Ablation of the Glucagon Receptor Gene Increases Fetal Lethality and Produces Alterations in Islet Development and Maturation

Abstract

Although glucagon (GLU) plays a pivotal role in glucose homeostasis, its role in the regulation of fetal growth and maturation is poorly understood. These issues were examined in a line of mice with a global deletion of the GLU receptor (Gcgr-/-), which are characterized by lower blood glucose levels and by alpha- and delta-cell hyperplasia in adults. Ablation of Gcgr was deleterious to fetal survival; it delayed beta-cell differentiation and perturbed the proportion of beta- to alpha-cells in embryonic islets. In adults, the mutation inhibited the progression of alpha-cells to maturity, affected the expression of several beta-cell-specific genes, and resulted in an augmentation of the alpha-, beta-, and delta-cell mass. This increase was due to an augmentation in both islet number and in the rate of proliferation of cells expressing GLU or insulin. These findings suggest that GLU participates in a feedback loop that regulates the proportion of the different endocrine cell types in islets, the number of islets per pancreas, and development of the mature alpha-cell phenotype.

Nestin expression in pancreatic endocrine and exocrine cells of mice lacking glucagon signaling

“…The persistence of nestin expression in differentiated endocrine cells of PC2 Ϫ/Ϫ and Gcgr Ϫ/Ϫ embryos follows the pattern of other embryonal traits that have protracted expression in islet cells of these two mutant lines (Vincent et al, 2003;Vuguin et al, 2006). Thus, while the pancreatic specific transcription factor Pdx-1 is expressed by pancreatic cells of PC2 ϩ/ϩ…”

“…Similar to Gcgr ϩ/ϩ and PC2 ϩ/ϩ embryos, the pancreatic primordia of e-11 Gcgr Ϫ/Ϫ and PC2 Ϫ/Ϫ embryos contained nestin ϩ glucagon ϩ cells (results not shown). However, e-11 Gcgr Ϫ/Ϫ and PC2 Ϫ/Ϫ embryos lacked IN ϩ cells (Vincent et al, 2003;Vuguin et al, 2006). Lack of glucagon signaling also affected the time-table of expression of nestin in islet cells.…”

“…Since our previous results indicated that pancreas of adult PC2 Ϫ/Ϫ and Gcgr Ϫ/Ϫ contain subsets of islet cells expressing traits characteristic of endocrine cells of embryos (Vincent et al, 2003;Vuguin et al, 2006), we sought to determine whether these cells also expressed nestin. Large numbers of nestin cells were found in approximately 10% of the islets in both strains of mutant mice and some of these cells co-expressed insulin (Fig.…”

“…and Gcgr ϩ/ϩ embryos but only by beta cells of adults, non-beta cells of embryos and adult PC2 Ϫ/Ϫ and Gcgr Ϫ/Ϫ mice expressed Pdx-1 (Vincent et al, 2003;Vuguin et al, 2006). Similarly, the glucose transporter 2 (GLUT2), which is transiently expressed by glucagon cells in control mice during development, is expressed by alpha cells of adult Gcgr Ϫ/Ϫ mice (Vuguin et al, 2006).…”

“…In the present study, we sought to determine whether nestin is expressed in vivo by islet cells of two mutant mouse models characterized by protracted expression of several embryonal properties (Vincent et al, 2003;Vuguin et al, 2006), speculating that they may also retain expression of nestin after the initiation of hormone expression. One mutant line comprised mice with a deletion in the gene encoding for prohormone convertase-2 (PC2 Ϫ/Ϫ ), responsible for the conversion of proglucagon into the glucagon (Furuta et al, 1997;Steiner, 1998) while a second line consisted of mice with a global deletion of the glucagon receptor (Gcgr Ϫ/Ϫ ) (Gelling et al, 2003).…”