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Low birth weight and zygosity status is associated with defective muscle glycogen and glycogen synthase regulation in elderly twins

¹ Steno Diabetes Center, Gentofte, Denmark
² Copenhagen Muscle Research Centre, Institute of Exercise and Sport Sciences, University of Copenhagen, Denmark.
³ Odense University Hospital, Odense C, Denmark

Correspondence: pepn{at}steno.dk

Objective An adverse intrauterine environment indicated by both low birth weight and monozygosity is associated with an age - or time dependent reduction in glucose disposal and non-oxidative glucose metabolism in twins suggesting impaired regulation of muscle glycogen synthesis.

Research design and methods We measured the activities of glycogen synthase (GS), glycogen synthase kinase 3 (GSK3), GS phosphorylation and glycogen levels, in muscle biopsies obtained from 184 young and elderly twins before and after a euglycaemic, hyperinsulinaemic clamp.

Results Elderly monozygotic twins had significantly lower fractional GS activity in the face of higher glycogen and GS protein levels compared to dizygotic twins. In addition, we demonstrated strong non-genetic associations between birth weight and defect muscle glycogen metabolism in elderly – but not in younger - twins. Thus, for every 100 gram increase in birth weight within pairs, GS fractional activity, GS protein level and glycogen content was increased by 4.2, 8.7 and 4.5%, respectively, in elderly twins. Similarly, for every 100 gram increase in birth weight, GSK3 activity and GS phosphorylation at the sites 2, 2+2a and 3a+3b was decreased by 3.1, 9.0, 10.1 and 9.5%, respectively.

Conclusions The age- or time dependent non-genetic impact of birth weight on insulin action in twins may partly be explained by reduced insulin activation of muscle GS, mediated through increased GSK3 activity and GS phosphorylation. Reduced GS activity and negative feed-back inhibition of glycogen metabolism by glycogen per se may contribute to the insulin resistance in elderly monozygotic compared to dizygotic twins.

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