Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic β-Cells

Shang, Jin; Li, Jing; Keller, Mark P.; Hohmeier, Hans E.; Wang, Yong; Feng, Yue; Zhou, Heather; Shen, Xiaolan; Rabaglia, Mary R.; Soni, Mufaddal; Attie, Alan D.; Newgard, Christopher B.; Thornberry, Nancy A.; Howard, Andrew D.; Zhou, Yun

doi:10.1210/me.2014-1335

Cited by 48 publications

(41 citation statements)

References 46 publications

(54 reference statements)

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“…In that study our group showed putative transcription factor binding sites for Calmodulin Binding Transcription Activator 1 (Camta1) and NK2 homeobox protein, Nkx2-2. Elsewhere, we and others also demonstrated cAMP-dependent regulation of the miR-132/212 cluster through a PKA-dependent mechanism35 involving cAMP-response element (CRE)-binding proteins and CRTC136. In db / db and high-fat diet fed mice, miR-132 and miR-184 in the pancreatic islets were suggested to be induced by hyperglycaemic and hyperlipidaemic conditions typically encountered in prediabetic and diabetic states37.…”

Section: Discussionmentioning

confidence: 69%

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Ofori

Salunkhe

Bagge

et al. 2017

Sci Rep

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MicroRNAs have emerged as important players of gene regulation with significant impact in diverse disease processes. In type-2 diabetes, in which impaired insulin secretion is a major factor in disease progression, dysregulated microRNA expression in the insulin-secreting pancreatic beta cell has been widely-implicated. Here, we show that miR-130a-3p, miR-130b-3p, and miR-152-3p levels are elevated in the pancreatic islets of hyperglycaemic donors, corroborating previous findings about their upregulation in the islets of type-2 diabetes model Goto-Kakizaki rats. We demonstrated negative regulatory effects of the three microRNAs on pyruvate dehydrogenase E1 alpha (PDHA1) and on glucokinase (GCK) proteins, which are both involved in ATP production. Consequently, we found both proteins to be downregulated in the Goto-Kakizaki rat islets, while GCK mRNA expression showed reduced trend in the islets of type-2 diabetes donors. Overexpression of any of the three microRNAs in the insulin-secreting INS-1 832/13 cell line resulted in altered dynamics of intracellular ATP/ADP ratio ultimately perturbing fundamental ATP-requiring beta cell processes such as glucose-stimulated insulin secretion, insulin biosynthesis and processing. The data further strengthen the wide-ranging influence of microRNAs in pancreatic beta cell function, and hence their potential as therapeutic targets in type-2 diabetes.

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Section: Discussionmentioning

confidence: 69%

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Ofori

Salunkhe

Bagge

et al. 2017

Sci Rep

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“…The inductions of miR-132 and miR-212 by GLP-1 were correlated with cyclic adenosine monophosphate (cAMP) production and were blocked by a protein kinase A inhibitor[17]. Overexpression of miRNA-132 or miRNA-212 increased glucose-stimulated insulin secretion [17]. We therefore hypothesized that miRNAs might be important in liraglutide-induced β-cell protection against lipid stress.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR-139-5p contributes to the antiapoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1

Gong

et al. 2017

PLoS ONE

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Liraglutide is administered as glucagon-like peptide-1 (GLP-1) receptor agonist for diabetic patients and can protect pancreatic β-cells by inhibiting their apoptosis. MicroRNA-139-5p (miRNA-139-5p) participates in the regulation of cancer cell apoptosis. However, it is not clear whether miR-139-5p contributes to the anti-apoptotic effect of liraglutide in β-cells. The objective of the present study was to investigate the role of miR-139-5p on apoptosis of pancreatic β-cells. MicroRNA levels in pancreatic tissue from diabetic rats and INS-1 cells treated with liraglutide were measured by real-time quantitative RT-PCR. The role of miR-139-5p on apoptosis was studied by transfecting INS-1 cells with miR-139-5p mimics. The mRNA and protein expression of the target gene, insulin receptor substrate-1 (IRS1), were measured by qRT-PCR and Western blot, respectively. Apoptosis in rat pancreatic tissue and INS-1 cells was detected by TUNEL and annexin V/propidium iodide costaining. Apoptosis of pancreatic tissue from diabetic rats and INS-1 cells was decreased by administration of liraglutide. The expression of miR-139-5p increased in the pancreas of diabetic rats and decreased with liraglutide treatment. Incubation with liraglutide (100 nM) for 48 h attenuated the expression of miR-139-5p and increased the mRNA and protein levels of IRS1. Direct regulatory effects of miR-139-5p on IRS1 were found by a dual-luciferase reporter assay. Transfection of INS-1 cells with miR-139-5p mimics led to decreases in the mRNA and protein expression of IRS1. In conclusion, our observations suggest that decreased miR-139-5p expression contributes to the anti-apoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1.

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“…We have previously demonstrated that several of the miRNAs showing altered expression in the GK rat are glucose-dependent (27), and we and others have shown cAMP-dependent regulation of miRNAs (28 -30). Specifically, the miR-212/miR-132 cluster has been suggested to be regulated by cAMP through a PKA-dependent mechanism (30) involving cAMP-response element (CRE)-binding proteins and CRTC1 (31).…”

Section: Camtasmentioning

confidence: 99%

Integrator of Stress Responses Calmodulin Binding Transcription Activator 1 (Camta1) Regulates miR-212/miR-132 Expression and Insulin Secretion

Mollet

Malm

Wendt

et al. 2016

Journal of Biological Chemistry

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Altered microRNA profiles have been demonstrated in experimental models of type 2 diabetes, including in islets of the diabetic Goto-Kakizaki (GK) rat. Our bioinformatic analysis of conserved sequences in promoters of microRNAs, previously observed to be up-regulated in GK rat islets, revealed putative CGCG-core motifs on the promoter of the miR-212/miR-132 cluster, overexpression of which has been shown to increase insulin secretion. These motifs are possible targets of calmodulin binding transcription activators Camta1 and Camta2 that have been recognized as integrators of stress responses. We also identified putative NKE elements, possible targets of NK2 homeobox proteins like the essential islet transcription factor Nkx2-2. As Camtas can function as co-activators with NK2 proteins in other tissues, we explored the role of Camta1, Camta2, and Nkx2-2 in the regulation of the miR-212/miR-132 cluster and insulin secretion. We demonstrate that exposure of control Wistar or GK rat islets to 16.7 mM glucose increases miR-212/ miR-132 expression but significantly less so in the GK rat. In addition, Camta1, Camta2, and Nkx2-2 were down-regulated in GK rat islets, and knockdown of Camta1 reduced miR-212/ miR-132 promoter activity and miR-212/miR-132 expression, even under cAMP elevation. Knockdown of Camta1 decreased insulin secretion in INS-1 832/13 cells and Wistar rat islets but increased insulin content. Furthermore, knockdown of Camta1 reduced K ؉ -induced insulin secretion and voltage-dependent Ca 2؉ currents. We also demonstrate Camta1 and Nkx2-2 protein interaction. These results indicate that Camta1 is required not only for expression of the miR-212/miR-132 cluster but at multiple levels for regulating beta cell insulin content and secretion.

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Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic β-Cells

Cited by 48 publications

References 46 publications

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell

Downregulation of miR-139-5p contributes to the antiapoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1

Integrator of Stress Responses Calmodulin Binding Transcription Activator 1 (Camta1) Regulates miR-212/miR-132 Expression and Insulin Secretion

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