The Dipeptidyl Peptidase IV Inhibitor Vildagliptin Suppresses Endogenous Glucose Production and Enhances Islet Function after Single-Dose Administration in Type 2 Diabetic Patients

• Published in: The journal of clinical endocrinology and metabolism 2007-04, Vol.92 (4), p.1249-1255
• Main Authors: Balas, Bogdan, Baig, Muhammad R., Watson, Catherine, Dunning, Beth E., Ligueros-Saylan, Monica, Wang, Yibin, He, Yan-Ling, Darland, Celia, Holst, Jens J., Deacon, Carolyn F., Cusi, Kenneth, Mari, Andrea, Foley, James E., DeFronzo, Ralph A.
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Adamantane - therapeutic use; Adenosine Deaminase - blood; Adenosine Deaminase Inhibitors; Biological and medical sciences; Body Mass Index; Cross-Over Studies; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes. Impaired glucose tolerance; Dipeptidyl Peptidase 4 - blood; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Glycated Hemoglobin A - analysis; Glycoproteins - antagonists & inhibitors; Glycoproteins - blood; Humans; Hypoglycemic Agents - therapeutic use; Islets of Langerhans - secretion; Kinetics; Male; Medical sciences; Middle Aged; Nitriles - therapeutic use; Obesity - complications; Pyrrolidines - therapeutic use; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2006-1882

Aims/Hypothesis: 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 (3-3H-glucose iv and 1-14C-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.