{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T02:49:55Z","timestamp":1793155795906,"version":"4.5.0"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1994,11,8]]},"abstract":"<jats:p>Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 +\/- 0.06 mM at the onset of hyperglycemia (P &lt; 0.001 vs. controls). At this time GSIS was absent and beta-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P &lt; 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P &lt; 0.001). Reduction of hyperlipacidemia to 1.3 +\/- 0.07 mM by pair feeding with lean littermates reduced all beta-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.<\/jats:p>","DOI":"10.1073\/pnas.91.23.10878","type":"journal-article","created":{"date-parts":[[2006,5,31]],"date-time":"2006-05-31T08:59:11Z","timestamp":1149065951000},"page":"10878-10882","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":690,"title":["Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships."],"prefix":"10.1073","volume":"91","author":[{"given":"Y","family":"Lee","sequence":"first","affiliation":[{"name":"Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75235."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Hirose","sequence":"additional","affiliation":[{"name":"Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75235."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Ohneda","sequence":"additional","affiliation":[{"name":"Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75235."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J H","family":"Johnson","sequence":"additional","affiliation":[{"name":"Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75235."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J D","family":"McGarry","sequence":"additional","affiliation":[{"name":"Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75235."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R H","family":"Unger","sequence":"additional","affiliation":[{"name":"Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75235."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1994,11,8]]},"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.91.23.10878","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T13:58:40Z","timestamp":1649858320000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.91.23.10878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1994,11,8]]},"references-count":0,"journal-issue":{"issue":"23","published-print":{"date-parts":[[1994,11,8]]}},"alternative-id":["10.1073\/pnas.91.23.10878"],"URL":"https:\/\/doi.org\/10.1073\/pnas.91.23.10878","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1994,11,8]]},"assertion":[{"value":"1994-11-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}