Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice

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M Kvist Reimer, Jens Juul Holst, B Ahrén

OBJECTIVES: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet.

DESIGN: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 micromol/g body weight) was administered in the drinking water for an 8 week period.

RESULTS: DPPIV inhibition reduced plasma DPPIV activity to 0.01+/-0.03 mU/ml vs 3.26+/-0.19 mU/ml in controls (P<0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P=0.029) and in mice fed a high-fat diet (P=0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P<0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7+/-2.6 x 10(3) microm(2) in controls to 7.6+/-1.0 x 10(3) microm(2) (P=0.0019).

CONCLUSION: Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance.

Original languageEnglish
JournalEuropean Journal of Endocrinology. Supplement
Issue number5
Pages (from-to)717-27
Number of pages11
Publication statusPublished - May 2002

    Research areas

  • Animals, Blood Glucose, Body Weight, Dietary Fats, Dipeptidyl Peptidase 4, Drinking, Eating, Female, Glucagon, Glucagon-Like Peptide 1, Glucose, Glucose Intolerance, Insulin, Insulin Resistance, Intubation, Gastrointestinal, Islets of Langerhans, Mice, Mice, Inbred C57BL, Nitriles, Organ Size, Peptide Fragments, Protease Inhibitors, Protein Precursors, Pyrrolidines, Time Factors

ID: 132056585