{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:39:05Z","timestamp":1791297545941,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2006,7,4]],"date-time":"2006-07-04T00:00:00Z","timestamp":1151971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2006,11]]},"abstract":"<jats:p>\n                    HIV\u20101 protease inhibitors have revolutionized the treatment of HIV infection, but their use has been associated with lipodystrophy and insulin resistance. One suggestion for this has been the inhibition of insulin\u2010degrading enzyme (IDE). We have previously demonstrated that insulin, through IDE, can inhibit the proteasome, thus decreasing cytosolic protein degradation. We examined whether the protease inhibitor nelfinavir inhibited IDE and its effect on protein degradation both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and in whole cells.\n                    <jats:sup>125<\/jats:sup>\n                    I\u2010Insulin degradation was measured by trichloroacetic acid precipitation. Proteasome activities were measured using fluorogenic peptide substrates. Cellular protein degradation was measured by prelabelling cells with\n                    <jats:sup>3<\/jats:sup>\n                    H\u2010leucine and determining the release of TCA\u2010soluble radioactivity. Nelfinavir inhibited IDE in a concentration\u2010dependent manner with 50% inhibition at the maximal concentration tested, 100\u2003\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    . Similarly, the chymotrypsin\u2010like and trypsin\u2010like activities of the proteasome were decreased with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of approximately 3\u2003\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    . The ability of insulin to inhibit the proteasome was abrogated by nelfinavir. Treatment of HepG2 cells with 50\u2003\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    nelfinavir decreased\n                    <jats:sup>125<\/jats:sup>\n                    I\u2010insulin degradation and increased cell\u2010associated radioactivity. Insulin alone maximally decreased protein degradation by 15%. Addition of 50\u2003\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    nelfinavir inhibited cellular protein degradation by 14% and blunted the effect of insulin. These data show that nelfinavir inhibits IDE, decreases insulin\u2019s ability to inhibit protein degradation via the proteasome and provides another possible mechanism for the insulin resistance seen in protease inhibitor\u2010treated HIV patients.\n                  <\/jats:p>","DOI":"10.1111\/j.1463-1326.2005.00546.x","type":"journal-article","created":{"date-parts":[[2006,7,5]],"date-time":"2006-07-05T19:58:53Z","timestamp":1152129533000},"page":"661-668","source":"Crossref","is-referenced-by-count":23,"title":["Effect of nelfinavir on insulin metabolism, proteasome activity and protein degradation in HepG2 cells"],"prefix":"10.1111","volume":"8","author":[{"given":"F. G.","family":"Hamel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Fawcett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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