{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:38:53Z","timestamp":1791923933489,"version":"4.3.4"},"reference-count":45,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,4,1]]},"abstract":"<jats:p>Serum aldosterone level is clinically known to correlate with body weight and insulin resistance. Because the underlying molecular mechanism is largely unknown, we examined the effect of aldosterone on insulin-induced metabolic signaling leading to glucose uptake in 3T3-L1 adipocytes. Aldosterone reduced the amounts of insulin receptor substrate (IRS) 1 and IRS2 in a time- and dose-dependent manner. As a result, insulin-induced phosphorylation of Akt-1 and -2, and subsequent uptake of 2-deoxyglucose were decreased. Degradation of IRSs was effectively prevented by a glucocorticoid receptor antagonist and antioxidant N-acetylcysteine, but not by a mineralocorticoid receptor antagonist. Because aldosterone induced phosphorylation of IRS1 at Ser307, responsible kinases were investigated, and we revealed that rapamycin and BMS345541, but neither SP600125 nor calphostin C, conferred for degradation of IRSs. Although lactacystin prevented the degradation of IRSs, glucose uptake was not preserved. Importantly, sucrose-gradient-sediment intracellular fraction analysis revealed that lactacystin did not effectively restore the reduction of IRS1 in the low-density microsome fraction, important for the transduction of insulin\u2019s metabolic signaling. These results indicate that aldosterone deteriorates metabolic action of insulin by facilitating the degradation of IRS1 and IRS2 via glucocorticoid receptor-mediated production of reactive oxygen species, and activation of I\u03baB Kinase \u03b2 and target of rapamycin complex 1. Thus, aldosterone appears to be a novel key factor in the development of insulin resistance in visceral obesity.<\/jats:p>","DOI":"10.1210\/en.2008-1018","type":"journal-article","created":{"date-parts":[[2008,12,19]],"date-time":"2008-12-19T01:44:24Z","timestamp":1229651064000},"page":"1662-1669","source":"Crossref","is-referenced-by-count":104,"title":["Aldosterone Inhibits Insulin-Induced Glucose Uptake by Degradation of Insulin Receptor Substrate (IRS) 1 and IRS2 via a Reactive Oxygen Species-Mediated Pathway in 3T3-L1 Adipocytes"],"prefix":"10.1210","volume":"150","author":[{"given":"Tsutomu","family":"Wada","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology (T.W., S.O., E.F., H.T., T.S.), University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Ohshima","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology (T.W., S.O., E.F., H.T., T.S.), University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Fujisawa","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology (T.W., S.O., E.F., H.T., T.S.), University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Koya","sequence":"first","affiliation":[{"name":"Department of Internal Medicine (D.K.), Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Tsuneki","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology (T.W., S.O., E.F., H.T., T.S.), University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyasu","family":"Sasaoka","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology (T.W., S.O., E.F., H.T., T.S.), University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2008,12,18]]},"reference":[{"key":"2020071612405400200_R1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.2337\/diacare.14.3.173","article-title":"Insulin resistance. 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