Direct measurement of the lumped constant for 2-deoxy-[1-<sup>14</sup>C]glucose in vivo in human skeletal muscle

Utriainen, Tapio; Lovisatti, S.; Mäkimattila, Sari; Bertoldo, Alessandra; Weintraub, Susan E; DeFronzo, Ralph A.; Cobelli, Claudio; Yki‐Järvinen, Hannele

doi:10.1152/ajpendo.2000.279.1.e228

Cited by 16 publications

(12 citation statements)

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“…18 F]FDG method used for the measurement of femoral glucose uptake (38), applying a lumped constant of 1.2, has been validated repeatedly for human skeletal muscle (30,47,48). Hepatic glucose output was assumed to be suppressed during hyperinsulinemia (40).…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone but Not Metformin Enhances Insulin- and Exercise-Stimulated Skeletal Muscle Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

et al. 2002

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Rosiglitazone, a thiazolidinedione, enhances peripheral insulin sensitivity in patients with type 2 diabetes. Because the synergic action of insulin and exercise has been shown to be decreased in insulin resistance, the aim of this study was to compare the effects of rosiglitazone and metformin on muscle insulin responsiveness at rest and during exercise in patients with type 2 diabetes. Therefore, 45 patients with newly diagnosed or diet-treated type 2 diabetes were randomized for treatment with rosiglitazone (4 mg b.i.d.), metformin (1 g b.i.d.), or placebo in a 26-week double-blind trial. Skeletal muscle glucose uptake was measured using fluorine-18 -labeled fluoro-deoxy-glucose and positron emission tomography (PET) during euglycemic-hyperinsulinemic clamp and one-legged exercise before and after the treatment period. Rosiglitazone (P < 0.05) and metformin (P < 0.0001) treatment lowered the mean glycosylated hemoglobin. The skeletal muscle glucose uptake was increased by 38% (P < 0.01) and whole-body glucose uptake by 44% in the rosiglitazone group. Furthermore, the exercise-induced increment during insulin stimulation was enhanced by 99% (P < 0.0001). No changes were observed in skeletal muscle or whole-body insulin sensitivity in the metformin group. In conclusion, rosiglitazone but not metformin 1) improves insulin responsiveness in resting skeletal muscle and 2) doubles the insulin-stimulated glucose uptake rate during physical exercise in patients with type 2 diabetes. Our results suggest that rosiglitazone improves synergic action of insulin and exercise. Diabetes 51:3479 -3485, 2002

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Section: Discussionmentioning

confidence: 99%

Rosiglitazone but Not Metformin Enhances Insulin- and Exercise-Stimulated Skeletal Muscle Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

et al. 2002

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“…In human skeletal muscle, the LC has been shown by two groups who utilized different approaches (28,29) to exhibit very small variations over a wide range of insulin concentrations with an average of 1.2.…”

Section: Methodsmentioning

confidence: 99%

“…To quantify the glucose kinetic model, i.e., k 5 , instead of calculating k 5 directly from Eq.13, with a fixed LC, potential interindividual differences in LC values were considered to account for interindividual differences in values for K and for k 1 , k 2 , k 3 , and k 4 . Thus, the [ 11 C]3-OMG model was utilized while assuming LC to have a Gaussian distribution with a mean of 1.2 and an SD of 0.08, as presented in previous studies (28,29), and utilizing maximum a posteriori Bayesian estimation (32). Statistics.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2006

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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...

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“…In both the rat heart and brain, the phosphorylation rate constant of [ 18 F]FDG is 60% that of glucose (28,29 (10,11,31), and this ratio was not altered under varying degrees of insulin stimulation or insulin resistance. Thus, although the absolute rates of glucose transport and phosphorylation may not be predicted with 100% accuracy, we feel that group comparisons are valid.…”

Section: Fig 6 Scatter Plot Of Lgu Determined By Leg-balance Technmentioning

confidence: 99%

Interactions of Impaired Glucose Transport and Phosphorylation in Skeletal Muscle Insulin Resistance

Williams¹,

Price

Kelley

2001

Diabetes

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It has been postulated that glucose transport is the principal site of skeletal muscle insulin resistance in obesity and type 2 diabetes, though a distribution of control between glucose transport and phosphorylation has also been proposed. The current study examined whether the respective contributions of transport and phosphorylation to insulin resistance are modulated across a dose range of insulin stimulation. Rate constants for transport and phosphorylation in skeletal muscle were estimated using dynamic positron emission tomography ( 18 F]FDG uptake determined by PET imaging strongly correlated with LGU across groups and across insulin doses (r ‫؍‬ 0.81, P < 0.001). Likewise, LGU correlated with PET parameters of glucose transport (r ‫؍‬ 0.67, P < 0.001) and glucose phosphorylation (r ‫؍‬ 0.86, P < 0.001). Glucose transport increased in response to insulin in the lean and obese groups (P < 0.05), but did not increase significantly in the type 2 diabetic group. A dose-responsive pattern of stimulation of glucose phosphorylation was observed in all groups of subjects (P < 0.05); however, glucose phosphorylation was lower in both the obese and type 2 diabetic groups compared with the lean group at the moderate insulin dose (P < 0.05). These findings indicate an important interaction between transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes.

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Direct measurement of the lumped constant for 2-deoxy-[1-¹⁴C]glucose in vivo in human skeletal muscle

Cited by 16 publications

References 47 publications

Rosiglitazone but Not Metformin Enhances Insulin- and Exercise-Stimulated Skeletal Muscle Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

Rosiglitazone but Not Metformin Enhances Insulin- and Exercise-Stimulated Skeletal Muscle Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

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

Interactions of Impaired Glucose Transport and Phosphorylation in Skeletal Muscle Insulin Resistance

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Direct measurement of the lumped constant for 2-deoxy-[1-14C]glucose in vivo in human skeletal muscle

Cited by 16 publications

References 47 publications

Rosiglitazone but Not Metformin Enhances Insulin- and Exercise-Stimulated Skeletal Muscle Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

Rosiglitazone but Not Metformin Enhances Insulin- and Exercise-Stimulated Skeletal Muscle Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

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

Interactions of Impaired Glucose Transport and Phosphorylation in Skeletal Muscle Insulin Resistance

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Direct measurement of the lumped constant for 2-deoxy-[1-¹⁴C]glucose in vivo in human skeletal muscle