The diabetic interstitium as an overlooked layer of insulin resistance: vascular delivery, tissue transport, and insulin clearance
- 1Chengdu University of Traditional Chinese Medicine
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.
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BibTeX
@article{wang2026diabetic,
title = {{The diabetic interstitium as an overlooked layer of insulin resistance: vascular delivery, tissue transport, and insulin clearance}},
author = {Renjie Wang and Xinxia Zhang},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1981356},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1981356/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The diabetic interstitium as an overlooked layer of insulin resistance: vascular delivery, tissue transport, and insulin clearance
AU - Renjie Wang
AU - Xinxia Zhang
PY - 2026
DA - 2026/10/08
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1981356
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1981356/full
AB - 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.
SN - 1664-2392
ER -