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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/E802    most recent 00205.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Iwakura, H. Articles by Akamizu, T. PubMed PubMed Citation Articles by Iwakura, H. Articles by Akamizu, T.

A mouse model of ghrelinoma exhibited activated growth hormone-insulin-like growth factor I axis and glucose intolerance

¹Ghrelin Research Project, Translational Research Center, Kyoto University Hospital, Kyoto University Graduate School of Medicine; ²Department of Medicine and Clinical Science, Endocrinology, and Metabolism, Kyoto University Graduate School of Medicine; ³Clinical Research Institute for Endocrine Metabolic Diseases, National Hospital Organization, Kyoto Medical Center, Kyoto; and ⁴Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan

Submitted 27 March 2009 ; accepted in final form 13 July 2009

Ghrelin is a stomach-derived peptide that has growth hormone-stimulating and orexigenic activities. Although there have been several reports of ghrelinoma cases, only a few cases have elevated circulating ghrelin levels, hampering the investigation of pathophysiological features of ghrelinoma and chronic effects of ghrelin excess. Furthermore, standard transgenic technique has resulted in desacyl ghrelin production only because of the limited tissue expression of ghrelin O-acyltransferase, which mediates acylation of ghrelin. Accordingly, we attempted to create ghrelin promoter SV40 T-antigen transgenic (GP-Tag Tg) mice, in which ghrelin-producing cells continued to proliferate and finally developed into ghrelinoma. Adult GP-Tag Tg mice showed elevated plasma ghrelin levels with preserved physiological regulation. Adult GP-Tag Tg mice with increased plasma ghrelin levels exhibited elevated IGF-I levels despite poor nutrition. Although basal growth hormone levels were not changed, those after growth hormone-releasing hormone injection tended to be higher. These results indicate that chronic elevation of ghrelin activates GH-IGF-I axis. In addition, GP-Tag Tg mice demonstrated glucose intolerance. Insulin secretion by glucose tolerance tests was significantly attenuated in GP-Tag Tg, whereas insulin sensitivity determined by insulin tolerance tests was preserved, indicating that chronic elevation of ghrelin suppresses insulin secretion and leads to glucose intorelance. Thus, we successfully generated a Tg model of ghrelinoma, which is a good tool to investigate chronic effects of ghrelin excess. Moreover, their characteristic features could be a hint on ghrelinoma.

ghrelin; glucose metabolism