miR-494 protects pancreatic β-cell function by targeting PTEN in gestational diabetes mellitus.

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Increasing evidence suggests that microRNAs (miRNAs) play key roles in the diverse types of diabetes, including GDM. However, the underlying mechanisms remain largely unknown. The purpose of this study is to investigate the role of microRNAs in GDM. The microarray data of dysregulated miRNAs in blood and placenta was retrieved in the GEO dataset under the accession number GSE19649. Quantitative reverse transcription PCR (qRT-PCR) was performed to analyze the expression levels of miR-494 in peripheral blood from twenty pairs of gestational diabetes (GDM) women and healthy women. Then, we investigated the effects of miR-494 on the insulin secretion of pancreatic β-cells. Moreover, the role of this miR-494 in regulating the proliferation and apoptosis of pancreatic β-cells were determined by MTT assay and flow cytometry, respectively in INS1 cells transfected with a miR-494 mimic or inhibitor. In addition, the direct target of miR-494 was confirmed using 3' untranslated region (UTR) luciferase reporter assay. Our data demonstrated that the miR-494 level was significantly decreased in the blood of GDM patients, and the low level was associated with a high concentration of blood glucose. Furthermore, overexpression of miR-494 improved pancreatic β-cell dysfunction by enhancing insulin secretion and total insulin content, inducing cell proliferation, and inhibiting cell apoptosis, whereas miR-494 knockdown exhibited decreased insulin secretion and proliferation, as well as stimulated apoptosis. In addition, phosphatase and tensin homolog (PTEN) which has been shown to play a pivotal role in apoptosis, was proved to be a direct target of miR-494 in pancreatic β-cells. More importantly, siRNA-induced downregulation of PTEN reversed the effects of miR-494 knockdown on insulin secretion, cell proliferation, and apoptosis of pancreatic β-cells.", "claims": [{"id": "claim-method", "statement": "The data were analyzed using limma (Smyth, 2004[30]) and significance analysis of microarray (SAM) (Tusher et al., 2001[34]), to determine differential expression of microRNAs between groups.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29333131", "locator": "sections[3] \"MicroRNA expression profile data from Gene Expression Omnibus (GEO)\" paragraph 2", "quote": "The data were analyzed using limma (Smyth, 2004[30]) and significance analysis of microarray (SAM) (Tusher et al., 2001[34]), to determine differential expression of microRNAs between groups."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The microarray data of dysregulated miRNAs in blood and placenta was retrieved in the GEO dataset under the accession number GSE19649. MicroRNA array expression profile data GSE19649 were downloaded from open Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29333131", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "The microarray data of dysregulated miRNAs in blood and placenta was retrieved in the GEO dataset under the accession number GSE19649."}, {"asset": "source:pmid:29333131", "locator": "sections[3] \"MicroRNA expression profile data from Gene Expression Omnibus (GEO)\" paragraph 2", "quote": "MicroRNA array expression profile data GSE19649 were downloaded from open Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Using GEO2R with limma and significance analysis of microarrays to analyze GSE19649, followed by qRT-PCR validation in 20 paired GDM and healthy women, the study found that miR-494 was significantly decreased in the blood of GDM patients and that low miR-494 was associated with high blood glucose.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:29333131"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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The microarray data of dysregulated miRNAs in blood and pla", "samples from GDM patients via retrieving the microarray data in the GEO dataset under the accession", "der the accession number GSE19649. The miRNA microarray identified 34 miRNAs that were up-regulated"], "order_basis": "paper_text_order:462", "id": "assay:1"}, {"role": "data_generation", "definition_id": "qpcr", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["dataset under the accession number GSE19649. Quantitative reverse transcription PCR (qRT-PCR) was performed to analyze the expre"], "order_basis": "paper_text_order:593", "id": "assay:2"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["miR-494 in regulating the proliferation and apoptosis of pancreatic β-cells were determined by MTT", "cing cell proliferation, and inhibiting cell apoptosis, whereas miR-494 knockdown exhibited decreas", "ion and proliferation, as well as stimulated apoptosis. In addition, phosphatase and tensin homolog", "ich has been shown to play a pivotal role in apoptosis, was proved to be a direct target of miR-494"], "order_basis": "paper_text_order:958", "id": "assay:3"}, {"role": "data_generation", "definition_id": "flow_cytometry", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["tic β-cells were determined by MTT assay and flow cytometry, respectively in INS1 cells transfected with"], "order_basis": "paper_text_order:1022", "id": "assay:4"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["d flow cytometry, respectively in INS1 cells transfected with a miR-494 mimic or inhibitor. In additi", "d inhibiting cell apoptosis, whereas miR-494 knockdown exhibited decreased insulin secretion and pr", "tion of PTEN reversed the effects of miR-494 knockdown on insulin secretion, cell proliferation, an", "494 in pancreatic β-cells. More importantly, siRNA-induced downregulation of PTEN reversed the"], "order_basis": "paper_text_order:1065", "id": "assay:5"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.69, "evidence": ["n The INS-1 cell line, a well differentiated mouse insulinoma β-cell line was maintained in Dul"], "order_basis": "paper_text_order:2778", "id": "assay:6"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.85, "evidence": ["ne, a well differentiated mouse insulinoma β-cell line was maintained in Dulbecco's modifed Eagle's medium contain"], "order_basis": "paper_text_order:2797", "id": "assay:7"}, {"role": "analysis", "definition_id": "differential_expression", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["The data were analyzed using limma (Smyth, 2004[30]) and significance analysis of microarray (SAM) (Tusher et al., 2001[34]), to determine differential expression of microRNAs between groups."], "order_basis": "consumes_earlier_output", "id": "assay:8"}]}