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Benjamin R. Fisher Professor of Pediatric Surgery and Surgeon-in-Chief, Chidren’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: George K. Gittes, M.D., Benjamin R. Fisher Professor of Pediatric Surgery and Surgeon-in-Chief, Children’s Hospital of Pittsburgh, University of Pittsburgh, 3705 5th Avenue, Pittsburgh, Pennsylvania 15213. E-mail: george.gittes{at}chp.edu.
Islet development and function have been extensively studied with regard to the role of transcription factors, extracellular matrix, and growth factors (1). Delineation of a transcription factor hierarchy regulating the development of islet cells, and ß-cells in particular, has greatly enhanced our understanding of the progressive lineage commitments that occur in these cells (2, 3). Similarly, the role of families of growth factors such as fibroblast growth factors, epidermal growth factors, TGF-ßs, activins, hedgehogs, and wnts have all been fairly well studied in pancreatic development (4). Interestingly, a role for the actual peptide hormones produced by the endocrine cells has not been well studied. Now, Vuguin et al. (5), in this issue of Endocrinology, present an important study of the effect of a glucagon receptor null mutation on islet cell development and maturation as well as on the overall growth and maturation of the fetus and postnatal pups.
In general, the study of glucagon signaling can present some difficulties, as there exists a whole family of glucagon-related peptides, including the pre-proglucagon gene products: glucagon, glucagon-like peptides 1 and 2, glicentin, etc. This glucagon family of proteins has significant promiscuity in binding to target receptors (6). Among these receptors, the glucagon-like peptide-1 and glucagon receptors can bind many of these glucagon family members. Thus, the approach used by Vuguin et al. (5) of targeting the glucagon receptor for a null mutation appears to be a good way to simplify the system.
The glucagon receptor is expressed in many cells throughout the body, but within the pancreas it is mainly expressed in the islets, especially in the ß-cells. Ontogenic studies of the glucagon receptor in the embryonic mouse pancreas revealed that it began to be expressed early in gestation, beginning by around d 11–12 of gestation. The current study by Vuguin et al. (5) represents a follow-up study on the initial description of the glucagon receptor null mutant mice by Gelling et al. (7). That study showed that the mice had disturbances in glucose metabolism, including a persistent hypoglycemia with normal insulin levels and elevated glucagon levels. The mice were also noted to have reduced adiposity and 
-cell hyperplasia.
In the current article by Vuguin et al. (5), the authors find first that there is a delayed onset of differentiation of insulin-positive cells in the early pancreas. Subsequently, they saw persistence of an immature version of insulin-positive cells that coexpressed insulin and glucagon. Later in gestation the glucagon receptor was interestingly found to play a novel and important role in maintaining an adequate intrauterine role as well as in maternal-fetal glucose transport. Lastly, the early postnatal adaptation of the pups, with the need for mobilization of hepatic glycogen stores, appeared to be strongly dependent on glucagon receptor signaling as well.
Historically, a potential role for glucagon in regulating the early differentiation of pancreatic endocrine progenitor cells was suggested as early as the 1970s by Rall et al. (8). They showed that glucagon was the first peptide hormone detectable in appreciable amounts in the developing embryonic pancreas. They speculated at that time that perhaps glucagon was necessary for the induction of differentiation of the other peptide hormone cell lineages during the so-called "protodifferentiated state." This state referred to an early phase of pancreatic differentiation wherein pancreas-committed cells expressed low levels of peptide hormones as evidence of their commitment to a specific lineage, but not with functional significance for the cells. Toward this end, several pieces of evidence have shown that glucagon signaling is indeed necessary for at least insulin-positive differentiation. St-Onge et al. (9) showed that pax6 null mutant mice, which lack glucagon-producing -cells, had a delay and a deficit in insulin-positive cell differentiation. Prasadan et al. (10) showed that pre-proglucagon inhibition with antisense treatment of the early embryonic pancreas in vitro led to absence of the early "first wave" of insulin-positive differentiation. This absence could be rescued in vitro with the application of exogenous glucagon, suggesting that, of the pre-proglucagon products, glucagon may be the key molecule. Vincent et al. (11) showed that deletion of the prohormone convertase 2 enzyme, which is necessary for the production of mature glucagon, also resulted in the absence of early insulin-positive cells. Most recently, in this issue of Endocrinology, Vuguin et al. (5) offer convincing evidence of the specific need for glucagon receptor signaling in this early insulin-positive differentiation. They saw no detectable insulin staining in the embryonic pancreas until embryonic d 13.5, much later than the typical onset at d 10.5 of gestation.
Beyond this delay in the "first wave" of insulin differentiation in the early embryonic pancreas, glucagon receptor signaling also appears to be important in multiple additional steps of differentiation of endocrine cells. Vincent et al. (11) showed that there was persistence of insulin/glucagon double-positive cells in the prohormone convertase 2 null mutant mice. Such cells, if present at all, would represent an immature cell that should be present only transiently. Similar to those findings by Vincent et al., now Vuguin et al. show that glucagon-positive cells were found to have persistent expression of pdx-1 and glut2. Coexpression of these markers in glucagon-positive cells is normally short-lived and occurs during the earliest stages of pancreatic endocrine differentiation.
Thus, glucagon receptor signaling in the early pancreas appears to perform a paracrine role in the induction of other pancreatic endocrine progenitor cells to both initiate a differentiation program toward ß-cells and to further mature out of the "protodifferentiated state." Interestingly, glucagon also appears to have an autocrine function in that, when there is absence of glucagon signaling to the glucagon receptor in glucagon-positive cells, those cells appear to be frozen in an immature state.
In addition to the important findings regarding the role of glucagon in early pancreatic endocrine development, Vuguin et al. (5) also found that signaling through the glucagon receptor appears to play an important role in creating the proper intrauterine milieu. Heterozygous mutants for the glucagon receptor were normal in every respect. Interestingly, for homozygous mutant fetuses late in gestation, viability was greatly affected by whether the mother was a heterozygous or a homozygous mutant. Homozygous mutant mothers were hypoglycemic, and their homozygous mutant fetuses were specifically severely hypoglycemic in utero but still had normal insulin levels. These results imply that not only does the absence of glucagon signaling likely create a poor uterine milieu for fetal growth, but also that glucagon signaling is important for the transfer of glucose from mother to fetus. Such a role has been suggested previously for glucagon signaling (12).
Postnatally these homozygous mutant pups of homozygous mutant mothers faired poorly, dying soon after birth with severe hypoglycemia. Here, it appears that the necessary transition to liver-derived glucose induced by glucagon soon after birth is blunted or absent, leading to neonatal demise (13). Apparently, the difference for these homozygous mutant pups of having a heterozygous mutant mother was enough to carry them through the perinatal period and maintain euglycemia, finally becoming hypoglycemic after the first week, in line with the baseline phenotype of the homozygous mutant animals.
Thus, this new work by Vuguin et al. (5) supports several key roles for glucagon receptor signaling and suggests some new and unexpected roles as well. Because of the complexity of the glucagon family of signaling, both at the ligand and receptor level, these new roles will require more careful analysis to better understand the exact nature of the mechanisms in place.
Received May 1, 2006.
Accepted for publication May 10, 2006.
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-cells in mouse pancreas. Nature 387:406–409[CrossRef][Medline]-cell proliferation, and islet neogenesis. 144:4061–4069
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