{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T05:12:39Z","timestamp":1776057159230,"version":"3.50.1"},"reference-count":26,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T00:00:00Z","timestamp":1599004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003197","name":"Agenzia Italiana del Farmaco, Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003197","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Metabolism Res"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>We evaluate whether the Pro12Ala polymorphism of peroxisome proliferator\u2010activated receptor \u03b32 (PPAR\u03b32) has a role in the progression of diabetes by modulating the occurrence of treatment failure to glucose\u2010lowering drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied 215 patients with type 2 diabetes participating in the Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents Intervention Trial study. All participants were insufficiently controlled (glycated haemoglobin [HbA<jats:sub>1c<\/jats:sub>] 7.0%\u20109.0%) with metformin 2 g\/day and were randomly allocated to add\u2010on pioglitazone or a sulfonylurea. Treatment failure was defined as HbA<jats:sub>1c<\/jats:sub> \u22658% on two consecutive visits, 3 months apart.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Carriers or non\u2010carriers of the polymorphism had similar age, body mass index, and diabetes duration. Ala carriers had lower fasting plasma insulin, better insulin sensitivity (Homeostasis Model Assessment [HOMA]2\u2010%S), and worse beta cell secretion (HOMA2\u2010%B) than non\u2010carriers. During 24\u2009months of follow\u2010up, 32.5% among the Ala carriers and 8.6% among non\u2010carriers (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) developed treatment failure with a cumulative incidence of 18.6 vs 4.6\/100 person\u2010years. Those patients who developed treatment failure were older, had a younger age at diabetes diagnosis (48\u2009\u00b1\u200910 vs 52\u2009\u00b1\u20097\u2009years; <jats:italic>P\u2009=<\/jats:italic> 0.032), higher HbA<jats:sub>1c<\/jats:sub> (8.1\u2009\u00b1\u20090.5 vs 7.7\u2009\u00b1\u20090.5%; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), and lower HOMA2\u2010%B (30\u2009\u00b1\u200912 vs 46\u2009\u00b1\u200929; <jats:italic>P<\/jats:italic> = 0.015) at study entry, as compared to those who did not develop treatment failure. At multivariate analysis, the Pro12Ala polymorphism was significantly associated with treatment failure (hazard ratio [HR] 4.45; 95% confidence interval [CI] 1.79\u201011.1; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001); HbA<jats:sub>1c<\/jats:sub> at study entry was the other independent predictor of failure in this study population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The Pro12Ala polymorphism is associated with a greater insulin sensitivity, reduced beta cell function and a substantially increased risk of treatment failure.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dmrr.3392","type":"journal-article","created":{"date-parts":[[2020,8,12]],"date-time":"2020-08-12T06:31:01Z","timestamp":1597213861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The <scp>Pro12Ala<\/scp> polymorphism of <scp>PPAR\u03b32<\/scp> modulates beta cell function and failure to oral 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