Fertility and pregnancy-associated ß-cell proliferation in mice deficient in proglucagon-derived peptides

• Published in: PloS one Vol. 7; no. 8; p. e43745
• Main Authors: Sugiyama, Chisato, Yamamoto, Michiyo, Kotani, Tomomi, Kikkawa, Fumitaka, Murata, Yoshiharu, Hayashi, Yoshitaka
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.08.2012; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Apoptosis; Biology; Blood; Blood glucose; Blood Glucose - metabolism; Breeding; Cell growth; Cell Proliferation; Cell Size; Complications and side effects; Diabetes; Dosage and administration; Environmental health; Fasting; Female; Females; Fertility; Fluorescence; Gene Knock-In Techniques; Genotype; Glucagon; Glucagon-like peptide 1; Gluconeogenesis; Glucose; Green fluorescent protein; Gynecology; Health aspects; Hormones; Hyperglycemia; Hypoglycemia; Insulin; Insulin - blood; Insulin secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Islets of Langerhans; Medicine; Mice; Newborn babies; Obstetrics; Peptide Fragments - metabolism; Peptide hormones; Peptides; Physiology; Pregnancy; Pregnant women; Proglucagon - chemistry; Proglucagon - genetics; Rodents; Secretion; Serotonin; Sexual Behavior, Animal; Type 2 diabetes; University graduates; Weaning; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043745

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.