The diabetic interstitium as an overlooked layer of insulin resistance: vascular delivery, tissue transport, and insulin clearance

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.