Inhibition of Dipeptidyl Peptidase-4 by Vildagliptin During Glucagon-Like Peptide 1 Infusion Increases Liver Glucose Uptake in the Conscious Dog

  1. Alan D. Cherrington1
  1. 1Vanderbilt University Medical Center, Nashville, Tennessee
  2. 2Lovelace Respiratory Research Institute, Albuquerque, New Mexico
  3. 3Novartis Institutes for BioMedical Research, Cambridge, Massachusetts
  1. Corresponding author: Dale S. Edgerton, dale.edgerton{at}vanderbilt.edu

Abstract

OBJECTIVE—This study investigated the acute effects of treatment with vildagliptin on dipeptidyl peptidase-4 (DPP-4) activity, glucagon-like peptide 1 (GLP-1) concentration, pancreatic hormone levels, and glucose metabolism. The primary aims were to determine the effects of DPP-4 inhibition on GLP-1 clearance and on hepatic glucose uptake.

RESEARCH DESIGN AND METHODS—Fasted conscious dogs were studied in the presence (n = 6) or absence (control, n = 6) of oral vildagliptin (1 mg/kg). In both groups, GLP-1 was infused into the portal vein (1 pmol · kg−1 · min−1) for 240 min. During the same time, glucose was delivered into the portal vein at 4 mg · kg−1 · min−1 and into a peripheral vein at a variable rate to maintain the arterial plasma glucose level at 160 mg/dl.

RESULTS—Vildagliptin fully inhibited DPP-4 over the 4-h experimental period. GLP-1 concentrations were increased in the vildagliptin-treated group (50 ± 3 vs. 85 ± 7 pmol/l in the portal vein in control and vildagliptin-treated dogs, respectively; P < 0.05) as a result of a 40% decrease in GLP-1 clearance (38 ± 5 and 22 ± 2 ml · kg−1 · min−1, respectively; P < 0.05). Although hepatic insulin and glucagon levels were not significantly altered, there was a tendency for plasma insulin to be greater (hepatic levels were 73 ± 10 vs. 88 ± 15 μU/ml, respectively). During vildagliptin treatment, net hepatic glucose uptake was threefold greater than in the control group. This effect was greater than that predicted by the change in insulin.

CONCLUSIONS—Vildagliptin fully inhibited DPP-4 activity, reduced GLP-1 clearance by 40%, and increased hepatic glucose disposal by means beyond the effects of GLP-1 on insulin and glucagon secretion.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 7 October 2008.

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    • Received April 18, 2008.
    • Accepted September 26, 2008.
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  1. Diabetes vol. 58 no. 1 243-249
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