Mice deficient for glucagon gene-derived peptides display normoglycemia and hyperplasia of islet {alpha}-cells but not of intestinal L-cells.
Multiple bioactive peptides, including glucagon, glucagon-like peptide-1 (GLP-1), and GLP-2, are derived from the glucagon gene (Gcg). In the present study, we disrupted Gcg by introduction of GFP cDNA and established a knock-in mouse line. Gcg(gfp/gfp) mice that lack most, if not all, of Gcg-derived peptides were born in an expected Mendelian ratio without gross abnormalities. Gcg(gfp/gfp) mice showed lower blood glucose levels at 2 wk of age, but those in adult Gcg(gfp/gfp) mice were not significantly different from those in Gcg(+/+) and Gcg(gfp/+) mice, even after starvation for 16 h. Serum insulin levels in Gcg(gfp/gfp) mice were lower than in Gcg(+/+) and Gcg(gfp/+) on ad libitum feeding, but no significant differences were observed on starvation. Islet alpha-cells and intestinal L-cells were readily visualized in Gcg(gfp/gfp) and Gcg(gfp/+) mice under fluorescence. The Gcg(gfp/gfp) postnatally developed hyperplasia of islet alpha-cells, whereas the population of intestinal L-cells was not increased. In the Gcg(gfp/gfp), expression of Aristaless-related homeobox (Arx) was markedly increased in pancreas but not in intestine and suggested involvement of Arx in differential regulation of proliferation of Gcg-expressing cells. These results illustrated that Gcg-derived peptides are dispensable for survival and maintaining normoglycemia in adult mice and that Gcg-derived peptides differentially regulate proliferation/differentiation of alpha-cells and L-cells. The present model is useful for analyzing glucose/energy metabolism in the absence of Gcg-derived peptides. It is useful also for analysis of the development, differentiation, and function of Gcg-expressing cells, because such cells are readily visualized by fluorescence in this model.
Hayashi
Yoshitaka
Y
Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Japan. hayashiy@riem.nagoya-u.ac.jp
Yamamoto
Michiyo
M
Mizoguchi
Hiroyuki
H
Watanabe
Chika
C
Ito
Ryoichi
R
Yamamoto
Shiori
S
Sun
Xiao-yang
XY
Murata
Yoshiharu
Y
D000818:Animals; D019858:Enteroendocrine Cells / Q000473:pathology; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D005838:Genotype; D005934:Glucagon / Q000235:genetics* / Q000502:physiology*; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D006965:Hyperplasia / Q000235:genetics*; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D051379:Mice
D005934:Glucagon