Bioinformatic analysis and experimental validation of hub autophagy-related genes as novel biomarkers for type 2 diabetes mellitus and Alzheimer's disease.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41081092", "kind": "science-record", "revision": 4, "content_hash": "sha256:8d5bb639a87375341810092d0a121693bb82b93d47c431cfff8f009a6a688384", "created_at": "2026-11-01T20:31:08Z", "updated_at": "2026-11-01T22:57:17Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Bioinformatic analysis and experimental validation of hub autophagy-related genes as novel biomarkers for type 2 diabetes mellitus and Alzheimer's disease.", "doi": "10.7717/peerj.20143", "pmid": "41081092", "authors": ["Rui Zhang", "Ruowei Wang", "Shuna Zhai", "Chunhong Shen", "Yu An", "Quanri Liu"], "journal": "PeerJ", "year": 2025, "abstract": "Background & Objectives: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share considerable similarities in their proposed patho mechanisms. Autophagy, an intrinsic cellular process involved in the degradation of dysfunctional organelles and abnormal proteins, has been implicated in the pathogenesis of both AD and T2DM. This study aims to identify potential shared biomarkers related to autophagy in AD and T2DM by analyzing hub differentially expressed autophagy-related genes (DEARGs) and examining their potential functions.\nMethods: Gene expression profiles for AD and T2DM were acquired from the Gene Expression Omnibus (GEO) database (training sets: GSE109887 for AD and GSE104674 for T2DM; validation sets: GSE122063 for AD and GSE64998 for T2DM). Autophagy-related genes (ARGs) were extracted from multiple databases. DEARGs were identified and integrated with module genes derived from weighted gene co-expression network analysis (WGCNA) to determine key shared ARGs. Then, the STRING database was used to construct a protein-protein interaction (PPI) network, from which hub genes were identified. These hub genes were validated using independent microarray datasets through differential expression analysis, and ROC curves were generated to assess their diagnostic value. Moreover, the expression of the hub genes was validated in brain tissues of T2DM mouse models using qRT-PCR.\nResults: A total of 33 shared DEARGs were identified, among which 12 were designated as hub genes (ANXA5, CCND1, MAP2K1, HSPB1, BNIP3, BAG3, YAP1, MET, FBXW7, CCL2, PFKFB3, CDKN1A) in both AD and T2DM patients. Validation using other datasets confirmed that ANXA5, BAG3, and CDKN1A remained significantly upregulated, while MET remained downregulated in both AD and T2DM patients. Additionally, PFKFB3 showed an inverse expression pattern between the two diseases. The diagnostic performance of these five hub genes was assessed using ROC curves, with all five exhibiting values of area under the curve (AUC) exceeding 0.7 for T2DM in both training and validation sets. However, only MET and PFKFB3 demonstrated good diagnostic efficacy in AD patients. In animal models, qRT-PCR analysis revealed that the expression of ANXA5, BAG3, and MET was consistent with the bioinformatics results. In contrast, the expression of PFKFB3 and CDKN1A did not differ significantly between db/db model mice and db/m control mice.\nConclusions: Our integrated bioinformatics analyses, supported by preliminary experimental validations, identified several hub ARGs shared between AD and T2DM. Among these, ANXA5, BAG3, and MET exhibited consistent expression trends across datasets and experimental models, while CDKN1A and PFKFB3 showed inconsistent expression patterns. These findings underscore the complexity of autophagy-related crosstalk in AD-T2DM comorbidity and highlight the need for further research to clarify their diagnostic and therapeutic potential.", "claims": [{"id": "claim-data-access", "statement": "The following information was supplied regarding data availability:\nThe raw data is available at GEO: GSE109887, GSE104674, GSE122063, and GSE64998.\nThe custom R scripts for bioinformatic analyses are available at GitHub:\n- https://github.com/anyu900222/AD-T2DM-Autophagy,\n- An, Y. (2025). Bioinformatic analysis of hub autophagy-related genes for type 2 diabetes mellitus and Alzheimer’s disease. Zenodo. https://doi.org/10.5281/zenodo.16869519.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41081092", "locator": "sections[31] \"Data Availability\" paragraphs 1-6", "quote": "The following information was supplied regarding data availability:\nThe raw data is available at GEO: GSE109887, GSE104674, GSE122063, and GSE64998.\nThe custom R scripts for bioinformatic analyses are available at GitHub:\n- https://github.com/anyu900222/AD-T2DM-Autophagy,\n- An, Y. (2025). Bioinformatic analysis of hub autophagy-related genes for type 2 diabetes mellitus and Alzheimer’s disease. Zenodo. https://doi.org/10.5281/zenodo.16869519."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The study identified 33 shared differentially expressed autophagy-related genes between Alzheimer’s disease and type 2 diabetes mellitus and selected 12 as hub genes.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41081092", "locator": "sections[19] \"PPI network construction and identification of hub genes\" paragraph 2", "quote": "The 33 shared genes between AD and T2DM were used to construct a PPI network via the STRING database. As indicated in Fig. 6A, the resulting network was visualized using Cytoscape. Based on node degree ranking, 12 genes (ANXA5, CCND1, MAP2K1, BAG3, BNIP3, HSPB1, CCL2, FBXW7, MET, YAP1, CDKN1A and PFKFB3) were identified as hub genes for further analysis (Fig. 6B)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The study identified 33 shared differentially expressed autophagy-related genes between Alzheimer’s disease and type 2 diabetes mellitus and selected 12 as hub genes.", "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:41081092"], "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. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE104674"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE104674"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:41081092", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.7717/peerj.20143", "sha256": "sha256:a3b43c03145c481d196869a422b3cf525c9bcd45b067b7e5dd9939c3a0f6b5cd", "bytes": 62716, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.7717/peerj.20143", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12510248", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE104674", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104674", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE104674", "version": null, "note": "The following information was supplied regarding data availability:\nThe raw data is available at GEO: GSE109887, GSE104674, GSE122063, and GSE64998.\nThe custom R scripts for bioinformatic analyses are available at GitHub:\n- https://github.com/anyu900222/AD-T2DM-Autophagy,\n- An, Y. 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"The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: edger."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE109887", "GSE104674", "GSE122063", "GSE64998"], "resolved_accessions": ["GSE109887", "GSE104674", "GSE122063", "GSE64998"], "statements": ["The following information was supplied regarding data availability:\nThe raw data is available at GEO: GSE109887, GSE104674, GSE122063, and GSE64998.\nThe custom R scripts for bioinformatic analyses are available at GitHub:\n- https://github.com/anyu900222/AD-T2DM-Autophagy,\n- An, Y. (2025). Bioinformatic analysis of hub autophagy-related genes for type 2 diabetes mellitus and Alzheimer’s disease. Zenodo. https://doi.org/10.5281/zenodo.16869519."], "basis": "The paper names GSE109887, GSE104674, GSE122063, GSE64998 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "assets": ["source:pmid:41081092", "data:geo:GSE104674"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE104674"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T20:02:56Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 17390, "completion_tokens": 1859, "cached_tokens": 128}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:41081092", "type": "paper", "label": "pmid:41081092"}, {"id": "source:pmid:41081092", "type": "manuscript", "label": "PMID 41081092 full text"}, {"id": "data:geo:GSE104674", "type": "dataset", "label": "GEO GSE104674"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:41081092", "type": "paper", "label": "pmid:41081092"}, {"id": "source:pmid:41081092", "type": "manuscript", "label": "PMID 41081092 full text"}, {"id": "data:geo:GSE104674", "type": "dataset", "label": "GEO GSE104674"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-41081092", "type": "extraction", "used": ["source:pmid:41081092"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE104674", "type": "accession_resolution", "used": ["data:geo:GSE104674"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:41081092", "parent_hash": "sha256:1ed7e34ee10b6cdb48b14a43944643b73bb847c9b536d89e424f7948dea75413", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE104674 licence not read", "asset:data:geo:GSE104674 not downloaded", "asset:data:geo:GSE109887 licence not read", "asset:data:geo:GSE109887 not downloaded", "asset:data:geo:GSE122063 licence not read", "asset:data:geo:GSE122063 not downloaded", "asset:data:geo:GSE64998 licence not read", "asset:data:geo:GSE64998 not downloaded", "execution.not_run", "method.reader_differs_from_extractor", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["e hub genes were validated using independent microarray datasets through differential expression ana"], "order_basis": "paper_text_order:1284", "id": "assay:1"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["genes was validated in brain tissues of T2DM mouse models using qRT-PCR. Results: A total of 33", "l age of 11 weeks at the study endpoint. The mice were housed under specific-pathogen-free (SPF) co", "were routinely cleaned and disinfected. Four mice were housed in each cage to meet social needs, wi", "e of the procedure. At the end of the study, mice were euthanized by intraperitoneal injection of e"], "order_basis": "paper_text_order:1491", "id": "assay:2"}, {"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": ["Differential expression analysis of autophagy-related genes (DEARGs) was performed using the “limma” R package for the AD and control groups in the GSE109887 dataset, and the “edgeR” package for the T2DM and control groups in the GSE104674 dataset."], "order_basis": "consumes_earlier_output", "id": "assay:3"}]}