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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.

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Gene expression of heparanase, matrix metalloproteinases (MMP)-2 and MMP-9 were examined in ventricles after chronic treatment with isoproterenol (ISO) induced cardiac hypertrophy in rats. Rats were treated with ISO (4 mg/kg, intraperitoneal) twice daily for 4 d. Ventricle weight of the heart and the ventricle weight/body weight ratio were increased respectively by 22% and 25% compared with control rats. Histology showed considerable cardiomyocyte hypertrophy in the ISO-treated rats in comparison to control rats. Northern blot hybridization revealed that heparanase and MMP-2 gene transcripts increased significantly in the ventricles of ISO-treated rats, whereas MMP-9 gene expression was not induced. Thus, heparanase and MMP-2 gene expressions are induced in the ventricle after chronic treatment with ISO, indicating that they might play an important role in development of ISO-induced cardiac hypertrophy.