Interactions Between Delivery, Transport, and Phosphorylation of Glucose in Governing Uptake Into Human Skeletal Muscle

Abstract

Skeletal muscle accounts for a large proportion of insulin-stimulated glucose utilization. It is generally regarded that much of the control over rates of uptake is posited within the proximal steps of delivery, transport, and phosphorylation of glucose, with glucose transport as the main locus of control. Whether insulin modulates the distribution of control across these steps and in what manner remains uncertain. The current study addressed this in vivo using dynamic positron emission tomography (PET) imaging of human muscle with sequential injections of three tracers ([¹⁵O]H₂O, [¹¹C]3-O-methyl glucose [3-OMG], and [¹⁸F]fluoro-deoxy glucose [FDG]) that enabled quantitative determinations of glucose delivery, transport, and its phosphorylation, respectively. Lean, healthy, research volunteers were studied during fasting conditions (n = 8) or during a euglycemic insulin infusion at 30 mU/min per m² (n = 8). PET images were coregistered with magnetic resonance imaging to contrast glucose kinetics in soleus, a highly oxidative muscle, with tibialis anterior, a less oxidative muscle. During fasting conditions, uptake of [¹¹C]3-OMG was similar in soleus and tibialis anterior muscles, despite higher delivery to soleus (by 35%; P < 0.01). Uptake of [¹⁸F]FDG was also similar between muscle during fasting, and glucose transport was found to be the dominant locus of control (90%) for glucose uptake under this condition. Insulin increased uptake of [¹¹C]3-OMG substantially and strongly stimulated the kinetics of bidirectional glucose transport. Uptake of [¹¹C]3-OMG was higher in soleus than tibialis anterior muscle (by 22%; P < 0.01), a difference partially due to higher delivery, which was again found to be 35% higher to soleus (P < 0.01). The uptake of [¹⁸F]FDG was 65% greater in soleus compared with tibialis anterior muscle, a larger difference than for [¹¹C]3-OMG (P < 0.01), indicating an added importance of glucose phosphorylation in defining insulin sensitivity. Analysis of the distribution of control during insulin-stimulated conditions revealed that most of the control was posited at delivery and transport and was equally divided between these steps. Thus, insulin evokes a broader distribution of control than during fasting conditions in governing glucose uptake into skeletal muscle. This redistribution of control is triggered by the robust stimulation of glucose transport, which in turn unmasks a greater dependence upon delivery and glucose phosphorylation.