miR-29a Negatively Affects Glucose-Stimulated Insulin Secretion and MIN6 Cell Proliferation via Cdc42/<i>β</i>-Catenin Signaling

Duan, Jing; Qian, Xiaoqin; Li, Jun; Xiao, Xiangyu; Lu, Xiangtong; Lv, Lin-Chen; Huang, Qing-Yun; Ding, Wen; Zhang, Hongyan; Xiong, Likuan

doi:10.1155/2019/5219782

Cited by 14 publications

(22 citation statements)

References 59 publications

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“…MiR-29a is a well-established regulator of insulin secretion and beta cell function (Bagge et al 2012 ; Dooley et al 2016 ; Pullen et al 2011 ; Duan et al . 2019 ) and therefore an exciting candidate to investigate further. Approximately, 33% of the GPS genes after iAs III exposure harbor predicted miR-29a target sites, and nearly 25% of the GPS genes after MAs III exposure are also predicted to be targeted by miR-29a (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

et al. 2022

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Arsenic is a pervasive environmental toxin that is listed as the top priority for investigation by the Agency for Toxic Substance and Disease Registry. While chronic exposure to arsenic is associated with type 2 diabetes (T2D), the underlying mechanisms are largely unknown. We have recently demonstrated that arsenic treatment of INS-1 832/13 pancreatic beta cells impairs glucose-stimulated insulin secretion (GSIS), a T2D hallmark. We have also shown that arsenic alters the microRNA profile of beta cells. MicroRNAs have a well-established post-transcriptional regulatory role in both normal beta cell function and T2D pathogenesis. We hypothesized that there are microRNA master regulators that shape beta cell gene expression in pathways pertinent to GSIS after exposure to arsenicals. To test this hypothesis, we first treated INS-1 832/13 beta cells with either inorganic arsenic (iAsIII) or monomethylarsenite (MAsIII) and confirmed GSIS impairment. We then performed multi-omic analysis using chromatin run-on sequencing, RNA-sequencing, and small RNA-sequencing to define profiles of transcription, gene expression, and microRNAs, respectively. Integrating across these data sets, we first showed that genes downregulated by iAsIII treatment are enriched in insulin secretion and T2D pathways, whereas genes downregulated by MAsIII treatment are enriched in cell cycle and critical beta cell maintenance factors. We also defined the genes that are subject primarily to post-transcriptional control in response to arsenicals and demonstrated that miR-29a is the top candidate master regulator of these genes. Our results highlight the importance of microRNAs in arsenical-induced beta cell dysfunction and reveal both shared and unique mechanisms between iAsIII and MAsIII.

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Section: Resultsmentioning

confidence: 99%

“…MiR-29a is a well-established modulator of insulin secretion, in part through regulation of target genes such as syntaxin-1 (Bagge et al 2012 ; Pullen et al 2011 ; Duan et al . 2019 ; Filios and Shalev 2015 ; Baran-Gale et al . 2013 ; Bagge et al 2012 ; Roggli et al 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

et al. 2022

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“…Interestingly, four of the five miRNAs that were significantly increased during the second visit (24–28 weeks of gestation), miR-29a, miR-134-5p, miR-433-3p and miR-330-3p, are involved in pancreatic beta cell function [ 9 , 43 , 44 , 45 , 46 , 47 ]. MiR-29a, which increased with increasing glucose concentrations, impairs glucose-stimulated insulin secretion at least partially via targeting the exocytosis protein Syntaxin 1 [ 43 , 44 , 45 ], while miR-330-3p targets glucokinase, the gene responsible for Maturity Onset Diabetes of the Young, subtype 2 (MODY2). Both miR-134-5p and miR-433-3p belong to a microRNA cluster (C14MC) within the imprinted DLK1-DIO3 locus on chromosome 14.…”

Section: Discussionmentioning

confidence: 99%

The Temporal Profile of Circulating miRNAs during Gestation in Overweight and Obese Women with or without Gestational Diabetes Mellitus

et al. 2022

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Circulating non-coding microRNAs (miRNAs) are important for placentation, but their expression profiles across gestation in pregnancies, which are complicated by gestational diabetes mellitus (GDM), have not been fully established. Investigating a single time point is insufficient, as pregnancy is dynamic, involving several processes, including placenta development, trophoblast proliferation and differentiation and oxygen sensing. Thus, the aim of this study was to compare the temporal expression of serum miRNAs in pregnant women with and without GDM. This is a nested case-control study of longitudinal data obtained from a multicentric European study (the ‘DALI’ study). All women (n = 82) were overweight/obese (BMI ≥ 29 kg/m2) and were normal glucose tolerant (NGT) at baseline (before 20 weeks of gestation). We selected women (n = 41) who were diagnosed with GDM at 24–28 weeks, according to the IADPSG/WHO2013 criteria. They were matched with 41 women who remained NGT in their pregnancy. miRNA (miR-16-5p, -29a-3p, -103-3p, -134-5p, -122-5p, -223-3p, -330-3p and miR-433-3p) were selected based on their suggested importance for placentation, and measurements were performed at baseline and at 24–28 and 35–37 weeks of gestation. Women with GDM presented with overall miRNA levels above those observed for women remaining NGT. In both groups, levels of miR-29a-3p and miR-134-5p increased consistently with progressing gestation. The change over time only differed for miR-29a-3p when comparing women with GDM with those remaining NGT (p = 0.044). Our findings indicate that among overweight/obese women who later develop GDM, miRNA levels are already elevated early in pregnancy and remain above those of women who remain NGT during their pregnancy. Maternal circulating miRNAs may provide further insight into placentation and the cross talk between the maternal and fetal compartments.

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“…Furthermore, one study demonstrated that miR-29a inhibits glucose-stimulated insulin secretion (GSIS) and cell proliferation in MIN6 cells via a negative effect on Cdc42/β-Catenin signaling [31]. It has also been suggested that miR-29a inhibits GSIS by targeting syntaxin-1 and Mct1, as well as insulin signaling by targeting INSIG1, CAV2, PIK3R1 [32,33].…”

Section: Discussionmentioning

confidence: 99%

Understanding the role of GLUT2 in dysglycemia associated with Fanconi-Bickel syndrome

Sharari

Kabeer

Mohammed

et al. 2022

Preprint

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Fanconi–Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C > T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.

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miR-29a Negatively Affects Glucose-Stimulated Insulin Secretion and MIN6 Cell Proliferation via Cdc42/β-Catenin Signaling

Cited by 14 publications

References 59 publications

Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

The Temporal Profile of Circulating miRNAs during Gestation in Overweight and Obese Women with or without Gestational Diabetes Mellitus

Understanding the role of GLUT2 in dysglycemia associated with Fanconi-Bickel syndrome

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