Skeletal muscle glucose metabolism in a dexamethasone model of insulin resistance in standardbred horses
The purpose of this thesis was to characterize the effects of dexamethasone treatment on (1) insulin sensitivity and glucose dynamics in healthy horses; and (2) selected aspects of insulin signalling and glucose metabolism in equine skeletal muscle. To address (1) six Standardbred horses received either dexamethasone or the equivalent volume of saline every 48 h over a 21-day period in a balanced crossover design. At the end of each treatment period, an insulin modified frequently-sampled intravenous glucose tolerance test with minimal model analysis was administered. To address (2) the same treatment protocol was used and the horses underwent a 2-h euglycemic-hyperinsulinemic clamp (EHC), including muscle biopsies before and after the EHC, to assess insulin sensitivity and measure GLUT-4 protein abundance, muscle glycogen content, glycogen synthase (GS) and hexokinase (HK) enzyme activities and Akt, GSK-3[alpha]/[beta] and PP-1[alpha] protein abundance and phosphorylation. Dexamethasone treatment significantly decreased insulin sensitivity and increased beta-cell responsiveness, increased HK activity and abrogated the insulin-stimulated increase in GS activity, Decreases in GSK-3[alpha]/[beta] Ser21/9 phosphorylation may, in part, explain the reduced GS activation.