Dynamic PET imaging reveals heterogeneity of skeletal muscle insulin resistance

Abstract

Purpose: Skeletal muscle insulin resistance (IR) often precedes hyperglycemia and type 2 diabetes. However, variability exists within different skeletal muscle types and can be influenced by 3 primary steps of control: glucose delivery, transport, and phosphorylation. We performed dynamic positron emission tomography imaging studies to determine the extent to which heterogeneity in muscle type and control of insulin action contribute to IR.

Methods: Thirteen volunteers from normal weight to obese underwent dynamic positron emission tomography imaging of [15O]H2O, [11C]3-O-methylglucose, and [18F]fluorodeoxyglucose, measuring delivery, transport, and phosphorylation rates, respectively, in soleus and tibialis anterior muscle during a hyperinsulinemic-euglycemic clamp. Subjects were classified as insulin-sensitive (IS) or insulin-resistant (IR) based on the median systemic glucose infusion rate needed to maintain euglycemia.

Results: In soleus, transport kinetic rates were significantly higher (P<.05) in IS (0.126±0.028 min(-1)) vs IR (0.051±0.008 min(-1)) subjects. These differences were not as evident in tibialis anterior. These differences were paralleled in overall insulin-stimulated tissue activity, higher in IS (0.017±0.001 mL·cm3·min(-1)) vs IR (0.011±0.002 mL·cm3·min(-1)) in soleus (P<.05), without significant differences in tibialis anterior. No significant differences were observed for either muscle in delivery or phosphorylation. Both muscle types displayed a control shift from an even distribution among the steps in IS to transport exerting greater control of systemic insulin sensitivity in IR.

Conclusion: Lower glucose transport rates are the major feature underlying IR preceding type 2 diabetes, although substantial heterogeneity in insulin action across muscle types highlight the complexity of skeletal muscle IR.

Figure 1.

Glucose delivery (top), transport (middle), and phosphorylation (bottom) kinetics in soleus (left) and tibialis anterior (right) muscles. The graphs represent kinetic parameters for skeletal muscle glucose metabolism with insulin stimulation of 40 mU · m⁻² · min⁻¹. Black bars represent IR, and white bars represent IS. *, P < .05.

Figure 2.

Control coefficient distribution under insulin stimulation. Black bars represent delivery, white bars represent transport, and gray bars represent phosphorylation. *, Significant difference between IS and IR (P < .05).