Abstract

Abstract 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.

Abstract Research design and methods We measured the activities of glycogen synthase (GS), glycogen synthase kinase 3α (GSK3α), GS phosphorylation and glycogen levels, in muscle biopsies obtained from 184 young and elderly twins before and after a euglycaemic, hyperinsulinaemic clamp.

Abstract 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, GSK3α 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.

Abstract 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 GSK3α 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.