Other indirect evidence also supports the concept that the in vivo effect of insulin is determined, at least in part, by insulin’s own effect to reach metabolically active tissues by changing local blood flow distribution

patterns. Recently, the effects of systemic insulin infusion on transport and distribution kinetics of the extracellular marker, [14C]inulin, were studied in an animal model that allowed access to hindlimb lymph, a surrogate for interstitial fluid [27]. Insulin, at physiological concentrations, augments the access of the labeled inulin to insulin-sensitive tissues. In addition, access of macromolecules to insulin-sensitive tissues is impaired during diet-induced insulin resistance [26]. The presented data suggest that insulin redirects blood flow from non-nutritive vessels to nutritive capillary beds, resulting in an increased and more homogeneous overall capillary Ferroptosis inhibition perfusion termed “functional capillary recruitment.” The latter would enhance the access of insulin and glucose to a greater mass of muscle for metabolism. Consistent with such a mechanism in humans, insulin increases microvascular blood volume as measured with CEU or positron emission tomography, and concomitantly enhances the distribution

volume of glucose in human muscle [6,7,14]. Subsequently, capillary recruitment FK228 cell line was reported in the forearm of healthy humans following a mixed meal and was found to follow closely the time-dependent rise in plasma insulin [112]. In addition, insulin-mediated microvascular recruitment in the forearm was shown to be impaired in obese women when they were exposed to a physiological insulin clamp [16]. By directly visualizing capillaries in human skin, it has been demonstrated that systemic hyperinsulinemia is capable of increasing the number of perfused capillaries [22,100]. Comparable to insulin-mediated microvascular recruitment in the forearm [16], the action of insulin on capillary recruitment is impaired in obese subjects [21,22]. Further insight

into the complex relationships among vasodilatation, blood flow velocity, and capillary recruitment was gained through measurement of the capillary permeability-surface area PS for glucose and insulin. PS for a substance describes its capacity to reach the interstitial fluid. This depends on the permeability and the capillary surface Molecular motor area, of which the latter in turn partly depends on the amount of perfused capillaries. A recent investigation employing direct measurements of muscle capillary permeability showed that PS for glucose increased after an oral glucose load, and a further increase was demonstrated during an insulin infusion [38]. Importantly, the increase of PS was exerted without any concomitant change in total blood flow. It was concluded that the insulin-mediated increase in PS seen after oral glucose is important for the glucose uptake rate in normal muscle [38].