title: Restoration of the insulinotropic effect of glucose-dependent insulinotropic polypeptide contributes to the antidiabetic effect of dipeptidyl peptidase-4 inhibitors.
abstract: OBJECTIVE
  To examine whether 12 weeks of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, influences the insulin secretion induced by glucose, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during a hyperglycaemic clamp in patients with type 2 diabetes (T2DM).
  
  
  METHODS
  A randomized, double-blind, placebo-controlled study was conducted over 12 weeks, during which 25 patients with T2DM completed treatment with either sitagliptin (100 mg once daily) or placebo as add-on therapy to metformin [sitagliptin group (n = 12): mean ± standard error of the mean (s.e.m.) age 54 ± 2.5 years, mean ± s.e.m. HbA1c 7.8 ± 0.2%; placebo group (n = 13): mean ± s.e.m. age: 57 ± 3.0 years, mean ± s.e.m. HbA1c 7.9 ± 0.2 %]. In weeks 1 and 12, the patients underwent three 2-h 15-mM hyperglycaemic clamp experiments with infusion of either saline, GLP-1 or GIP. β-cell function was evaluated according to first-phase, second-phase, incremental and total insulin and C-peptide responses.
  
  
  RESULTS
  In the sitagliptin group, the mean HbA1c concentration was significantly reduced by 0.9% (p = 0.01). The total β-cell response during GIP infusion improved significantly from week 1 to week 12, both within the sitagliptin group (p = 0.004) and when compared with the placebo group (p = 0.04). The total β-cell response during GLP-1 infusion was significantly higher (p = 0.001) when compared with saline and GIP infusion, but with no improvement from week 1 to week 12. No significant changes in β-cell function occurred in the placebo group.
  
  
  CONCLUSIONS
  Treatment with the DPP-4 inhibitor sitagliptin over 12 weeks in patients with T2DM partially restored the lost insulinotropic effect of GIP, whereas the preserved insulinotropic effect of GLP-1 was not further improved. A gradual enhancement of the insulinotropic effect of GIP, therefore, possibly contributes to the antidiabetic actions of DPP-4 inhibitors.
authors.affiliation: Department of Endocrinology I, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Aaboe
authors.forename: S
authors.initials: S
authors.lastname: Akram
authors.forename: C F
authors.initials: CF
authors.lastname: Deacon
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
authors.forename: S
authors.initials: S
authors.lastname: Madsbad
authors.forename: T
authors.initials: T
authors.lastname: Krarup
mesh_terms: D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D002096:C-Peptide; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D014230:Triazoles; C517652:hemoglobin A1c protein, human
keywords: DPP-IV inhibitor; GIP; GLP-1; insulin secretion; metformin; randomised trial