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 Goodpaster, Alessandra Bertoldo, Jason M Ng, Koichiro Azuma, R Richard Pencek, Carol Kelley, Julie C Price, Claudio Cobelli, David E Kelley, Bret H Goodpaster, Alessandra Bertoldo, Jason M Ng, Koichiro Azuma, R Richard Pencek, Carol Kelley, Julie C Price, Claudio Cobelli, David E Kelley

Abstract

Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([(15)O]H2O, [(11)C]3-O-methylglucose [3-OMG], and [(18)F]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 [(11)C]3-OMG and [(18)F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [(18)F]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 [(18)F]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.

Figures

Figure 1
Figure 1
Glucose infusion rate and glucose infusion rate vs. K. A: Glucose infusion rate with each PET tracer. *A difference vs. NW, P < 0.05. White bars, NW; gray bars, OB; black bars, T2D. B: Glucose infusion rate vs. K (overall rate constant).
Figure 2
Figure 2
[11C]3-OMG tissue–activity curves for the basal (A) and insulin-stimulated (B) conditions. ♦, NW; ■, OB; ▲, T2D. % ID*kg, percent of the injected dose of tracer * body weight in kg.
Figure 3
Figure 3
Inward glucose transport (k3) at basal and insulin-stimulated conditions. White bars, NW; gray bars, OB; black bars, T2D. *A difference at P < 0.05 between T2D and both NW and OB.
Figure 4
Figure 4
[18F]FDG tissue–activity curves for the basal (A) and insulin-stimulated (B) conditions. ♦, NW; ■, OB; ▲, T2D. % ID*kg, percent of the injected dose of tracer * body weight in kg.
Figure 5
Figure 5
Fractional phosphorylation of glucose (k5) under basal and insulin-stimulated conditions. White bars, NW; gray bars, OB; black bars, T2D. *A difference at P < 0.05 between T2D and both NW and OB.
Figure 6
Figure 6
Control coefficients for delivery, transport, and phosphorylation. Control coefficients representing the distribution of control among the proximal steps of skeletal muscle (soleus) glucose metabolism under basal and insulin-stimulated conditions. White bars, NW; gray bars, OB; black bars, T2D. *P < 0.05 T2D vs. NW.

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