II- Regulation of glucagon expression
1. Structure of the glucagon gene
The glucagon gene (Gcg) is expressed in the α-cells of the endocrine pancreas but also in the L-cells of the intestine and in specific areas of the brain.12 Signal peptide is cleaved from preproglucagon encoded by Gcg mRNA to produce proglucagon, which serves as a precursor for multiple peptides (Figure 4).13 Glucagon is produced in islet α-cells through cleavage by prohormone convertase 2 (Pcsk2), whereas glucagonlike peptides (GLP-1 and GLP-2) are produced simultaneously in intestinal L-cells and some neurons of the central nervous system14 through cleavage by prohormone convertase 1 (Pcsk1). Thus, pancreatic proglucagon is mostly processed to glucagon. However, GLP-1 can also be found in islets co-localized with glucagon under certain conditions such as β-cell damage. Several other peptides produced by alternative or incomplete cleavage of proglucagon, ie, glicentin and oxyntomodulin, have been described but their physiological role is not well characterized (Hayashi, Lecture;Hayashi, unpublished; Irwin, Lecture; Irwin and Prentice, unpublished).
Figure 4. Structure of preproglucagon and derived peptides (from Hayashi et al, unpublished). Multiple peptides including glucagon, glucagonlike peptide (GLP)-1 and GLP-2 are produced from proglucagon. The sites of cleavage by prohormone convertases, Pcsk 1 and Pcsk 2, are also shown. The receptors for preproglucagon-derived peptides are also depicted.
2. Transcription factors involved inglucagon gene transcription
a. The other main transcription factors
Foxa1 and Foxa2 are present in the α-cells both during development and in adulthood. Data from mutant mice suggest that Foxa1 is involved in glucagon gene transcription while Foxa2 directs α-cell differentiation more globally. Maf B is expressed specifically in adult α-cells, although it is present in both developing α- and β-cells. Experimentson mice deficient for Maf B showed that this factor regulates important steps in the differentiation of both insulin- and glucagon-producing cells.
b. Hypothesis on the regulation of glucagon gene expression
Philippe and colleagues proposed that glucagon gene expression results from a default pathway: the absence of β-cell−specific factors such as Pdx1, Pax4, and Nkx6.1 would allow for the glucagon gene to be expressed and for the differentiation of the α-cell in the presence of other islet-specific factors. However, since mutant mice lacking Pax6, Foxa2, or Arx have no or few α-cells, this suggests that these factors are the most critical for α-cell differentiation (but not for cell proliferation, as the total number of endocrine cells is not affected by their absence) (Philippe, Lecture; Gosmain et al, unpublished).
Numerous transcription factors are involved in the transcription of the glucagon gene (Figure 2). Pax-6 is expressed in all pancreatic endocrine cells, in the nose, eyes, and central nervous system, and is required for maintaining expression of genes essential for the function of the α-, β-, and δ-cells (Philippe et al, unpublished data). Pax-6 binding is critical to the basal expression of the glucagon gene and to the regulation of proglucagon processing to glucagon in α-cells since inhibition of Pax-6 expression or Pax-6 deletion in mice resulted in a strong decrease in glucagon mRNA levels.15-16 Note that Pax-6 is also critical for L-cell differentiation and Gcg gene expression in these cells, suggesting that GLP-1 production could also depend on Pax-6 (Philippe,Lecture; Gosmain et al, unpublished).
“Pancreatic α-cells and glucagon—neglected metabolic actors”
I- Birth and death of the α-cell
II- Regulation of glucagon expression
III- Regulation of glucagon secretion
IV- Role of glucagon in metabolism
V- Therapeutic perspectives
Lectures during IGIS meeting and unpublished reviews