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

• Published in: European journal of endocrinology Vol. 146; no. 5; pp. 717 - 727
• Main Authors: Reimer, MK, Holst, JJ, Ahren, B
• Format: Journal Article
• Language: English
• Published: Colchester European Society of Endocrinology 01.05.2002; Portland Press
• Subjects: Animal; Animals; Antigens; Biological and medical sciences; Blood Glucose - analysis; Body Weight; CD26 : blood; CD26 : drug effects; Clinical Medicine; Dietary Fats - administration & dosage; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - drug effects; Drinking; Eating; Endocrine pancreas; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Fundamental and applied biological sciences. Psychology; Gastrointestinal; Glucagon - blood; Glucagon-Like Peptide 1; Glucose - administration & dosage; Glucose - pharmacology; Glucose Intolerance - drug therapy; Hormones. Régulation; Inbred C57BL; Insulin - blood; Insulin Resistance - physiology; Intubation; Intubation, Gastrointestinal; Islets of Langerhans - anatomy & histology; Islets of Langerhans - drug effects; Islets of Langerhans - physiology; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Nitriles - therapeutic use; Non-U.S. Gov't; Organ Size - drug effects; Organ Weight : drug effects; Peptide Fragments - blood; Protease Inhibitors - therapeutic use; Protein Precursors - blood; Pyrrolidines - therapeutic use; Support; Time Factors; Vertebrates: endocrinology; Dipeptidyl-peptidase IV; Stomach; Glucagon; Enzyme; Immunocytochemistry; Rodentia; Langerhans islet; Tolerance; Selectivity; Glucose; Long term; Glucagon like peptide 1; Peptidases; Vertebrata; Mammalia; Treatment; Mouse; Animal; Hydrolases; Inhibitor; Inhibition
• ISSN: 0804-4643; 1479-683X; 1479-683X
• DOI: 10.1530/eje.0.1460717

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.