Tissue- and time-dependent effects of endothelin-1 on insulin-stimulated glucose uptake

Hyperendothelinaemia is associated with various insulin-resistant states, e.g., diabetes, obesity and heart failure, but whether endothelin-1 (ET-1) has a direct effect on insulin-mediated glucose uptake is unclear because the interpretation of in vivo metabolic studies is complicated by ET-1 effects on muscle blood flow and insulin secretion. This study investigated the effects of ET-1 (1-10 nM) on basal and insulin-stimulated 2-deoxy-D-[H-3]glucose (2-DOG) uptake in cultured L6 myoblasts and 3T3-adipocytes. RT-PCR analysis showed that both cell types express ETA but not ETB receptors. ET-1 had no effect on basal (non-insulin-mediated) glucose transport, but there was evidence of a tissue- and time-dependent inhibitory effect of ET-1 on insulin-stimulated glucose uptake. Specifically. ET-I 10 nM had a transient (0.5 h) inhibitory effect on glucose uptake in 3T3 cells (CI-150 [dose of insulin required to increase glucose uptake by 50%, relative to control 100%] increased from 89 +/- 14 nM to 270 +/- 12 nM at 30 mins, P < 0.05) but no effect on insulin sensitivity in L6 myoblasts (CI-150 was 56 +/- 14 nM [control], 43 +/- 14 [30 mins] and 26 +/- 16 [2 h]). In conclusion. the inhibitory effect of ET-1 on insulin-stimulated glucose uptake is transient and occurs in 3T3-L1 adipocytes but not skeletal muscle-derived cells, perhaps reflecting tissue differences in ETA-receptor signaling. It is therefore unlikely that chronic hyperendothelinaemia has a direct insulin-antagonist effect contributing to peripheral (ie muscle/fat) insulin resistance in vivo. (C) 2001 Elsevier Science Inc. All rights reserved.