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Experimental Diabesity Research
Volume 4 (2003), Issue 2, Pages 93-105
http://dx.doi.org/10.1155/EDR.2003.93

Valine Pyrrolidide Preserves Intact Glucose-Dependent Insulinotropic Peptide and Improves Abnormal Glucose Tolerance in Minipigs With Reduced β-Cell Mass

1Department of Pharmacological Research I, Novo Nordisk A/S, Bagsvaerd, Denmark
2Department of Pharmacology and Pathobiology, the Royal Veterinary and Agricultural University, Copenhagen, Denmark
3Department of Assay and Cell Technology, Novo Nordisk A/S, Bagsvaerd, Denmark
4Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
5Department of Histology, Novo Nordisk A/S, Bagsvaerd, Denmark
6Department of Pharmacological Research I, Pharmacology, Research and Development, Novo Allé, 1Q1.28, Bagsvaerd DK-2880, Denmark

Received 14 November 2002; Accepted 16 March 2003

Copyright © 2003 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation.However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced β-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)–treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg).VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 ± 1880 to 9208 ± 3267 pM × min; P<.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 ± 480 to 1582 ± 353 mM × min;P = .05).VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 ± 42 to 192 ± 108; P < .05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced β-cell mass.