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


METHODS
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).


CONCLUSIONS
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.
Reimer
M Kvist
MK
Department of Medicine, Lund University, Sweden.
Holst
J J
JJ
Ahrén
B
B
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D004041:Dietary Fats / Q000008:administration & dosage; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000187:drug effects*; D004326:Drinking; D004435:Eating; D005260:Female; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D018149:Glucose Intolerance / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D007441:Intubation, Gastrointestinal; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000097:blood; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011498:Protein Precursors / Q000097:blood; D011759:Pyrrolidines / Q000627:therapeutic use*; D013997:Time Factors
C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D009570:Nitriles; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011498:Protein Precursors; D011759:Pyrrolidines; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D005947:Glucose