Interactions among Glucose Delivery, Transport and Phosphorylation that Underlie Skeletal Muscle Insulin Resistance in Obesity and Type 2 Diabetes: Studies with Dynamic PET Imaging

  1. David E. Kelley1
  1. 1The Departments of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania,
  2. 2Department of Information Engineering, University of Padova, Padova, Italy,
  3. 3The Departments of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
  1. To whom correspondence should be addressed: Bret H. Goodpaster, E-mail: Bret.Goodpaster{at}FLHosp.org

Abstract

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.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.