Interactions Among Glucose Delivery, Transport, and Phosphorylation That Underlie Skeletal Muscle Insulin Resistance in Obesity and Type 2 Diabetes: Studies With Dynamic PET Imaging
- Bret H. Goodpaster1⇑,
- Alessandra Bertoldo2,
- Jason M. Ng1,
- Koichiro Azuma1,
- R. Richard Pencek1,
- Carol Kelley1,
- Julie C. Price3,
- Claudio Cobelli2 and
- David E. Kelley1
- 1Department of Medicine, University of Pittsburgh, Pittsburgh, PA
- 2Department of Information Engineering, University of Padova, Padova, Italy
- 3Department of Radiology, University of Pittsburgh, Pittsburgh, PA
- Corresponding author: Bret H. Goodpaster, .
Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([15O]H2O, [11C]3-O-methylglucose [3-OMG], and [18F]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·m−2·min−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 [11C]3-OMG and [18F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [18F]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 [18F]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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/DB13-1249/-/DC1.
- Received August 14, 2013.
- Accepted November 6, 2013.
- © 2014 by the American Diabetes Association.
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