Differential expression of glucagon and glucagon-like peptide 1 receptors in mouse pancreatic alpha and beta cells in two models of alpha cell hyperplasia

Abstract

Glucose homeostasis is determined by a balance between insulin and glucagon, produced by beta and alpha cells of the pancreas respectively. The levels of circulating hormones is partly determined by the mass of these two endocrine cell types. However, in contrast to ß cells, the identity of the signals regulating alpha cell number is not known. Mice with a global deletion of the glucagon receptor (Gcgr−/−) and mice with ablation of prohormone convertase 2 (PC2), the enzyme involved in the conversion of proglucagon into mature glucagon, develop alpha cell hyperplasia. These observations and the fact that Gcgr−/− mice exhibit high levels of circulating glucagon-like peptide-1 (GLP-1) suggested that members of the glucagon family of peptides could be directly involved in the regulation of alpha cell number. In this study we sought to determine whether alpha cells express receptors for Gcgr and/or the glucagon-like peptide-1 (GLP1r). We examined the expression of these receptors in islets of Gcgr−/−, PC2−/− mice and control littermates, in an alpha (αTC1/9) and in a beta (βTC3) cell line. Gcgr was expressed exclusively by islet beta cells, but not by alpha cells, of the two lines of mice lacking glucagon signaling. Similarly, ßTC but not αTC cells, expressed Gcgr. The expression of GLP-1r by alpha cells was determined by the genotype and age of the mice. In embryos, GLU+ cells of Gcgr+/+ mice cells express GLP-1r during early development, but not in adults. In contrast, alpha cells of Gcgr−/− mice were GLP-1r+ throughout life, reflecting the immature state of GLU+ cells when Gcgr is deleted. Unlike alpha cells, beta cells of all mice lines examined initiate GLP-1r expression after birth. These results suggest that GLP-1 may affect the maturation of postnatal but not prenatal beta cells. In addition, they also suggest that the incretin could mediate alpha cell proliferation, inducing the development of alpha cell hyperplasia in Gcgr−/− mice.

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

“…GLP1R mRNA levels were similar in juvenile and adult human islets (Figure 2A), suggesting that human β cell GLP-1R expression is not age-dependent. Moreover, in FACSisolated islet cell subsets, GLP1R mRNA was principally expressed in β cells and was very low, or not detectable, in α cells (Supplemental Figure 2, A-C), consistent with prior findings (10,(31)(32)(33)(34)(35).…”

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

“…Thus, it is possible that the increased glucagon/GLP-1 signaling observed in our zebrafish β cell ablation model reflects a conserved function of GLP-1 signaling in mammalian β cell regeneration. GLP-1 receptor is abundantly expressed in pancreatic ducts, β cells and embryonic α cells (Kedees et al, 2009). Although it is unclear whether adult α cells express GLP-1 receptors, these receptors are expressed in insulin/glucagon dual hormone-positive cells in the rat pancreas (Tornehave et al, 2008;Kedees et al, 2009).…”

“…GLP-1 receptor is abundantly expressed in pancreatic ducts, β cells and embryonic α cells (Kedees et al, 2009). Although it is unclear whether adult α cells express GLP-1 receptors, these receptors are expressed in insulin/glucagon dual hormone-positive cells in the rat pancreas (Tornehave et al, 2008;Kedees et al, 2009). Thus, we anticipate that GLP-1 receptor expression increases in α cells during transdifferentiation; this will be an area of future study.…”

Mechanism of the beneficial and protective effects of exenatide in diabetic rats

“…Exenatide may inhibit glucagon expression and release from a-cells via GLP1r found on the plasma membrane of a-cells (Heller et al 1997). This may in turn result in increased GLP1 synthesis from the a-cells as observed in the mouse pancreas (Kedees et al 2009). The increased release of GLP1 can in turn stimulate insulin secretion from pancreatic b-cells (Nie et al 2000).…”