Effects of long-term dipeptidyl peptidase-IV inhibition on body composition and glucose tolerance in high fat diet-fed mice.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are major incretins associated with body weight regulation. Dipeptidyl peptidase-IV (DPP-IV) inhibitor increases plasma active GLP-1 and GIP. However, the magnitude of the effects of enhanced GLP-1 and GIP signaling by long-term DPP-IV inhibition on body weight and insulin secretion has not been determined. In this study, we compared the effects of long-term DPP-IV inhibition on body composition and insulin secretion of high fat diet (HFD)-fed wild-type (WT) and GLP-1R knockout (GLP-1R(-/-)) mice.


METHODS
HFD-fed WT and GLP-1R(-/-) mice were treated with or without DPP-IV inhibitor by drinking water. Food and water intake and body weight were measured during 8 weeks of study. CT-based body composition analysis, Oral glucose tolerance test (OGTT), batch incubation study for insulin secretion and quantitative RT-PCR for expression of incretin receptors in isolated islets were performed at the end of study.


RESULTS
DPP-IV inhibitor had no effect on food and water intake and body weight, but increased body fat mass in GLP-1R(-/-) mice. DPP-IV inhibitor-treated WT and GLP-1R(-/-) mice both showed increased insulin secretion in OGTT. In isolated islets of DPP-IV inhibitor-treated WT and GLP-1R(-/-) mice, glucose-induced insulin secretion was increased and insulin secretion in response to GLP-1 or GIP was preserved, without downregulation of incretin receptor expression.


CONCLUSIONS
Long-term DPP-IV inhibition may maintain body composition through counteracting effects of GLP-1 and GIP while improving glucose tolerance by increasing glucose-induced insulin secretion through the synergistic effects of GLP-1 and GIP.
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Xibao
X
Liu
Norio
N
Harada
Shunsuke
S
Yamane
Lisa
L
Kitajima
Saeko
S
Uchida
Akihiro
A
Hamasaki
Eri
E
Mukai
Kentaro
K
Toyoda
Chizumi
C
Yamada
Yuichiro
Y
Yamada
Yutaka
Y
Seino
Nobuya
N
Inagaki
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism*; D001823:Body Composition; D001835:Body Weight; D004041:Dietary Fats / Q000008:administration & dosage; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors
D001786:Blood Glucose; D004041:Dietary Fats; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D012333:RNA, Messenger; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4