Motivation Maladaptive microvascular changes are of major interest in understanding the physiological consequences of Type 2 Diabetes (T2D). Several studies have demonstrated alterations in skeletal muscle microvasculature in humans [5], and in animal models of T2D [1,3]. Elevated levels of glucose and insulin in obese Zucker Diabetic Fatty (ZDF) rats have been shown to cause decreases to capillary Red Blood Cell (RBC) supply rate, RBC oxygen saturation, and Functional Capillary Density (FCD) [1]. Structural changes to the vasculature have been quantified in capillaries, but the direct geometric effect higher heterogeneity and overall decreased capillary density has on tissue oxygenation has not been entirely elucidated. The compounding effect of heterogeneous blood flow distribution within tissue also may serve to impair mass transport and exchange of humoral substances with tissue. We aim to describe how basic changes to capillary geometry effect both tissue oxygenation and the uptake of blood glucose. Methods Capillary density and hemodynamic measurements (RBC supply rate, velocity, and oxygen saturation) from a previous study were used as input parameters for the oxygen transport and glucose uptake models [1]. These data were collected using in vivo intravital video microscopy of rat extensor digitorum longus muscle. A three-dimensional parallel capillary geometry was randomly generated based on mean volumetric vascular density from reconstructed in vivo networks. Six variants of the geometry were created that correspond with the measured densities for Mean FCD, High FCD (Mean FCD + 1 standard deviation), and Low FCD (Mean FCD – 1 standard deviation) for both lean and obese ZDF animals. Hemodynamics and saturation values from ZDF lean and obese animals were assigned to the vessels in the generated geometries and the resulting RBC supply rates were scaled to create a Mean RBC SR, High RBC SR (Mean SR + 1 standard deviation) and Low RBC SR (Mean SR – 1 standard deviation) for each group. By combining these varying cases we produced 9 cases to represent the variability seen in the ZDF Lean group and 9 cases for the ZDF Obese group. A previously described finite difference model of oxygen transport [4] was used to calculate PO2 in each of the 18 cases using an isotropic volume descritization with 2 micron spacing. The transport of glucose and insulin from capillaries, and through the interstitial space to skeletal muscle fibers was determined using a novel finite element model. The cross-sectional distribution of capillaries from the Mean FCD, High FCD, and Low FCD parallel networks for Lean and Obese groups were used to define the two-dimensional capillary geometry. Results Mean volumetric capillary densities were 1.46±0.38% and 1.33±0.34% of the total bounding volume for ZDF lean and Obese groups respectively. Mean volumetric RBC SR calculated from experimental measurements and applied simulation cases were 8.40E-±0.63 and 6.71±1.21 mL RBC × mL Tissue-1 × s-1 for ZDF Lean and Obese groups. Minimum tissue PO2 in low FCD and low SR cases were 30.3 mmHg in the lean simulation and 25.1 mmHg in the obese (Figure 1). Visualization of the combined effect of altered capillary density and SR on tissue PO2 in edge cases (High SR and High FCD; Low SR and Low FCD) for both groups is shown in Figure 1. Interstitial postprandial glucose concentration in the low FCD obese case was 7.3 mmol/L compared to 7.0 mmol/L in the high FCD lean glucose case. Glucose uptake rate was 17.4% lower in the low FCD obese case compared to the high FCD lean. Substantially higher heterogeneity of glucose concentration was observed in the low FCD obese case compared to the high FCD lean simulation (Figure 2). Discussion Our model predicts that substantial decreases to FCD should cause little impact on mean tissue PO2 and minor increase in PO2 heterogeneity given maintenance of RBC SR. Changes to mean tissue PO2 were found to scale linearly with RBC SR as has been observed previously [2]. The compound effect of decreased FCD and RBC SR yield a 10% lower tissue PO2 in the obese edge case compared to the lean (Figure 1); the driving volumes into hypoxia. With respect to tissue oxygenation, the changes related to decreased FCD were modest. The glucose uptake model predicted interstitial glucose concentrations would vary due to capillary density (Figure 2). The presence of a significant gradients between the abluminal side of capillary endothelium and muscle fibres should be necessary in order to drive glucose uptake. Further work is needed to investigate the additional effect of higher metabolism and high heterogeneity of blood flow on mass transport into skeletal muscle.