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Mice Deficient for Glucagon Gene-Derived Peptides Display Normoglycemia and Hyperplasia of Islet -Cells But Not of Intestinal L-Cells

Department of Genetics, Division of Stress Adaptation and Recognition (Y.H., M.Y., C.W., R.I., S.Y., X.S., Y.M.) and Futuristic Environmental Simulation Center (H.M.), Research Institute of Environmental Medicine, Nagoya University, 464-8601, Nagoya, Japan

Address all correspondence and requests for reprints to: Yoshitaka Hayashi, Research Institute of Environmental Medicine, E3-2(310), Nagoya University, 464-8601, Nagoya, Japan. E-mail: hayashiy{at}riem.nagoya-u.ac.jp.

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 -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 -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 -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.