{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T13:44:47Z","timestamp":1762004687204},"reference-count":29,"publisher":"American Physiological Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"],"published-print":{"date-parts":[[2015,4,1]]},"abstract":"<jats:p> Plasma glucose thresholds for diagnosis of type 2 diabetes are currently based on outcome data (risk of retinopathy), an inherently ill-conditioned approach. A radically different approach is to consider the mechanisms that control plasma glucose, rather than its relation to an outcome. We developed a constraint optimization algorithm to find the minimal glucose levels associated with the maximized combination of insulin sensitivity and \u03b2-cell function, the two main mechanisms of glucose homeostasis. We used a training cohort of 1,474 subjects (22% prediabetic, 7.7% diabetic) in whom insulin sensitivity was measured by the clamp technique and \u03b2-cell function was determined by mathematical modeling of an oral glucose tolerance test. Optimized fasting glucose levels were \u226487 and \u226489 mg\/dl in \u226445-yr-old women and men, respectively, and \u226492 and \u226495 mg\/dl in &gt;45-yr-old women and men, respectively; the corresponding optimized 2-h glucose levels were \u226496, \u226498, \u2264103, and \u2264105 mg\/dl. These thresholds were validated in three prospective cohorts of nondiabetic subjects (Relationship Between Insulin Sensitivity and Cardiovascular Disease Study, Botnia Study, and Mexico City Diabetes Study) with baseline and follow-up oral glucose tolerance tests. Of 5,593 participants, 452 progressed to diabetes. Similarly, in the three cohorts, subjects with glucose levels above the estimated thresholds had an odds ratio of 3.74 (95% confidence interval = 2.64\u20135.48) of progressing, substantially higher than the risk carried by baseline conventionally defined prediabetes [odds ratio = 2.32 (95% confidence interval = 1.91\u20132.81)]. The concept that optimization of glucose concentrations by direct measures of insulin sensitivity and \u03b2-cell function identifies gender- and age-specific thresholds that bear on disease progression is proven in a physiologically sound, quantifiable manner. <\/jats:p>","DOI":"10.1152\/ajpregu.00325.2014","type":"journal-article","created":{"date-parts":[[2015,1,1]],"date-time":"2015-01-01T05:09:12Z","timestamp":1420088952000},"page":"R590-R596","source":"Crossref","is-referenced-by-count":5,"title":["Identifying glucose thresholds for incident diabetes by physiological analysis: a mathematical solution"],"prefix":"10.1152","volume":"308","author":[{"given":"Ele","family":"Ferrannini","sequence":"first","affiliation":[{"name":"Institute of Clinical Physiology, Consiglio Nazionale Delle Ricerche, Pisa, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Laura","family":"Manca","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; and"},{"name":"Department of Mathematics, University of Pisa, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4614-8615-2_9"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.4.4.493"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(13)70175-X"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-0334"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1289-8"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0707"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-011-2112-x"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/diab.45.7.947"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1263-9"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-2878-1"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1109\/TCBB.2007.070203"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-3061-3"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.3.5542"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62154-6"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.1.166"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1177\/1479164111424762"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00093.2002"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1647-6"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s00158-003-0368-6"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/BFb0000035"},{"key":"B22","volume-title":"Manuale di Economia Politica","author":"Pareto V","year":"1906"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-1577"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2011.06.003"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.11.2.119"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-136-8-200204160-00006"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60283-9"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2011.10.029"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.167.10.1068"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60343-8"}],"container-title":["American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpregu.00325.2014","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T17:39:42Z","timestamp":1567964382000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpregu.00325.2014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,1]]},"references-count":29,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2015,4,1]]}},"alternative-id":["10.1152\/ajpregu.00325.2014"],"URL":"https:\/\/doi.org\/10.1152\/ajpregu.00325.2014","relation":{},"ISSN":["0363-6119","1522-1490"],"issn-type":[{"value":"0363-6119","type":"print"},{"value":"1522-1490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4,1]]}}}