Fertility and Pregnancy-Associated ß-Cell Proliferation in Mice Deficient in Proglucagon-Derived Peptides

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.