Combined use of insulin and endothelin-1 causes decrease of protein expression of beta-subunit of insulin receptor, insulin receptor substrate-1, and insulin-stimulated glucose uptake in rat adipocytes.
Previously, we reported that insulin-stimulated glucose uptake (ISGU) can be inhibited by endothelin (ET-1). However, the mechanism by which ET-1 impairs ISGU in adipocytes remains unclear. This study investigated the effects of ET-1 on insulin action in rat adipocytes in order to elucidate the molecular mechanism of action of ET-1 on ISGU. The results show that ISGU was increased fivefold after 3-h treatment with 1 nM insulin. Treatment with 100 nM ET-1 had no effect on basal glucose uptake. However, ET-1 inhibited approximately 25% of ISGU and 20% of insulin binding after 3-h treatment in the presence of 1 nM insulin. Expression of the beta-subunit of the insulin receptor (IRbeta) and the insulin receptor substrate-1 (IRS-1) in adipocytes was not significantly affected by 1 nM insulin or by 100 nM ET-1, even after 3-h treatment. However, expressions of IRbeta and IRS-1 were dramatically decreased in a dose- and time-dependent manner when adipocytes were treated with both insulin and ET-1. Approximately 50% of IRbeta and 65% of IRS-1 expression levels were suppressed when adipocytes were simultaneously treated with both 1 nM insulin and 100 nM ET-1 for 3 h. These results suggest that the inhibitory effect of ET-1 on ISGU may be mediated via the insulin receptor and suppression of IRbeta/IRS-1 expression.
Shih
K C
KC
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Kwok
C F
CF
Ho
L T
LT
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D004347:Drug Interactions; D019332:Endothelin-1 / Q000008:administration & dosage*; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage*; D055504:Insulin Receptor Substrate Proteins; D007700:Kinetics; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism*
D019332:Endothelin-1; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D011972:Receptor, Insulin; D005947:Glucose