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Glucose Transport and Phosphorylation in Skeletal Muscle in Obesity: Insight from a Muscle-Specific Positron Emission Tomography Model

Departments of Medicine (K.V.W., D.E.K.) and Radiology (J.C.P.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Information Engineering, University of Padova (A.B., B.M., C.C.), 35131 Padova, Italy

Address all correspondence and requests for reprints to: Katherine Williams, M.D., M.P.H., Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, 809N Montefiore University Hospital, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213. E-mail: williamsk{at}msx.dept-med.pitt.edu.

A controversial area in understanding the contribution of obesity to skeletal muscle insulin resistance is the distribution of control of glucose metabolism across proximal steps of glucose delivery, trans-membrane transport, and intracellular trapping via phosphorylation. Dynamic positron emission tomography (PET) imaging of skeletal muscle [¹⁸F]2-deoxy-2-D-glucose (¹⁸F-FDG) uptake provides an in vivo method for assessment of these steps in humans. In the current study we have examined the application of a four-compartment skeletal muscle-specific model for assessment of ¹⁸F-FDG metabolism that takes interstitial ¹⁸F-FDG kinetics into account and compared this to the classic three-compartment model in lean and obese volunteers. We assessed the effects of insulin infusions at three rates (0, 40, and 120 mU/m²·min). In comparison with the classic model, the skeletal muscle-specific model reveals more clearly definable effects of insulin on transmembrane glucose transport and an impairment of this response in obesity. Compared with the classic model for assessment of ¹⁸F-FDG metabolism, both the skeletal muscle-specific and the classic model indicate that, with respect to distribution of control, glucose phosphorylation has an important effect at low to moderate levels of insulin stimulation in both lean and obese subjects.

This work was supported by a Mid-Career Development Award for Patient-Oriented Research (NIDDK, NIH; K23-DK-02782), a Mentored Patient-Oriented Research Career Development Award (NIDDK, NIH; K24-DK-02647), University Pittsburgh General Clinical Research Center (5MO1-RR-00056), and the Obesity and Nutrition Research Center (NIDDK, NIH; P30-DK-46204-01). This work was also supported by a grant from the Italian Ministero dell’Istruzione, dell’Università e della Ricerca (MURST 40%), Modelistica e Imaging Quantitativo del Sistema Serotoninergico con Tomografia ad Emissione di Positroni, and NIH Grant RR-12609.

Abbreviations: 2D or 3D, Two- or three-dimensional; ¹⁸F-FDG, [¹⁸F]2-deoxy-2-D-glucose; ¹⁸F-FDG-6-P, [¹⁸F]2-deoxy-2-D-glucose-phosphate; IR, insulin resistance; 3K, three-rate constant; 5K, five-rate constant; PET, positron emission tomography.

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