title: Effects of sitagliptin on glycemia, incretin hormones, and antropyloroduodenal motility in response to intraduodenal glucose infusion in healthy lean and obese humans and patients with type 2 diabetes treated with or without metformin.
abstract: The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis.
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, AustraliaCentre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Tongzhi
authors.initials: T
authors.lastname: Wu
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, AustraliaCentre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, AustraliaCentre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Bound
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, AustraliaCentre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Checklin
authors.affiliation: Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Deacon
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, AustraliaCentre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Jones
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, AustraliaCentre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Horowitz
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide, SA, AustraliaCentre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, Australia chris.rayner@adelaide.edu.au.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Rayner
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D002149:Energy Intake; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D054795:Incretins / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D009765:Obesity / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D054795:Incretins; D011719:Pyrazines; D014230:Triazoles; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D005947:Glucose; D000068900:Sitagliptin Phosphate