Strain‐Dependent Differences for Suppression of Insulin‐Stimulated Glucose Uptake in Skeletal and Cardiac Muscle by Ethanol

Abstract

Chronic ethanol (EtOH) consumption impairs the ability of insulin to suppress hepatic glucose production in a strain-dependent manner, with hepatic insulin resistance being greater in Long-Evans (LE) than Sprague-Dawley (SD) rats. We assessed whether strain differences exist for whole-body and tissue glucose uptake under basal and insulin-stimulated conditions and whether they were associated with coordinate strain-dependent elevations in muscle cytokines. Male rats (160 g) were provided the Lieber-DeCarli EtOH-containing (36% total energy) diet or pair-fed a control diet for 8 weeks. Rats were studied in the basal state or during a euglycemic hyperinsulinemic clamp, and whole-body glucose flux assessed using (3) H-glucose and in vivo tissue glucose uptake by (14) C-2-deoxyglucose. EtOH impaired whole-body insulin-mediated glucose uptake (IMGU) more in SD than LE rats. This difference was due to impaired IMGU by gastrocnemius and heart in EtOH-fed SD versus LE rats. However, decreased IMGU in adipose tissue (epididymal and perirenal) produced by EtOH was comparable between strains. EtOH-induced insulin resistance in muscle from SD rats was associated with reduced AKT and AS160 phosphorylation and plasma membrane-localized GLUT4 protein as well as enhanced phosphorylation of c-Jun N-terminal kinase (JNK) and IRS-1 (S307), changes which were absent in muscle from LE rats. EtOH increased tumor necrosis factor alpha (TNFα) mRNA in gastrocnemius and fat under basal conditions in both SD and LE rats; however, hyperinsulinemia decreased TNFα in skeletal muscle from LE, but not SD rats. Interleukin (IL)-6 mRNA in gastrocnemius was increased under basal conditions and increased further in response to insulin in SD rats, but no EtOH- or insulin-induced change was detected in muscle IL-6 of LE rats. These data indicate strain-dependent differences in EtOH-induced IMGU in skeletal and cardiac muscle, but not fat, associated with sustained increases in TNFα and IL-6 mRNA and JNK activation and decreased plasma membrane GLUT4 in response to insulin.