The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients.
OBJECTIVE
Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration.


METHODS
Sixteen patients with type 2 diabetes (age, 48+/-3 yr; body mass index, 34.4+/-1.7 kg/m2; hemoglobin A1c, 9.0+/-0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-(3)H-glucose iv and 1-(14)C-glucose orally).


RESULTS
After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02+/-0.06 vs. 0.74+/-0.06 mg.kg-1.min-1; P=0.004), and insulin secretion rate increased by 21% (P=0.003) despite significant reduction in mean plasma glucose (213+/-4 vs. 230+/-4 mg/dl; P=0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P=0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P<0.02). The decline in EGP was positively correlated (r=0.55; P<0.03) with the decrease in fasting plasma glucose (change=-14 mg/dl).


CONCLUSIONS
During MTT, vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of EGP. During the postprandial period, a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP.
Balas
Bogdan
B
Diabetes Division, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Drive, MC 7886, San Antonio, Texas 78229, USA. balas@uthscsa.edu
Baig
Muhammad R
MR
Watson
Catherine
C
Dunning
Beth E
BE
Ligueros-Saylan
Monica
M
Wang
Yibin
Y
He
Yan-Ling
YL
Darland
Celia
C
Holst
Jens J
JJ
Deacon
Carolyn F
CF
Cusi
Kenneth
K
Mari
Andrea
A
Foley
James E
JE
DeFronzo
Ralph A
RA
D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000243:Adenosine Deaminase / Q000097:blood*; D058892:Adenosine Deaminase Inhibitors; D015992:Body Mass Index; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000032:analysis; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000097:blood*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use*; D009765:Obesity / Q000150:complications; D011759:Pyrrolidines / Q000627:therapeutic use*; D000077597:Vildagliptin
D000218:Adamantane; D000243:Adenosine Deaminase; D058892:Adenosine Deaminase Inhibitors; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D005947:Glucose; D006442:Glycated Hemoglobin; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; C042807:DPP4 protein, human