Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes.
OBJECTIVE
Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes.


METHODS
Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m(2); glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR).


RESULTS
V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g. AUC(ISR oral), by 32.7%, P = 0.0006; AUC(ISR iv), by 33.1%, P = 0.01). The numerical incretin effect was not changed (IE(ISR), V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80).


CONCLUSIONS
DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.
Diabeteszentrum Bad Lauterberg, 37431 Bad Lauterberg, Germany.
Irfan
I
Vardarli
Michael A
MA
Nauck
Lars D
LD
Köthe
Carolyn F
CF
Deacon
Jens J
JJ
Holst
Anja
A
Schweizer
James E
JE
Foley
D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000008:administration & dosage*; D006801:Humans; D054795:Incretins / Q000494:pharmacology; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000077597:Vildagliptin
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D005947:Glucose; D000218:Adamantane