Improvement of high fat-diet-induced insulin resistance in dipeptidyl peptidase IV-deficient Fischer rats.
F344/DuCrj rats are genetically deficient in dipeptidyl peptidase IV (DPPIV). This enzyme degrades glucagon-like peptide-1 (GLP-1), which induces glucose-dependent insulin secretion. Glucose tolerance of F344/DuCrj rats is improved as a result of enhanced insulin release induced by high levels of plasma GLP-1. In this study, we fed F344/DuCrj rats and DPPIV-positive F344/Jcl rats, aged five weeks, on a high-fat (HF) diet to examine the effect of DPPIV deficiency on food intake and insulin resistance. F344/Jcl rats gained significantly more body weight and consumed significantly more food than F344/DuCrj rats from Week 4 on either control or HF diet. Glucose excursion in the oral glucose tolerance test (OGTT) was improved in F344/DuCrj rats fed on the control or HF diet at all times examined, compared with F344/Jcl rats. Homeostasis model assessment (HOMA) insulin resistance values of F344/DuCrj and F344/Jcl rats fed on HF diet were higher than those of animals fed on control diet up to Week 6. However, HOMA insulin resistance values of F344/DuCrj rats fed on HF diet became significantly lower than those of F344/Jcl rats on HF diet during Weeks 8-10. The area under the insulin curve in the OGTT at Week 10 showed that the insulin resistance of HF-diet-fed F344/DuCrj rats was greatly ameliorated. Plasma active GLP-1 concentrations of F344/DuCrj rats in the fed state were significantly higher than those of F344/Jcl rats. These observations suggest that DPPIV deficiency results in improved glucose tolerance and ameliorated insulin resistance owing to enhanced insulin release and inhibition of food intake as a result of high active GLP-1 levels.
Yasuda
Nobuyuki
N
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Nagakura
Tadashi
T
Yamazaki
Kazuto
K
Inoue
Takashi
T
Tanaka
Isao
I
D000818:Animals; D001835:Body Weight; D004041:Dietary Fats / Q000009:adverse effects*; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D004041:Dietary Fats; D007328:Insulin; D018819:Dipeptidyl Peptidase 4; D005947:Glucose