title: Fertility and pregnancy-associated ß-cell proliferation in mice deficient in proglucagon-derived peptides.
abstract: Proglucagon, which is encoded by the glucagon gene (Gcg), is the precursor of several peptide hormones, including glucagon and glucagon-like peptide 1 (GLP-1). Whereas glucagon stimulates hepatic glycogenolysis and gluconeogenesis, GLP-1 stimulates insulin secretion to lower blood glucose and also supports ß-cell proliferation and protection from apoptotic stimuli. Pregnancy is a strong inducer of change in islet function, however the roles of proglucagon-derived peptides in pregnancy are only partially understood. In the present study, we analyzed fertility and pregnancy-associated changes in homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp)), which lack all the peptides derived from proglucagon. Female Gcg(gfp/gfp) mice could deliver and raise Gcg(gfp/gfp) pups to weaning and Gcg(gfp/gfp) pups from Gcg(gfp/gfp) dams were viable and fertile. Pregnancy induced ß-cell proliferation in Gcg(gfp/gfp) mice as well as in control mice. However, serum insulin levels in pregnant Gcg(gfp/gfp) females were lower than those in control pregnant females under ad libitum feeding, and blood glucose levels in pregnant Gcg(gfp/gfp) females were higher after gestational day 12. Gcg(gfp/gfp) females showed a decreased pregnancy rate and smaller litter size. The rate of successful breeding was significantly lower in Gcg(gfp/gfp) females and was not improved by experience of breeding. Taken together, proglucagon-derived peptides are not required for pregnancy-associated ß-cell proliferation, however, are required for regulation of blood glucose levels and normal reproductive capacity. Gcg(gfp/gfp) mice may serve as a novel model to analyze the effect of mild hyperglycemia during late gestational periods.
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Sugiyama
authors.forename: Michiyo
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kotani
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D048429:Cell Size; D005260:Female; D005298:Fertility; D055879:Gene Knock-In Techniques; D005838:Genotype; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D011247:Pregnancy; D052336:Proglucagon / Q000737:chemistry* / Q000235:genetics; D012726:Sexual Behavior, Animal
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D052336:Proglucagon