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The Experimental Type 2 Diabetes Therapy Glycogen Phosphorylase Inhibition Can Impair Aerobic Muscle Function During Prolonged Contraction

¹ Centre for Integrated Systems Biology and Medicine, School of Biomedical Science, University of Nottingham, Nottingham, U.K
² Department of Cardiovascular Pharmacology, Pfizer Global Research and Development, St. Louis Laboratories, Chesterfield, Missouri
³ Centre for Molecular Biology, Karolinska Institutet, Stockholm, Sweden

Address correspondence and reprint requests to Dr. James Timmons, Center for Genomics and Bioinformatics and Department of Physiology and Pharmacology, Karolinska Institutet, Berzelius Väg 35, Stockholm, Sweden, 171 77. E-mail: jamie.timmons{at}gmail.com

Abbreviations: GPi, glycogen phosphorylase inhibitors; GPS, gastrocnemius-plantaris-soleus; HMP, hexosemonophosphate; QOL, quality of life

Glycogen phosphorylase inhibition represents a promising strategy to suppress inappropriate hepatic glucose output, while muscle glycogen is a major source of fuel during contraction. Glycogen phosphorylase inhibitors (GPi) currently being investigated for the treatment of type 2 diabetes do not demonstrate hepatic versus muscle glycogen phosphorylase isoform selectivity and may therefore impair patient aerobic exercise capabilities. Skeletal muscle energy metabolism and function are not impaired by GPi during high-intensity contraction in rat skeletal muscle; however, it is unknown whether glycogen phosphorylase inhibitors would impair function during prolonged lower-intensity contraction. Utilizing a novel red cell–perfused rodent gastrocnemius-plantaris-soleus system, muscle was pretreated for 60 min with either 3 µmol/l free drug GPi (n = 8) or vehicle control (n = 7). During 60 min of aerobic contraction, GPi treatment resulted in 35% greater fatigue. Muscle glycogen phosphorylase a form (P < 0.01) and maximal activity (P < 0.01) were reduced in the GPi group, and postcontraction glycogen (121.8 ± 16.1 vs. 168.3 ± 8.5 mmol/kg dry muscle, P < 0.05) was greater. Furthermore, lower muscle lactate efflux and glucose uptake (P < 0.01), yet higher muscle VO₂, support the conclusion that carbohydrate utilization was impaired during contraction. Our data provide new confirmation that muscle glycogen plays an essential role during submaximal contraction. Given the critical role of exercise prescription in the treatment of type 2 diabetes, it will be important to monitor endurance capacity during the clinical evaluation of nonselective GPi. Alternatively, greater effort should be devoted toward the discovery of hepatic-selective GPi, hepatic-specific drug delivery strategies, and/or alternative strategies for controlling excess hepatic glucose production in type 2 diabetes.

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