Abstract
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 language | English |
|---|---|
| Journal | European Journal of Endocrinology. Supplement |
| Volume | 146 |
| Issue number | 5 |
| Pages (from-to) | 717-27 |
| Number of pages | 11 |
| ISSN | 0804-4643 |
| Publication status | Published - May 2002 |
Keywords
- 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
