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
- 1The Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania,
- 2Department of Information Engineering, University of Padova, Padova, Italy,
- 3The Departments of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
- To whom correspondence should be addressed: Bret H. Goodpaster, E-mail:
Dynamic PET imaging was performed using sequential tracer injections ([15O]-H2O, [11C]3-O-methylglucose (3-OMG), and [18F]fluoro-deoxyglucose (FDG) to quantify, respectively, skeletal muscle tissue perfusion (glucose delivery), kinetics of bi-directional glucose transport and glucose phosphorylation to interrogate the individual contribution and interaction amongst these steps in muscle insulin resistance (IR) in type 2 diabetes (T2D). PET imaging was performed in normal weight non-diabetic (N=5), obese non-diabetic (N=6) and obese subjects with T2D (N=7) during fasting conditions and separately during a 6-hour euglycemic insulin infusion at 40 mU/min-m2. Tissue tracer activities were derived specifically within soleus muscle with PET images and MRI. During fasting, NW, OB and T2D 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 (2-fold) than in NW (7-fold) or OB (6-fold). 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.
- Received August 14, 2013.
- Accepted September 20, 2013.
- © 2013 by the American Diabetes Association.
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