CONTEXT: Dipeptidyl peptidaseIV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-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)H(2)]-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 A(1c) = 7.4 ± 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and β-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 μmol · kg(-1) · 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, β-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 β-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 β-cell glucose sensing in response to both oral and iv glucose.
RCT Entities:
CONTEXT: Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-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)H(2)]-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 diabetespatients (hemoglobin A(1c) = 7.4 ± 0.8%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and β-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 μmol · kg(-1) · 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10%, whereas total insulin secretion was unchanged. During the meal, β-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 β-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 β-cell glucose sensing in response to both oral and iv glucose.
Authors: Brenno Astiarraga; Valéria B Chueire; Aglécio L Souza; Ricardo Pereira-Moreira; Sarah Monte Alegre; Andrea Natali; Andrea Tura; Andrea Mari; Ele Ferrannini; Elza Muscelli Journal: Diabetologia Date: 2018-05-07 Impact factor: 10.122
Authors: Ron T Varghese; Chiara Dalla Man; Marcello C Laurenti; Francesca Piccinini; Anu Sharma; Meera Shah; Kent R Bailey; Robert A Rizza; Claudio Cobelli; Adrian Vella Journal: Diabetes Obes Metab Date: 2017-09-27 Impact factor: 6.577
Authors: M Seghieri; E Rebelos; A Gastaldelli; B D Astiarraga; A Casolaro; E Barsotti; A Pocai; M Nauck; E Muscelli; E Ferrannini Journal: Diabetologia Date: 2012-10-12 Impact factor: 10.122
Authors: Darline Garibay; Anne K McGavigan; Seon A Lee; James V Ficorilli; Amy L Cox; M Dodson Michael; Kyle W Sloop; Bethany P Cummings Journal: Endocrinology Date: 2016-08-08 Impact factor: 4.736