Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets

Tugay, Ksenia; Guay, Claudiane; Marques, Ana C.; Allagnat, Florent; Locke, Jonathan M.; Harries, Lorna W.; Rutter, Guy A.; Regazzi, Romano

doi:10.1007/s00125-015-3783-5

Cited by 44 publications

(43 citation statements)

References 46 publications

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“…Moreover, an ageing-associated upregulation of miR-34a, miR-124a and miR-383, and downregulations of miR-130b and miR-181a were found in the pancreas of 12-month-old rats [43]. Importantly, besides the well-established age-induced modification of gut microbiota [44], clear evidences between the link of pancreas health and sensing of microbial antigens have been provided by several publications.…”

Section: Pancreatic Mirsmentioning

confidence: 94%

MicroRNAs: Decoders of Dysbiosis into Metabolic Diseases?

Sérino¹

2016

J Diabetes Metab

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The identification of molecular factors bridging gut microbiota dysbiosis to alterations of host metabolism still remains a major goal in biomedical research. In fact, on one hand, there is a worldwide consensus about the systemic impact, from brain to liver, from heart to adipose tissue, of gut microbiota dysbiosis. On the other hand, beyond the microbial production of short chain fatty acids and their vast metabolic properties, little is known about the molecular mechanisms linking a change in the activity of gut microbes to a modification of host cell metabolism. In this context, microRNAs (also known as miRs) are promising molecules which could allow explaining how dysbiosis is converted into metabolic outcomes since: 1-miRs are pleiotropic regulators of gene expression, targeting multiple mRNAs at once; 2-miRs expression in specific organs such as the intestine has been demonstrated to be under the control of gut microbiota; 3-alterations in miRs expression have been found in the majority of tissues targeted by gut microbiota dysbiosis during metabolic diseases such as liver, adipose tissue, pancreas, skeletal muscle, intestine, heart and also the brain. In this review publications in the growing field of miRsbased metabolic control at a systemic level will be discussed together with a putative link with gut microbiota dysbiosis.

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Section: Pancreatic Mirsmentioning

confidence: 94%

MicroRNAs: Decoders of Dysbiosis into Metabolic Diseases?

Sérino¹

2016

J Diabetes Metab

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“…Glu, glucose; Pyr, pyruvate; Lac, lactate; Glut, glutamante; Orn, ornitine; PolII, RNA polymerase II; Mito, mitochondria. Data source: Pullen et al (2011), Klein et al (2013), Liang et al (2015), Martinez-Sanchez et al (2015), Tugay et al (2016). See the main text for further details.…”

Section: Mirnas and Disallowed Genesmentioning

confidence: 99%

“…Indeed, Pdgfra is an experimentally validated target for miR-34a in pulmonary artery smooth muscle and colon cancer cells and glioblastoma (Genovese et al, 2012; Li C. et al, 2015; Wang P. et al, 2016), miR-130a during mesodermal specification (Singh et al, 2015), miR-146b-5p in blood cells and hepatocellular carcinoma (Zhu et al, 2013; Zhai et al, 2014) and miR-140 during palatogenesis (Eberhart et al, 2008). Moreover, the Regazzi laboratory, in collaboration with ourselves, has very recently demonstrated that miR-34a targets Pdgfra in rat islet cells (Tugay et al, 2016). As discuss below, miR-34a expression increases with age in rat and human islets and might thus be involved in the age-related decline in β-cell proliferation through its target Pdgfra (Tugay et al, 2016).…”

Section: Mirnas and Disallowed Genesmentioning

confidence: 99%

MiRNAs in β-Cell Development, Identity, and Disease

2017

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Pancreatic β-cells regulate glucose metabolism by secreting insulin, which in turn stimulates the utilization or storage of the sugar by peripheral tissues. Insulin insufficiency and a prolonged period of insulin resistance are usually the core components of type 2 diabetes (T2D). Although, decreased insulin levels in T2D have long been attributed to a decrease in β-cell function and/or mass, this model has recently been refined with the recognition that a loss of β-cell “identity” and dedifferentiation also contribute to the decline in insulin production. MicroRNAs (miRNAs) are key regulatory molecules that display tissue-specific expression patterns and maintain the differentiated state of somatic cells. During the past few years, great strides have been made in understanding how miRNA circuits impact β-cell identity. Here, we review current knowledge on the role of miRNAs in regulating the acquisition of the β-cell fate during development and in maintaining mature β-cell identity and function during stress situations such as obesity, pregnancy, aging, or diabetes. We also discuss how miRNA function could be harnessed to improve our ability to generate β-cells for replacement therapy for T2D.

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“…MiR-30a has been associated with glucotoxicity-induced defects in insulin secretion17. A role for miR-34a has also been repeatedly reported in both type 1 and type 2 diabetes as well as in age-associated diabetes212223. The effects of miR-375 , miR-30a , and miR-34a have been examined in pancreatic islet cells under diabetic conditions, but their contributions to a specific pathway have never been reported.…”

mentioning

confidence: 99%

A Presenilin/Notch1 pathway regulated by miR-375, miR-30a, and miR-34a mediates glucotoxicity induced-pancreatic beta cell apoptosis

Zhang

Zhou

et al. 2016

Sci Rep

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The presenilin-mediated Notch1 cleavage pathway plays a critical role in controlling pancreatic beta cell fate and survival. The aim of the present study was to investigate the role of Notch1 activation in glucotoxicity-induced beta cell impairment and the contributions of miR-375, miR-30a, and miR-34a to this pathway. We found that the protein levels of presenilins (PSEN1 and PSEN2), and NOTCH1 were decreased in INS-1 cells after treatment with increased concentrations of glucose, whereas no significant alteration of mRNA level of Notch1 was observed. Targeting of miR-375, miR-30a, and miR-34a to the 3′utr of Psen1, Psen2, and Notch1, respectively, reduced the amounts of relevant proteins, thereby reducing NICD1 amounts and causing beta cell apoptosis. Overexpression of NICD1 blocked the effects of glucotoxicity as well as miRNA overabundance. Downregulating the expression of miR-375, miR-30a, and miR-34a restored PSEN1, PSEN2, and NICD1 production and prevented glucotoxicity-induced impairment of the beta cells. These patterns of miRNA regulation of the Notch1 cleavage pathway were reproduced in GK rats as well as in aged rats. Our findings demonstrated that miRNA-mediated suppression of NICD1 links the presenilin/Notch1 pathway to glucotoxicity in mature pancreatic beta cells.

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Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets

Cited by 44 publications

References 46 publications

MicroRNAs: Decoders of Dysbiosis into Metabolic Diseases?

MicroRNAs: Decoders of Dysbiosis into Metabolic Diseases?

MiRNAs in β-Cell Development, Identity, and Disease

A Presenilin/Notch1 pathway regulated by miR-375, miR-30a, and miR-34a mediates glucotoxicity induced-pancreatic beta cell apoptosis

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