{
  "abstract": "Insulin resistance is commonly framed as impaired receptor or post-receptor signaling, but that description begins only after insulin has reached a receptor-accessible compartment. In vivo insulin action also depends on delivery through the microcirculation, passage across the endothelium, distribution within interstitial fluid, and the balance between secretion and organ-specific clearance. This review integrates these upstream processes as an insulin-access continuum and asks whether diabetes can create a physiologically meaningful mismatch between plasma insulin and the insulin available to target cells. Human studies consistently show that skeletal-muscle interstitial insulin is lower than plasma insulin during hyperinsulinemia, although evidence that this gradient is uniformly greater in type 2 diabetes is mixed. Obesity, microvascular dysfunction, endothelial insulin resistance, extracellular-matrix remodeling, and altered tissue geometry can plausibly delay or spatially distort insulin access, but structural abnormalities alone do not prove a diffusion barrier. Clearance adds a second layer: reduced clearance may initially support compensation, whereas persistent hyperinsulinemia or, in selected phenotypes, excessive clearance may generate maladaptive exposure. We therefore view insulin resistance as a coupled exposure–response disorder rather than an exclusively intracellular defect. The framework is testable: informative studies should align plasma insulin and C-peptide kinetics with microvascular exchange, interstitial insulin, tissue glucose uptake, and downstream signaling. Such synchronized phenotyping can help distinguish causal access defects from compensation or association.",
  "abstract_shown": true,
  "affiliations": [
    "Chengdu University of Traditional Chinese Medicine"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Renjie Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xinxia Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3zkd615zp0msf.bib",
  "cited_by": 0,
  "doi": "10.3389/fendo.2026.1981356",
  "fulltext_url": "https://europepmc.org/articles/PMC13688250",
  "id": "3zkd615zp0msf",
  "issns": [
    "1664-2392"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1981356/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2712|Diabetes, Cardiovascular Risks, and Lipoproteins"
    ]
  ],
  "openalex": "W7220982591",
  "pdf_url": "https://europepmc.org/articles/PMC13688250?pdf=render",
  "pmcid": "PMC13688250",
  "pmid": "42923900",
  "published": "2026-10-08",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/3zkd615zp0msf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:20Z",
      "native_id": "10.3389/fendo.2026.1981356",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1981356/full"
    },
    {
      "first_seen": "2026-10-30T12:20:33Z",
      "native_id": "MED:42923900",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42923900"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2712|Diabetes, Cardiovascular Risks, and Lipoproteins",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "The diabetic interstitium as an overlooked layer of insulin resistance: vascular delivery, tissue transport, and insulin clearance",
  "title_text": "The diabetic interstitium as an overlooked layer of insulin resistance: vascular delivery, tissue transport, and insulin clearance",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:33Z",
  "url": "https://research.draconitic.com/paper/3zkd615zp0msf",
  "venue": "Frontiers in Endocrinology",
  "versions": []
}