{
  "abstract": "Background.Type 2 diabetes mellitus (T2D) involves progressive pancreatic beta-cell dysfunction, but conserved islet programs require cross-cohort and single-cell validation.\n\nMethods.We integrated four human islet transcriptomic cohorts using differential expression, random-effects meta-analysis, Hallmark scoring, and module scoring. To test generalizability without reusing held-out outcomes, modules were re-derived from three cohorts and scored in the fourth in rotating study-level cross-fitting, with expression-and detection-matched random gene-set nulls. Machine-learning performance in GSE164416 was estimated by nested stratified 5-fold cross-validation with DEG calling and feature selection repeated within each outer training fold. An annotation-compatible score was tested in GSE50244, and beta-cell validation used GSE221156.\n\nResults.Cross-fitted IsletDysfunctionScore effects were positive in all four held-out cohorts (d = 0.39-1.36; pooled Hedges g = 0.905, 95% CI 0.501-1.309, p = 1.14 x 10^-5, I2 = 5.5%). Matched gene-set null testing supported effects beyond random expectation in two cohorts. Nested machine learning yielded AUC = 0.960 (bootstrap 95% CI 0.900-0.997); GABRA2 and ENSG00000284653 were selected in all outer folds. The external 8-gene consensus-pool score achieved AUC = 0.907 (DeLong 95% CI 0.818-0.996), but its fixed threshold did not transfer. In GSE221156, the single-cell dysfunction-score analog increased and BetaIdentitySecretion decreased in T2D; ImmuneStress was nominally increased but did not survive false-discovery correction across the single-cell score family.\n\nConclusions.Human T2D islets show a reproducible stress/identity-loss framework that generalizes directionally under study-level cross-fitting and beta-cell-resolved validation. The candidate panel is a research transcriptomic signature requiring further validation.",
  "abstract_shown": true,
  "affiliations": [
    "Universidad Autónoma Metropolitana Unidad Cuajimalpa"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "R. Romero"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e8yerdexxan3s.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.06.08.26355184",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.06.08.26355184v2.full",
  "id": "e8yerdexxan3s",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.06.08.26355184v2",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "endocrinology"
    ],
    [
      "openalex",
      "2746|Pancreatic function and diabetes"
    ]
  ],
  "openalex": "W7164356475",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.06.08.26355184v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-08",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/e8yerdexxan3s.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:43Z",
      "native_id": "10.64898/2026.06.08.26355184",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.06.08.26355184v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:endocrinology",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Human Islet Transcriptomics in Type 2 Diabetes Reveals Conserved Dysfunction Axes and a Candidate Gene Panel",
  "title_text": "Human Islet Transcriptomics in Type 2 Diabetes Reveals Conserved Dysfunction Axes and a Candidate Gene Panel",
  "type": "preprint",
  "updated_at": "2026-10-30T12:21:43Z",
  "url": "https://research.draconitic.com/paper/e8yerdexxan3s",
  "venue": "medRxiv",
  "versions": []
}