Jason M Ng1, Alessandra Bertoldo, Davneet S Minhas, Nicole L Helbling, Paul M Coen, Julie C Price, Claudio Cobelli, David E Kelley, Bret H Goodpaster. 1. Division of Endocrinology and Metabolism Department of Medicine (J.M.N., N.L.H., B.H.G.) and Departments of Radiology (D.S.M., J.C.P.) and Health and Physical Activity (P.M.C.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15231; Department of Information Engineering (A.B., C.C.), University of Padova, Padova, Italy; and Merck, Sharp, and Dohme Corporation (D.E.K.), Rahway, New Jersey 07065.
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.
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.
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