{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T13:57:24Z","timestamp":1773323844978,"version":"3.50.1"},"reference-count":40,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context:<\/jats:title><jats:p>Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, \u03b2-cell function, endogenous glucose production) are not well known.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective:<\/jats:title><jats:p>The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Patients:<\/jats:title><jats:p>We administered a mixed meal with glucose tracers ([6,6-2H2]-glucose infused, [1-2H]-glucose ingested), and on a separate day, a glucose infusion matched the glucose responses to the meal (isoglycemic test) in 50 type 2 diabetes patients (hemoglobin A1c = 7.4 \u00b1 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and \u03b2-cell function was assessed by mathematical modeling. The incretin effect was calculated as the ratio of oral to iv insulin secretion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Intervention:<\/jats:title><jats:p>We conducted a 6-wk, double-blind, randomized treatment with sitagliptin (100 mg\/d; n = 25) or placebo (n = 22).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>Relative to placebo, meal-induced changes in fasting glucose and glucose area under the curve (AUC) were greater with sitagliptin, in parallel with a lower appearance of oral glucose [difference (post-pre) AUC = \u2212353 \u00b1 915 vs. +146 \u00b1 601 \u03bcmol \u00b7 kg\u22121 \u00b7 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, \u03b2-cell glucose sensitivity improved (+19[29] vs. 5[21] pmol \u00b7 min\u22121 \u00b7 m\u22122 \u00b7 mm\u22121; median [interquartile range]) and glucagon AUC decreased (19.6 \u00b1 7.5 to 17.3 \u00b1 7.1 ng \u00b7 ml\u22121 \u00b7 5 h), whereas intact glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 AUC increased with sitagliptin vs. placebo. The incretin effect was unchanged because sitagliptin increased \u03b2-cell glucose sensitivity also during the isoglycemic test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>Chronic sitagliptin treatment improves glycemic control by lowering the appearance of oral glucose, postprandial endogenous glucose release, and glucagon response, and by improving insulin sensitivity and \u03b2-cell glucose sensing in response to both oral and iv glucose.<\/jats:p><\/jats:sec>","DOI":"10.1210\/jc.2012-1205","type":"journal-article","created":{"date-parts":[[2012,6,9]],"date-time":"2012-06-09T03:54:57Z","timestamp":1339214097000},"page":"2818-2826","source":"Crossref","is-referenced-by-count":87,"title":["Mechanisms for the Antihyperglycemic Effect of Sitagliptin in Patients with Type 2 Diabetes"],"prefix":"10.1210","volume":"97","author":[{"given":"Elza","family":"Muscelli","sequence":"first","affiliation":[{"name":"Department of Medicine (E.M., A.C., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturo","family":"Casolaro","sequence":"additional","affiliation":[{"name":"Department of Medicine (E.M., A.C., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amalia","family":"Gastaldelli","sequence":"additional","affiliation":[{"name":"Consiglio Nazionale delle Ricerche (CNR) (A.G., E.F.), Institute of Clinical Physiology, 5110 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Mari","sequence":"additional","affiliation":[{"name":"CNR Institute of Biomedical Engineering (A.M.), 35127 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Seghieri","sequence":"additional","affiliation":[{"name":"Pistoia General Hospital (G.S.), 56124 Pistoia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brenno","family":"Astiarraga","sequence":"additional","affiliation":[{"name":"Department of Medicine (E.M., A.C., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Merck Sharp & Dohme Corp. 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