MicroRNA-29 Fine-tunes the Expression of Key FOXA2-Activated Lipid Metabolism Genes and Is Dysregulated in Animal Models of Insulin Resistance and Diabetes

Kurtz, C. Lisa; Peck, Bailey C. E.; Fannin, Emily E.; Beysen, Carine; Miao, Ji; Landstreet, Stuart R.; Ding, Shengli; Turaga, Vandana; Lund, P. Kay; Turner, Scott; Biddinger, Sudha B.; Vickers, Kasey C.; Sethupathy, Praveen

doi:10.2337/db13-1015

Cited by 110 publications

(106 citation statements)

References 47 publications

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“…Increasing evidence has suggested that miRNAs play key roles in insulin resistance and are widely involved in the progression of type 2 diabetes [14,15]. In the present study, we found that miR-499-5p was reduced in the livers of db/db mice and HFD-fed mice and was accompanied by impaired insulin signaling and glycogen synthesis.…”

Section: Discussionsupporting

confidence: 61%

MiR-499-5p Contributes to Hepatic Insulin Resistance by Suppressing PTEN

Wang

Zhang

Pan

et al. 2015

Cell Physiol Biochem

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Background: Type 2 diabetes afflicts 95% of diabetes patients. Recent data suggest that miRNAs play a key role in insulin production, secretion and function. This study aims to explore the specific role of miR-499-5p in hepatic insulin resistance. Methods: The miRNA expression levels in the livers of db/db mice were analyzed using miRNA chips and were verified by real-time PCR. miR-499-5p mimics and an inhibitor were transfected into NCTC1469 cells. Then, the PI3K/AKT signaling pathway and glycogen level were determined. The target genes of miR-499-5p were predicted by bioinformatics and then confirmed by dual luciferase reporter assay and Western blot. To establish an insulin resistance (IR) animal model, C57BL/6 mice were fed a high-fat diet (HFD). The level of miR-499-5p in the livers of HFD-fed mice was upregulated through tail vein injection of adenovirus vectors (ad) containing miR-499-5p mimics. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to determine glucose tolerance and insulin tolerance, respectively. Results: MicroRNA chips and qPCR showed that miR-499-5p was significantly decreased in the livers of db/db mice. Downregulation of miR-499-5p impaired the insulin signaling pathway and glycogen synthesis, whereas upregulation of miR-499-5p promoted the insulin signaling pathway and glycogen synthesis in NCTC1469 cells. The dual luciferase reporter assay and Western blot demonstrated that PTEN was the target gene of miR-499-5p. Compared with the control group, miR-499-5p was increased 2.1-fold in the livers of HFD-fed mice. By tail vein injection of adenovirus vector containing miR-499-5p mimics, GTT and ITT were improved in HFD-fed mice. Conclusion: Downregulation of the miR-499-5p level impaired the PI3K/AKT/GSK signaling pathway and glycogen synthesis by targeting PTEN.

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Section: Discussionsupporting

confidence: 61%

MiR-499-5p Contributes to Hepatic Insulin Resistance by Suppressing PTEN

Wang

Zhang

Pan

et al. 2015

Cell Physiol Biochem

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“…miR-29 signaling reportedly targets adipocyte marker LPL expression in liver lipogenesis and lipogenic gene expression in high fat diet-mediated diabetic mice [17,35]. In this study, declined expression of PPARγ2, LPL and adipokine leptin explained the phenomenon that miR-29a transgenic mice had low adipogenic activities in bone tissue.…”

Section: Accepted Manuscriptmentioning

confidence: 43%

MicroRNA-29a mitigates glucocorticoid induction of bone loss and fatty marrow by rescuing Runx2 acetylation

Chuang

et al. 2015

Bone

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“…For example, expression of miR-29a/b/c was elevated in muscle, fat, and/or liver of diabetic rats [86], fa/fa rats, and high-fat diet-fed mice [87]. Overexpression of miR-29a/b/c in 3T3-L1 adipocytes decreased insulin-stimulated glucose uptake by inhibiting p85alpha and AKT activation [86,88], and led to insulin resistance through mechanisms not involving AKT as the direct target of the miRNA [86].…”

Section: Mirna Dysregulation In Insulin-sensitive Peripheral Tissuesmentioning

confidence: 99%

Beyond the Protein-Coding Sequence: Noncoding RNAs in the Pathogenesis of Type 2 Diabetes

DiStefano¹

2015

Rev Diabet Stud

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■ AbstractDiabetes mellitus results from a deficiency or failure to maintain normal glucose homeostasis. The most common form of the disease is type 2 diabetes (T2D), a progressive metabolic disorder characterized by elevated glucose levels that develops in response to either multi-organ insulin resistance or insufficient insulin secretion from pancreatic β-cells. Although the etiology of T2D is complex, many factors are known to contribute to defects of glucose homeostasis, including obesity, unhealthy lifestyle choices, genetic susceptibility, and environmental exposures. In addition to these factors, noncoding RNAs (ncRNAs) have been recently implicated in the pathogenesis of T2D, playing roles in several of the pathophysiological mechanisms underlying the disease, particularly in insulin-sensitive tissues such as pancreatic β-cells, liver, muscle, and adipose tissue. A growing number of publications demonstrate that polymorphisms in ncRNAs or their target genes may represent a new class of genetic variation contributing to the development of T2D. This review summarizes both the current state of knowledge of ncRNAs, specifically microRNAs (miRNAs), involved in the regulation of β-cell function, insulin sensitivity, and insulin action in peripheral organs. The role of genetic variation in miRNAs or miRNA binding sites in the pathogenesis of T2D is also discussed. While far less is known about the impact of long ncRNAs (lncRNAs) in the development of T2D, emerging evidence suggests that these molecules may be able to contribute to β-cell dysfunction in response to hyperglycemia. This article provides an overview of the studies conducted to date in this field, focusing on lncRNAs that are dysregulated in human pancreatic islets.

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MicroRNA-29 Fine-tunes the Expression of Key FOXA2-Activated Lipid Metabolism Genes and Is Dysregulated in Animal Models of Insulin Resistance and Diabetes

Cited by 110 publications

References 47 publications

MiR-499-5p Contributes to Hepatic Insulin Resistance by Suppressing PTEN

MiR-499-5p Contributes to Hepatic Insulin Resistance by Suppressing PTEN

MicroRNA-29a mitigates glucocorticoid induction of bone loss and fatty marrow by rescuing Runx2 acetylation

Beyond the Protein-Coding Sequence: Noncoding RNAs in the Pathogenesis of Type 2 Diabetes

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