A novel GIP receptor splice variant influences GIP sensitivity of pancreatic beta-cells in obese mice.
Gastric inhibitory polypeptide (GIP) is an incretin that potentiates insulin secretion from pancreatic beta-cells by binding to GIP receptor (GIPR) and subsequently increasing the level of intracellular adenosine 3',5'-cyclic monophosphate (cAMP). We have identified a novel GIPR splice variant in mouse beta-cells that retains intron 8, resulting in a COOH-terminal truncated form (truncated GIPR). This isoform was coexpressed with full-length GIPR (wild-type GIPR) in normal GIPR-expressing tissues. In an experiment using cells transfected with both GIPRs, truncated GIPR did not lead to cAMP production induced by GIP but inhibited GIP-induced cAMP production through wild-type GIPR (n = 3-4, P < 0.05). Wild-type GIPR was normally located on the cell surface, but its expression was decreased in the presence of truncated GIPR, suggesting a dominant negative effect of truncated GIPR against wild-type GIPR. The functional relevance of truncated GIPR in vivo was investigated. In high-fat diet-fed obese mice (HFD mice), blood glucose levels were maintained by compensatory increased insulin secretion (n = 8, P < 0.05), and cAMP production (n = 6, P < 0.01) and insulin secretion (n = 10, P < 0.05) induced by GIP were significantly increased in isolated islets, suggesting hypersensitivity of the GIPR. Total GIPR mRNA expression was not increased in the islets of HFD mice, but the expression ratio of truncated GIPR to total GIPR was reduced by 32% compared with that of control mice (n = 6, P < 0.05). These results indicate that a relative reduction of truncated GIPR expression may be involved in hypersensitivity of GIPR and hyperinsulinemia in diet-induced obese mice.
Harada
Norio
N
Dept. Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yamada
Yuichiro
Y
Tsukiyama
Katsushi
K
Yamada
Chizumi
C
Nakamura
Yasuhiko
Y
Mukai
Eri
E
Hamasaki
Akihiro
A
Liu
Xibao
X
Toyoda
Kentaro
K
Seino
Yutaka
Y
Inagaki
Nobuya
N
D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism / Q000503:physiopathology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D004041:Dietary Fats; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP