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Impact of Genetic Versus Environmental Factors on the Control of Muscle Glycogen Synthase Activation in Twins

¹ Steno Diabetes Center, Gentofte, Denmark
² Copenhagen Muscle Research Centre, Institute of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
³ Danish Twin Registry, University of Southern Denmark, Odense, Denmark
⁴ Department of Endocrinology, Odense University Hospital, Odense, Denmark

Storage of glucose as glycogen accounts for the largest proportion of muscle glucose metabolism during insulin infusion in normal and insulin-resistant subjects. Studies in first-degree relatives have indicated a genetic origin of the defective insulin activation of muscle glycogen synthase (GS) in type 2 diabetes. The aim of this study was to evaluate the relative impact of genetic versus nongenetic factors on muscle GS activation and regulation in young and elderly twins examined with a 2-h euglycemic-hyperinsulinemic (40 mU · m^–2 · min^–1) clamp combined with indirect calorimetry and excision of muscle biopsies. The etiological components were determined using structural equation modeling. Fractional GS activity; GS phosphorylation at sites 2, 2 + 2a, and 3a + 3b corrected for total GS protein; and GS kinase 3 (GSK3) activity were similar in both age groups, whereas total GS activity and protein were lower in elderly compared with younger twins. GS fractional activity increased significantly during insulin stimulation in both young and elderly twins. Conversely, there was a significant decrease in GS phosphorylation at site 3a + 3b and GSK3 activity during insulin stimulation in both age groups, whereas GS phosphorylation at site 2 and 2 + 2a only decreased on insulin stimulation in the younger twins. The increment in whole-body glucose disposal (R_d) and nonoxidative glucose metabolism (insulin – basal) correlated significantly with the increment in GS fractional activity. Fractional GS activity had a major environmental component in both age groups. GSK3 activity exhibited a genetic component in young (basal: a² = 0.42; insulin: a² = 0.58) and elderly (insulin: a² = 0.56) twins. Furthermore, GS phosphorylation at site 2 (insulin: a² = 0.69) in the elderly and at site 3a + 3b (insulin: a² = 0.50) in the young twins had a genetic component. In conclusion, GSK3 activity and GS phosphorylation, particularly at sites 2 and 3a + 3b, had major genetic components. Total and fractional GS activities per se were, on the other hand, predominantly controlled by environmental factors. Moreover, GS activity was intact with increasing age, despite a significant reduction in nonoxidative glucose metabolism.

Abbreviations: G6P, glucose-6-phosphate; GS, glycogen synthase; GSK3, GS kinase 3; HRP, horseradish peroxidase; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; TBST, Tris-buffered saline plus Tween

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