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

Abstract

Skeletal muscle accounts for a large proportion of insulinstimulated 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 18 F]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 [ 11 C]3-OMG substantially and strongly stimulated the kinetics of bidirectional glucose transport. Uptake of [ 11 C]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 [ 18 F]FDG was 65% greater in soleus compared with tibialis anterior muscle, a larger difference than for [ 11 C]3-OMG (P < 0.01), indicating an added importance of glucose phosphorylation in defining insulin sensitivity. Analysis of the distribution of control during insulinstimulated 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. Diabetes 55:3028 -3037, 2006 I nsulin accelerates the clearance of glucose from plasma into tissues. Uptake of glucose into skeletal muscle is a powerful determinant of this systemic effect (1,2). It is generally considered that much of the control of rates of glucose uptake into skeletal muscle is posited at the proximal steps of glucose delivery, transport, and phosphorylation (3-6) and that among these, stimulation of GLUT4 translocation by insulin is pivotal. Because only slight accumulation of free glucose occurs within muscle during insulin-stimulated conditions, it is cited as clear support for transport as the dominant locus of control rather than more distal steps (5,7-9). However, an absence of glucose accumulation could also be consistent with constraint (and hence rate control) proximal to glucose transport, at glucose delivery (10). There is a general conceptual paradigm regarding what primarily determines control manifest by substrate delivery, and this concerns tissue permeability for a substrate (11). When permeability is low, and with regard to muscle, glucose transport capacity can be considered to represent a permeability factor; rates of delivery should have only minor influence, and, conversely, increases of permeability should proportionately increase control manifest by d...

A new Michaelis–Menten‐based kinetic model for transport and phosphorylation of glucose and its analogs in skeletal muscle

“…Since [ 18 F]6FDG is not phosphorylated, a priori, we expected insulin stimulation to impact the rate at which it achieves steady state between interstitial and intracellular spaces but not to impact the steady state concentration. Importantly, the model offers a mechanistic explanation for the increase of tissue radioactivity during EH conditions that was observed with nonphosphorylated analogs both in our own prior data 21 using [ 18 F]6FDG and those of Bertoldo et al 4 using [ 11 C]3OMG. It is well known that insulin increases the number of functional GLUT4 transporters at the plasma membrane.…”

“…4 They endeavored to more reliably resolve the transport and phosphorylation steps. This approach seems appropriate, yet challenges remain: First, [ 11 C]3OMG, a reference tracer for glucose transport in PET has a limitation in its clinical use due to the 20-min half-life of 11 C. Second, a value for a lumped constant (LC) must be assumed so that one may infer the glucose metabolic rate from that of the analog, whereas the value depends on plasma and tissue glucose concentrations.…”

Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal

“…In Vivo Glucose Distribution in Insulin-Resistant DIO mice: PET-CT Scanning PET combined with X-ray CT scan analysis is a noninvasive in vivo imaging approach that has been used to study glucose disposal in lean healthy adults (16), and in insulin-resistant individuals (17) and in individuals with type 2 diabetes (18), as well as to study glucose disposal in rodents (19). We here used PET-CT scanning together with the glucose tracer molecule 18 F-FDG to study tissuespecific accumulation of glucose in HFD-fed animals.…”

Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature

“…For each of these substrates the control systems regulating delivery and tissue uptake are likely to be quite complex. This is emphasized by work from the laboratories of Wasserman (110) and Kelley (11,12,116). Both laboratories have provided evidence for a distributed control of glucose's metabolism between tissue delivery, transit through the interstitium, plasma membrane glucose transport, and hexokinase activity.…”