Improved glucose tolerance via enhanced glucose-dependent insulin secretion in dipeptidyl peptidase IV-deficient Fischer rats.
Glucagon-like peptide-1 (GLP-1) is an incretin, which induces glucose-dependent insulin secretion. GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPPIV) after its release. We investigated whether DPPIV-deficient F344/DuCrj rats show improved glucose tolerance when compared with DPPIV-positive F344/Jcl rats. Oral glucose tolerance test indicated improved glucose tolerance in F344/DuCrj rats, but blood glucose levels of the two strains were almost the same 120 min after the glucose bolus. Valine-pyrrolidide, a DPPIV inhibitor, had no effect on the glucose tolerance of F344/DuCrj rats, but improved that of F344/Jcl rats. Enhanced insulin secretion and high plasma active GLP-1 levels were detected in an intraduodenal glucose tolerance test. Glucose tolerance is improved in DPPIV-deficient F344/DuCrj rats via enhanced insulin release mediated by high active GLP-1 levels. Our results suggest that DPPIV inhibition is a rational strategy to treat diabetic patients by improving glucose tolerance with low risk of hypoglycemia.
Nagakura
T
T
Tsukuba Research Laboratories, Eisai Company, Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki, 300-2635, Japan.
Yasuda
N
N
Yamazaki
K
K
Ikuta
H
H
Yoshikawa
S
S
Asano
O
O
Tanaka
I
I
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007441:Intubation, Gastrointestinal; D008297:Male; D010446:Peptide Fragments / Q000097:blood; D011498:Protein Precursors / Q000097:blood; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D013045:Species Specificity; D014633:Valine / Q000494:pharmacology
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D011758:Pyrroles; C112092:valine-pyrrolidide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D014633:Valine; D005947:Glucose