Beta cell-specific PAK1 enrichment ameliorates diet-induced glucose intolerance in mice by promoting insulin biogenesis and minimising beta cell apoptosis.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:39404845", "kind": "science-record", "revision": 4, "content_hash": "sha256:6944c9996e1b8b51e9eef1025423c9f14c99fe26239d19a8997e9dd0fee54547", "created_at": "2026-11-01T20:29:38Z", "updated_at": "2026-11-01T22:55:24Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Beta cell-specific PAK1 enrichment ameliorates diet-induced glucose intolerance in mice by promoting insulin biogenesis and minimising beta cell apoptosis.", "doi": "10.1007/s00125-024-06286-2", "pmid": "39404845", "authors": ["Miwon Ahn", "Sangeeta Dhawan", "Erika M McCown", "Pablo A Garcia", "Supriyo Bhattacharya", "Roland Stein", "Debbie C Thurmond"], "journal": "Diabetologia", "year": 2025, "abstract": "AIMS/HYPOTHESIS: p21 (CDC42/RAC1) activated kinase 1 (PAK1) is depleted in type 2 diabetic human islets compared with non-diabetic human islets, and acute PAK1 restoration in the islets can restore insulin secretory function ex vivo. We hypothesised that beta cell-specific PAK1 enrichment in vivo can mitigate high-fat-diet (HFD)-induced glucose intolerance by increasing the functional beta cell mass.\nMETHODS: Human islets expressing exogenous PAK1 specifically in beta cells were used for bulk RNA-seq. Human EndoC-βH1 cells overexpressing myc-tagged PAK1 were used for chromatin immunoprecipitation (ChIP) and ChIP-sequencing (ChIP-seq). Novel doxycycline-inducible beta cell-specific PAK1-expressing (iβPAK1-Tg) mice were fed a 45% HFD pre-induction for 3 weeks and for a further 3 weeks with or without doxycycline induction. These HFD-fed mice were evaluated for GTT, ITT, 6 h fasting plasma insulin and blood glucose, body composition, islet insulin content and apoptosis.\nRESULTS: Beta cell-specific PAK1 enrichment in type 2 diabetes human islets resulted in decreased beta cell apoptosis and increased insulin content. RNA-seq showed an upregulation of INS gene transcription by PAK1. Using clonal human beta cells, we found that PAK1 protein was localised in the cytoplasm and the nucleus. ChIP studies revealed that nuclear PAK1 enhanced pancreatic and duodenal homeobox1 (PDX1) and neuronal differentiation 1 (NEUROD1) binding to the INS promoter in a glucose-responsive manner. Importantly, the iβPAK1-Tg mice, when challenged with HFD and doxycycline induction displayed enhanced glucose tolerance, increased islet insulin content and reduced beta cell apoptosis when compared with iβPAK1-Tg mice without doxycycline induction.\nCONCLUSIONS/INTERPRETATION: PAK1 plays an unforeseen and beneficial role in beta cells by promoting insulin biogenesis via enhancing the expression of PDX1, NEUROD1 and INS, along with anti-apoptotic effects, that culminate in increased insulin content and beta cell mass in vivo and ameliorate diet-induced glucose intolerance.\nDATA AVAILABILITY: The raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available at Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/ , can be accessed in GSE239382.", "claims": [{"id": "claim-method", "statement": "All data were evaluated for statistical significance by two-tailed Student’s t test for comparison of two groups or by ANOVA Tukey or Fisher’s least significant difference (LSD) test for more than two groups.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39404845", "locator": "sections[15] \"Statistical analyses\" paragraph 2", "quote": "All data were evaluated for statistical significance by two-tailed Student’s t test for comparison of two groups or by ANOVA Tukey or Fisher’s least significant difference (LSD) test for more than two groups."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available at Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/, can be accessed in GSE239382.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39404845", "locator": "sections[0] \"Abstract\" paragraph 5", "quote": "The raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available at Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/, can be accessed in GSE239382."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The paper tested statistical significance using two-tailed Student’s t test or ANOVA and made its raw and processed RNA-seq and ChIP-seq data publicly accessible through GEO under accession GSE239382.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:39404845", "locator": "sections[15] \"Statistical analyses\" paragraph 2", "quote": "All data were evaluated for statistical significance by two-tailed Student’s t test for comparison of two groups or by ANOVA Tukey or Fisher’s least significant difference (LSD) test for more than two groups."}, {"asset": "source:pmid:39404845", "locator": "sections[0] \"Abstract\" paragraph 5", "quote": "The raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available at Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/, can be accessed in GSE239382."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The paper tested statistical significance using two-tailed Student’s t test or ANOVA and made its raw and processed RNA-seq and ChIP-seq data publicly accessible through GEO under accession GSE239382.", "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:39404845"], "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:GSE239382"], "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:GSE239382"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:39404845", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1007/s00125-024-06286-2", "sha256": "sha256:801953264cafa4d25fd9476408f715955f54f8eceaa787150d92cf227fe802b3", "bytes": 52925, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1007/s00125-024-06286-2", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC11663170", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE239382", "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=GSE239382", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE239382", "version": null, "note": "The raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available at Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/, can be accessed in GSE239382.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available at Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/, can be accessed in GSE239382.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM7662985", "GSM7662986", "GSM7663942", "GSM7663943", "GSM7663944", "GSM7663945", "GSM7663946", "GSM7663947", "GSM7663948", "GSM7663949", "GSM7663950", "GSM7663951", "GSM7663952", "GSM7663953", "GSM7663954", "GSM7663955", "GSM7663956", "GSM7663957", "GSM7663958", "GSM7663959", "GSM7663960", "GSM7663961"], "sample_count": 22, "group_sizes": null, "group_sizes_basis": null, "platform": "16791;18573", "taxon": "Homo sapiens", "title": "Beta cell-specific PAK1 enrichment ameliorates diet-induced glucose intolerance by promoting insulin biogenesis and minimizing beta cell apoptosis", "resolution_checked_at": "2026-11-01T20:16:08Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE239382 not downloaded", "asset:data:geo:GSE239382 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "group_comparison", "specific": "anova", "label": "Group comparison", "dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "All data were evaluated for statistical significance by two-tailed Student’s t test for comparison of two groups or by ANOVA Tukey or Fisher’s least significant difference (LSD) test for more than two groups."}}, {"id": "method-2", "family": "multi_omics_integration", "specific": "pathway_progeny", "label": "Multi-omics integration", "dsl_operations": ["multiomics_factor_analysis", "joint_pathway_score"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["aligned_multi_layer_matrices"], "evidence": {"score": 0.8, "band": "high", "quote": "progeny"}}], "targets": [], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: anova."}, "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": ["GSE239382"], "resolved_accessions": ["GSE239382"], "statements": ["The raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available at Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/, can be accessed in GSE239382."], "basis": "The paper names GSE239382 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": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "assets": ["source:pmid:39404845", "data:geo:GSE239382"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE239382"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:35:08Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 16000, "completion_tokens": 1220, "cached_tokens": 256}}, "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:39404845", "type": "paper", "label": "pmid:39404845"}, {"id": "source:pmid:39404845", "type": "manuscript", "label": "PMID 39404845 full text"}, {"id": "data:geo:GSE239382", "type": "dataset", "label": "GEO GSE239382"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:39404845", "type": "paper", "label": "pmid:39404845"}, {"id": "source:pmid:39404845", "type": "manuscript", "label": "PMID 39404845 full text"}, {"id": "data:geo:GSE239382", "type": "dataset", "label": "GEO GSE239382"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-39404845", "type": "extraction", "used": ["source:pmid:39404845"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE239382", "type": "accession_resolution", "used": ["data:geo:GSE239382"], "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:39404845", "parent_hash": "sha256:9134f723c9467e39b952b3e72d98732c32b6c4b522894151c71aa5ddc96de771", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE239382 licence not read", "asset:data:geo:GSE239382 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"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": ["ameliorates diet-induced glucose intolerance in mice by promoting insulin biogenesis and minimisi", "ta cell-specific PAK1-expressing (iβPAK1-Tg) mice were fed a 45% HFD pre-induction for 3 weeks and", "without doxycycline induction. These HFD-fed mice were evaluated for GTT, ITT, 6 h fasting plasma i", "ised that beta cell-specific PAK1 enrichment in vivo can mitigate high-fat-diet (HFD)-induced glu"], "order_basis": "paper_text_order:35", "id": "assay:1"}, {"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": ["insulin biogenesis and minimising beta cell apoptosis.", "body composition, islet insulin content and apoptosis. RESULTS: Beta cell-specific PAK1 enrichment", "human islets resulted in decreased beta cell apoptosis and increased insulin content. RNA-seq showe", "islet insulin content and reduced beta cell apoptosis when compared with iβPAK1-Tg mice without do"], "order_basis": "paper_text_order:101", "id": "assay:2"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["pecifically in beta cells were used for bulk RNA-seq. Human EndoC-βH1 cells overexpressing myc-ta", "ell apoptosis and increased insulin content. RNA-seq showed an upregulation of INS gene transcrip", "ce. DATA AVAILABILITY: The raw and processed RNA-seq data and ChIP-seq data, which has been made"], "order_basis": "paper_text_order:609", "id": "assay:3"}, {"role": "data_generation", "definition_id": "chip_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["unoprecipitation (ChIP) and ChIP-sequencing (ChIP-seq). Novel doxycycline-inducible beta cell-spec", "LITY: The raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available"], "order_basis": "paper_text_order:743", "id": "assay:4"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["All data were evaluated for statistical significance by two-tailed Student’s t test for comparison of two groups or by ANOVA Tukey or Fisher’s least significant difference (LSD) test for more than two groups."], "order_basis": "consumes_earlier_output", "id": "assay:5"}]}