Transgenic overexpression of microRNA-30d in pancreatic beta-cells progressively regulates beta-cell function and identity

Mao, Yiping; Schoenborn, Jacob; Wang, Zhihong; Chen, Xinqian; Matson, Katy; Mohan, Ramkumar; Zhang, Shungang; Tang, Xiaohu; Arunagiri, Anoop; Arvan, Peter; Tang, Xiaoqing

doi:10.1038/s41598-022-16174-7

Cited by 4 publications

(3 citation statements)

References 53 publications

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“…Instead, we chose to study hsa-mir-30e-3p, a member of the miRNA-30 family, which is highly expressed in beta-cells, according to the same database. Interestingly, members of the miRNA-30 family have been reported to affect beta-cell insulin production, apoptosis and transdifferentiation to alpha-cells, and to function as biomarkers for pre-diabetes (30)(31)(32). We observed that blocking the binding of hsamir-30e-3p to ADA1 mRNA resulted in reduced intracellular adenosine levels, both at control conditions and in cells exposed to palmitate + high glucose (Figure 8A).…”

Section: Sirna-mediated Downregulation Of Ada1 Increases Cell Death I...mentioning

confidence: 85%

Metabolic stress-induced human beta-cell death is mediated by increased intracellular levels of adenosine

et al. 2023

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IntroductionHigh intracellular concentrations of adenosine and 2’-deoxyadenosine have been suggested to be an important mediator of cell death. The aim of the present study was to characterize adenosine-induced death in insulin-producing beta-cells, at control and high glucose + palmitate-induced stress conditions.MethodsHuman insulin-producing EndoC-betaH1 cells were treated with adenosine, 2’-deoxyadenosine, inosine and high glucose + sodium palmitate, and death rates using flow cytometry were studied.ResultsWe observed that adenosine and the non-receptor-activating analogue 2-deoxyadenosine, but not the adenosine deamination product inosine, promoted beta-cell apoptosis at concentrations exceeding maximal adenosine-receptor stimulating concentrations. Both adenosine and inosine were efficiently taken up by EndoC-betaH1 cells, and inosine counteracted the cell death promoting effect of adenosine by competing with adenosine for uptake. Both adenosine and 2’-deoxyadenosine promptly reduced insulin-stimulated production of plasma membrane PI(3,4,5)P3, an effect that was reversed upon wash out of adenosine. In line with this, adenosine, but not inosine, rapidly diminished Akt phosphorylation. Both pharmacological Bax inhibition and Akt activation blocked adenosine-induced beta-cell apoptosis, indicating that adenosine/2’-deoxyadenosine inhibits the PI3K/Akt/BAD anti-apoptotic pathway. High glucose + palmitate-induced cell death was paralleled by increased intracellular adenosine and inosine levels. Overexpression of adenosine deaminase-1 (ADA1) in EndoC-betaH1 cells, which increased Akt phosphorylation, prevented both adenosine-induced apoptosis and high glucose + palmitate-induced necrosis. ADA2 overexpression not only failed to protect against adenosine and high glucose + palmitate-activated cell death, but instead potentiated the apoptosis-stimulating effect of adenosine. In line with this, ADA1 overexpression increased inosine production from adenosine-exposed cells, whereas ADA2 did not. Knockdown of ADA1 resulted in increased cell death rates in response to both adenosine and high glucose + palmitate. Inhibition of miR-30e-3p binding to the ADA1 mRNA 3’-UTR promoted the opposite effects on cell death rates and reduced intracellular adenosine contents.DiscussionIt is concluded that intracellular adenosine/2’-deoxyadenosine regulates negatively the PI3K pathway and is therefore an important mediator of beta-cell apoptosis. Adenosine levels are controlled, at least in part, by ADA1, and strategies to upregulate ADA1 activity, during conditions of metabolic stress, could be useful in attempts to preserve beta-cell mass in diabetes.

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Section: Sirna-mediated Downregulation Of Ada1 Increases Cell Death I...mentioning

confidence: 85%

Metabolic stress-induced human beta-cell death is mediated by increased intracellular levels of adenosine

et al. 2023

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“…At the same time though, miR-375 has been found to be dysregulated both in experimental [273,274] and real-life conditions related to T2D [275]. In addition, other malfunctioning miRNAs have been found to play a role in β-cell failure and T2D pathogenesis, such as miR-7, miR-9, miR-29, and miR-30d, among several others [272,276]. No studies have been published so far regarding the possible association between micronutrients and miRNA levels in patients with T2D, but a recent study by Ferrero et al [277] showed a link between habitual diet nutrients and circulating miRNA profiles in healthy subjects.…”

Section: Role Of Mirnas Dysfunctionmentioning

confidence: 99%

Beta Cell Dysfunction in Youth- and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients

et al. 2023

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Traditionally a disease of adults, type 2 diabetes (T2D) has been increasingly diagnosed in youth, particularly among adolescents and young adults of minority ethnic groups. Especially, during the recent COVID-19 pandemic, obesity and prediabetes have surged not only in minority ethnic groups but also in the general population, further raising T2D risk. Regarding its pathogenesis, a gradually increasing insulin resistance due to central adiposity combined with a progressively defective β-cell function are the main culprits. Especially in youth-onset T2D, a rapid β-cell activity decline has been observed, leading to higher treatment failure rates, and early complications. In addition, it is well established that both the quantity and quality of food ingested by individuals play a key role in T2D pathogenesis. A chronic imbalance between caloric intake and expenditure together with impaired micronutrient intake can lead to obesity and insulin resistance on one hand, and β-cell failure and defective insulin production on the other. This review summarizes our evolving understanding of the pathophysiological mechanisms involved in defective insulin secretion by the pancreatic islets in youth- and adult-onset T2D and, further, of the role various micronutrients play in these pathomechanisms. This knowledge is essential if we are to curtail the serious long-term complications of T2D both in pediatric and adult populations.

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“…Its overexpression in beta-cells leads to hyperglycemia, reduced insulin level and glucose intolerance in mice fed HFD. Interestingly, miR-30d negatively affects beta-cells identity by downregulating beta-cell markers and inducing the expression of alpha-cell markers (73).…”

Section: Mirnas As Gatekeepers For Beta-cell Apoptosismentioning

confidence: 99%

miRNAs provide mechanisms for integrated control of endocrine pancreas homeostasis and metabolic disease pathogenesis: a narrative review

Du¹,

Vidal-Puig²,

Rodríguez‐Cuenca³

2022

ExRNA

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Background and Objective: microRNAs (miRNAs) are short non-coding RNAs that have emerged to be the novel post-transcriptional regulators of gene expression, contributing to the development of metabolic diseases such as diabetes. Also, new and more precise high-throughput analytical tools have made it possible to study miRNAs' complex causative roles and targets. Here, we summarise the available evidence for the roles of miRNAs in the endocrine pancreas regulating fundamental cellular processes in beta-cells and the pathology of diabetes.Methods: We searched PubMed for research conducted and published before June 2022 using classical Boolean expressions. Only manuscripts written in English were considered.Key Content and Findings: Numerous miRNAs in the endocrine pancreas have been reported to regulate the fundamental cellular processes in beta-cells, such as proliferation, differentiation, apoptosis, and insulin biosynthesis and secretion by post-transcriptionally repressing their targets, as well as contributing to the pathology of diabetes. Also, many miRNAs, as molecular cargo of exosomes-mediate the crosstalk between the pancreas and other peripheral organs, unravelling new pathophysiological mechanisms related to the onset and worsening of diabetes.Conclusions: This review summarised the existing evidence of the complex network of miRNAs regulating the endocrine pancreas function and pathology of diabetes, providing the theoretical base for a future scientific study revealing the mechanism of diabetes and facilitating the discovery of new therapeutical targets in clinical practise.

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Transgenic overexpression of microRNA-30d in pancreatic beta-cells progressively regulates beta-cell function and identity

Cited by 4 publications

References 53 publications

Metabolic stress-induced human beta-cell death is mediated by increased intracellular levels of adenosine

Metabolic stress-induced human beta-cell death is mediated by increased intracellular levels of adenosine

Beta Cell Dysfunction in Youth- and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients

miRNAs provide mechanisms for integrated control of endocrine pancreas homeostasis and metabolic disease pathogenesis: a narrative review

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