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Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([[sup.15]O][H.sub.2]O, [[sup.11]C]3-O-methylglucose [3-OMG], and [[sup.18]F]fluorodeoxyglucose [FDG]) to quantify, respectively, skeletal muscle tissue perfusion (glucose delivery), kinetics of bidirectional glucose transport, and glucose phosphorylation to interrogate the individual contribution and interaction among these steps in muscle insulin resistance (IR) in type 2 diabetes (T2D). PET imaging was performed in normal weight nondiabetic subjects (NW) (n = 5), obese nondiabetic subjects (OB) (n = 6), and obese subjects with T2D (n = 7) during fasting conditions and separately during a 6-h euglycemic insulin infusion at 40 mU x [m.sup.-2] x [m.sup.-1]. Tissue tracer activities were derived specifically within the soleus muscle with PET images and magnetic resonance imaging. During fasting, NW, OB, and T2D subjects had similar [[sup.11]C]3-OMG and [[sup.18]F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [[sup.18]F]FDG uptake by muscle was inversely correlated with systemic IR (P < 0.001). The increase in insulin-stimulated glucose transport was less (P < 0.01) in T2D (twofold) than in NW (sevenfold) or OB (sixfold) subjects. The fractional phosphorylation of [[sup.18]F]FDG during insulin infusion was also significantly lower in T2D (P < 0.01). Dynamic triple-tracer PET imaging indicates that skeletal muscle IR in T2D involves a severe impairment of glucose transport and additional impairment in the efficiency of glucose phosphorylation. Diabetes 2014;63:1058-1068 | DOI: 10.2337/DB13-1249, The rate of glucose uptake into skeletal muscle during insulin-stimulated conditions is a strong determinant of systemic insulin sensitivity (and insulin resistance [IR]). Much of the control of glucose uptake [...]