTS: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls. Among these, only one miRNA was similarly regulated: miR-194 expression was significantly reduced by 25 to 50% in both the rat model and in human with pre-diabetes and established diabetes. Knockdown of miR-194 in L6 skeletal muscle cells induced an increase in basal and insulin-stimulated glucose uptake and glycogen synthesis. This occurred in conjunction with an increased glycolysis, indicated by elevated lactate production. Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP. When miR-194 was down-regulated in vitro, western blot analysis showed an increased phosphorylation of AKT and GSK3β in response to insulin, and an increase in expression of proteins controlling mitochondrial oxidative phosphorylation.

CONCLUSIONS: Type 2 diabetes mellitus is associated with regulation of several miRNAs in skeletal muscle. Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM. We have shown miR-194 is involved in multiple aspects of skeletal muscle glucose metabolism from uptake, through to glycolysis, glycogenesis and glucose oxidation, potentially via mechanisms involving AKT, GSK3 and oxidative phosphorylation. MiR-194 could be down-regulated in patients with early features of diabetes as an adaptive response to facilitate tissue glucose uptake and metabolism in the face of insulin resistance.
Language eng
DOI 10.1371/journal.pone.0155108
Field of Research 110306 Endocrinology
Socio Economic Objective 920104 Diabetes
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30085233

Document type: Journal Article
Collections: School of Medicine
Open Access Collection
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Created: Mon, 10 Oct 2016, 09:38:40 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.