Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes (Articolo in rivista)

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  • Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes (Articolo in rivista) (literal)
Anno
  • 2012-01-01T00:00:00+01:00 (literal)
Alternative label
  • Muscelli, E.;Casolaro, A.;Gastaldelli, A.;Mari, A.;Seghieri, G.;Astiarraga, B.;Chen, Y.;Alba, M.;Holst, J.;Ferrannini, E., (2012)
    Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes
    in The Journal of clinical endocrinology and metabolism
    (literal)
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  • Muscelli, E.;Casolaro, A.;Gastaldelli, A.;Mari, A.;Seghieri, G.;Astiarraga, B.;Chen, Y.;Alba, M.;Holst, J.;Ferrannini, E., (literal)
Pagina inizio
  • 2818 (literal)
Pagina fine
  • 2826 (literal)
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  • 97 (literal)
Rivista
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  • 8 (literal)
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  • Scopu (literal)
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  • Muscelli, Casolaro, Astiarraga: Department of Medicine, University of Pisa School of Medicine, 56100 Pisa, Italy; Gastaldelli: Consiglio Nazionale Delle Ricerche, Institute of Clinical Physiology, 5110 Pisa, Italy ; Mari: CNR Institute of Biomedical Engineering, 35127 Padova, Italy; Seghieri: Pistoia General Hospital, 56124 Pistoia, Italy; Chen, Alba: Merck Sharp and Dohme Corp., Whitehouse Station, NJ 08889, United States; Holst: Department of Biomedical Science, Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark Ferrannini: Department of Medicine, University of Pisa School of Medicine, 56100 Pisa, Italy / Consiglio Nazionale Delle Ricerche, Institute of Clinical Physiology, 5110 Pisa, Italy; (literal)
Titolo
  • Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes (literal)
Abstract
  • Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, ?-cell function, endogenous glucose production) are not well known. Objective: The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors. Design, Setting, and Patients: We administered a mixed meal with glucose tracers ([6,6- 2 H2 ]- glucose infused, [1- 2 H]-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 ? 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and ?-cell function was assessed by mathematical modeling. The incretin effect was calculated as the ratio of oral to iv insulin secretion. Intervention: We conducted a 6-wk, double-blind, randomized treatment with sitagliptin (100 mg/d; n ? 25) or placebo (n ? 22). Results: 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 ? ?353 ? 915 vs. ?146 ? 601 ?mol ? kg?1 ? 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, ?-cell glucose sensitivity improved (?19[29] vs. 5[21] pmol ? min?1 ? m?2 ? mM ?1 ; median [interquartile range]) and glucagon AUC decreased (19.6 ? 7.5 to 17.3 ? 7.1 ng ? ml?1 ? 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 ?-cell glucose sensitivity also during the isoglycemic test. Conclusions: 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 ?-cell glucose sensing in response to both oral and iv glucose. (literal)
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