Plasma insulin must traverse the vascular endothelium to reach its major sites of action on myocytes and adipocytes. In study simultaneously measuring plasma and lymphatic insulin concentrations in normal, conscious dogs during euglycemic insulin clamps it was found that the steady-state plasma insulin concentration was consistently higher than lymph with a rough ratio of 3:2 during the basal period. In addition, while plasma insulin concentration rose quickly to reach the steady-state during the insulin clamp, the lymph insulin concentration rose very slowly indicating a barrier function of the vascular endothelium. Most importantly, this study showed that the dynamics of glucose disposal correlated very strikingly with the insulin concentration in lymph but not plasma, suggesting that trans-capillary insulin transport is a rate limiting step for peripheral insulin action. Consistent with this, direct injection of insulin into canine skeletal muscle in vivo was recently noted to significantly hasten the onset of muscle glucose utilization compared with intravenously delivered insulin. Multiple other studies also support such an important role of vascular endothelium during insulin clamp by measurement of the insulin concentration within skeletal muscle interstitium in humans and animals using either lymphatic sampling or microdialysis methods. Results obtained using either method indicate that even after several hours of steady state hyperinsulinemia, muscle interstitial insulin concentration is only 40-50% of that in plasma and the time course for insulin-mediated glucose disposal during the euglycemic clamp correlates strongly with interstitial but not plasma insulin concentrations. Based on these findings, it has been estimated that slow trans-endothelial insulin transport may account for 30-40% of insulin resistance seen with human obesity or type-2 diabetes.
Last date updated on March, 2021