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1 Diabetes and Obesity Research Program, Garvan Insititute of Medical Research, Darlinghurst, New South Wales, Australia
2 Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
3 Diabetes and Obesity Research Program, Garvan Insitute of Medical Research, Darlinghurst, New South Wales, Australia; School of Health Sciences, University of Wollongong, Wollongong, New South Wales, Australia
4 Diabetes and Metabolism Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
5 Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales, 2010, Australia; St. Vincent's Hospital Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
6 Diabetes and Obesity Research Program, Garvan Insititute of Medical Research, Darlinghurst, New South Wales, Australia; St. Vincent's Hospital Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
* To whom correspondence should be addressed. E-mail: e.kraegen{at}garvan.org.au.
Hyperglycemia is a defining feature of type 1 and 2 diabetes. Hyperglycemia also causes insulin resistance and we have recently demonstrated that hyperglycemia generated by glucose infusion results in insulin resistance after 5h but not after 3h. The aim of this study was to investigate possible mechanism(s) by which glucose infusion causes insulin resistance in skeletal muscle, and in particular to examine whether this was associated with changes in insulin signaling. Hyperglycemia (~10mM) was produced in cannulated male Wistar rats for up to 5h. The glucose infusion rate required to maintain this hyperglycemia progressively lessened over 5h (by 25%, P < 0.0001 at 5h) without any alteration in plasma insulin levels consistent with the development of insulin resistance. Muscle glucose uptake in vivo (44%, P < 0.05) and glycogen synthesis rate (52%, P < 0.001) were reduced after 5h compared with 3h infusion. Despite these changes there was no decrease in the phosphorylation state of multiple insulin signaling intermediates (IR, Akt, AS160, GSK3
) over the same time course. In isolated soleus strips taken from control, 1h or 5h glucose infused animals, insulin stimulated 2-deoxyglucose transport was similar, but glycogen synthesis was significantly reduced in the 5h muscle sample (68% vs 1h sample, P < 0.001). These results suggest that the reduced muscle glucose uptake in rats after 5h of acute hyperglycemia is due more to the metabolic effects of excess glycogen storage than a defect in insulin signaling or glucose transport.
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