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The Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves β-Cell Function and Insulin Sensitivity in Subjects With Impaired Fasting Glucose

¹ Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and VA Puget Sound Health Care System, Seattle, Washington
² Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, Washington
³ Novartis Institute of Biomedical Research, Cambridge, Massachusetts
⁴ Novartis Pharmaceuticals, East Hanover, New Jersey
⁵ Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark

Address correspondence and reprint requests to Kristina M. Utzschneider, MD, VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108. E-mail: kutzschn{at}u.washington.edu

OBJECTIVE—To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and β-cell function in subjects with impaired fasting glucose (IFG).

RESEARCH DESIGN AND METHODS—A total of 22 subjects with IFG (11 female and 11 male, mean ± SD age 59.6 ± 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test (FSIGT), followed by a 2-h meal tolerance test (MTT), was performed at 2, 8, and 10 weeks. From the FSIGT, the acute insulin response to glucose (AIR_g) and insulin sensitivity index (S_I) were determined and used to compute the disposition index (AIR_g x S_I) as a measure of β-cell function.

RESULTS—Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean ± SEM AIR_g increased from 224 ± 44 to 286 ± 52 pmol/l (P < 0.05), and S_I improved from 2.8 ± 0.5 to 3.5 ± 0.5 x 10^–5 · min^–1 · pmol^–1 · l (P < 0.01), resulting in an increase in the disposition index from 688 ± 180 to 1,164 ± 318 x 10^–5/min (P < 0.05). These effects were not sustained after washout. During the MTT, the incremental area under the glucose curve was significantly decreased after treatment (240 ± 15 vs. 191 ± 14 mmol · l^–1 · min^–1; P = 0.002), but this effect was not sustained after washout.

CONCLUSIONS—The DPP-4 inhibitor vildagliptin improves insulin sensitivity and β-cell function, leading to improved postprandial glycemia in subjects with IFG, who are known to have β-cell dysfunction. Thus, vildagliptin may prevent progression to diabetes in high-risk subjects.

Abbreviations: ACR_g, acute C-peptide response to glucose • AIR_g, acute insulin response to glucose • AUC, area under the curve • DPP, dipeptidyl peptidase • FPG, fasting plasma glucose • FSIGT, frequently sampled intravenous glucose tolerance test • GIP, glucose-dependent insulinotropic peptide • GLP-1, glucagon-like peptide 1 • IFG, impaired fasting glucose • IGT, impaired glucose tolerance • K_g, glucose disappearance constant • MTT, meal tolerance test • S_g, glucose effectiveness at basal insulin

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